Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
QVA149, Health related quality of life, Formoterol, Tiotropium, COPD
Brief summary
This study will assess the efficacy and safety of QVA149 compared to tiotropium plus formoterol in patients with moderate to severe COPD.
Interventions
DRUGQVA149
QVA149 110/50µg, once daily (q.d.) is administered via a single-dose dry powder inhaler
Placebo to tiotropium capsules daily (q.d.) for inhalation, delivered via proprietary inhaler (Handihaler®). Placebo tiotropium inhalation capsules were matched in size and color to tiotropium 18 μg q.d. inhalation capsules
Placebo to formoterol capsules twice daily (b.i.d) delivered via Aerolizer® device. Placebo formoterol inhalation capsules were equally matched in size, shape and color to formoterol 12 μg b.i.d. inhalation capsules.
DRUGTiotropium
Tiotropium 18µg, once daily is administered via the manufacturer's proprietary inhalation device.
DRUGFormoterol
Formoterol 12µg, twice daily is administered via the manufacturer's proprietary inhalation device.
Placebo to QVA149 is administered via a single-dose dry powder inhaler. Placebo QVA149 inhalation capsules were equally matched in size, shape and color to QVA149 110/50 μg q.d. inhalation capsules
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female adults aged ≥ 40 yrs * Patients with moderate to severe chronic obstructive pulmonary disease (GOLD 2010 guidelines) * Smoking history of at least 10 pack years * Post-bronchodilator FEV1 \< 80% and ≥30% of the predicted normal value and post-bronchodilator FEV1/FVC (forced vital capacity) \<70%
Exclusion criteria
* Pregnant women or nursing mothers or women of child-bearing potential not using adequate contraception * 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 |
|---|---|---|
| St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis). | Baseline, week 26 | SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis). | Baseline, week 26 | SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative. Superiority of QVA 110/50 μg to tiotropium 18 μg q.d. plus formoterol 12 μg b.i.d. in terms of health related quality of life as assessed by St George's Respiratory Questionnaire (SGRQ-C) after 26 weeks of treatment |
| Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment. | Week 26 | Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. missing values were replaced by the latest observed value (LOCF) |
| Percent of Participants With at Least One Exacerbation Requiring Systemic Corticosteroids and/or Antibiotics Over 26 Weeks | Week 26 | The percent of participants with at least one moderate exacerbation within the 26 weeks that required systemic corticosteroids and/or antibiotics during the treatment |
| Percent of Participants With at Least One Exacerbation Requiring Hospitalization | Week 26 | The percent of patients with at least one severe exacerbation within the 26 weeks that required hospitalization. COPD exacerbations were considered to be severe if hospitalization were required. |
| Time- Event Analysis, Number of Participants With at Least One COPD Exacerbation (Moderate or Severe) During the Treatment Period | Week 26 | The number of participants with at least one moderate or severe COPD exacerbation. COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if hospitalizations were required. |
| Trough FEV1 at Baseline and Week 26 | Baseline, Week 26 | Trough FEV1 is the mean value of FEV1 (forced expiratory volume in one second) measured at 23:15h and 23:45h after the morning doses. The baseline value was measured at day 1 prior to the first dose. |
| FEV1 30 Min After the Morning Dose at Baseline and Week 26 | Baseline, Week 26 | FEV1 30min is the forced expiratory volume in one second measured 30 min after the morning dose. |
| Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C | Baseline, Week 26 | Part I of the SGRQ-C covers symptoms and is concerned with respiratory symptoms, their frequency and severity. Each questionnaire response has a unique empirically derived weight. A score was calculated from these weights. The lowest possible value is zero and the highest 100. A higher value corresponds to greater impairment of health status. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol QVA149 110/50µg, once daily for inhalation use plus placebo to tiotropium, once daily for inhalation use and placebo to formoterol, twice daily for inhalation use. | 476 |
| Tiotropium Plus Formoterol and Placebo to QVA149 Tiotropium 18µg, once daily for inhalation use plus Formoterol 12µg, twice daily for inhalation use and placebo to QVA149, once daily for inhalation use. | 458 |
| Total | 934 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 0 |
| Overall Study | Abnormal test procedure result(s) | 1 | 1 |
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Adverse Event | 36 | 27 |
| Overall Study | Death | 3 | 3 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Patient's inability to use the device | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 5 |
| Overall Study | Unsatisfactory therapeutic effect | 6 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 10 |
Baseline characteristics
| Characteristic | QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Tiotropium Plus Formoterol and Placebo to QVA149 | Total |
|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 8.43 | 63.1 Years STANDARD_DEVIATION 8.15 | 62.9 Years STANDARD_DEVIATION 8.29 |
| Sex: Female, Male Female | 159 Participants | 160 Participants | 319 Participants |
| Sex: Female, Male Male | 317 Participants | 298 Participants | 615 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 72 / 476 | 79 / 458 |
| serious Total, serious adverse events | 30 / 476 | 24 / 458 |
Outcome results
Primary
St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis).
SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative.
Time frame: Baseline, week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis). | Baseline (n=452,441) | 44.70 Score on a scale | Standard Deviation 17.718 |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis). | Week 26 (n=475,456) | 41.30 Score on a scale | Standard Deviation 19.923 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis). | Baseline (n=452,441) | 45.68 Score on a scale | Standard Deviation 17.72 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Non-inferiority Analysis). | Week 26 (n=475,456) | 43.19 Score on a scale | Standard Deviation 19.284 |
Secondary
FEV1 30 Min After the Morning Dose at Baseline and Week 26
FEV1 30min is the forced expiratory volume in one second measured 30 min after the morning dose.
Time frame: Baseline, Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | FEV1 30 Min After the Morning Dose at Baseline and Week 26 | Baseline (n=475,458) | 1.517 Liters | Standard Deviation 0.5025 |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | FEV1 30 Min After the Morning Dose at Baseline and Week 26 | Week 26 (n=476,458) | 1.605 Liters | Standard Deviation 0.5356 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | FEV1 30 Min After the Morning Dose at Baseline and Week 26 | Baseline (n=475,458) | 1.495 Liters | Standard Deviation 0.486 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | FEV1 30 Min After the Morning Dose at Baseline and Week 26 | Week 26 (n=476,458) | 1.565 Liters | Standard Deviation 0.5124 |
Secondary
Percent of Participants With at Least One Exacerbation Requiring Hospitalization
The percent of patients with at least one severe exacerbation within the 26 weeks that required hospitalization. COPD exacerbations were considered to be severe if hospitalization were required.
Time frame: Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Percent of Participants With at Least One Exacerbation Requiring Hospitalization | 2.1 Percent of participants |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Percent of Participants With at Least One Exacerbation Requiring Hospitalization | 2.4 Percent of participants |
Secondary
Percent of Participants With at Least One Exacerbation Requiring Systemic Corticosteroids and/or Antibiotics Over 26 Weeks
The percent of participants with at least one moderate exacerbation within the 26 weeks that required systemic corticosteroids and/or antibiotics during the treatment
Time frame: Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Percent of Participants With at Least One Exacerbation Requiring Systemic Corticosteroids and/or Antibiotics Over 26 Weeks | 10.9 Percent of participants |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Percent of Participants With at Least One Exacerbation Requiring Systemic Corticosteroids and/or Antibiotics Over 26 Weeks | 13.3 Percent of participants |
Secondary
St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis).
SGRQ is a health related quality of life questionnaire consisting of 40 items in three areas: symptoms (respiratory symptoms and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). The total score is 0 to 100 with a higher score indicating poorer health status. For patients who completed the study but with missing SGRQ-C during treatment, the missing SGRQ-C were replaced by the last observation carried forward (LOCF). Symptom scores were expected to improve over treatment, therefore the replacement of missing values with earlier measurements did not result in overoptimistic imputation and this procedure could be regarded as conservative. Superiority of QVA 110/50 μg to tiotropium 18 μg q.d. plus formoterol 12 μg b.i.d. in terms of health related quality of life as assessed by St George's Respiratory Questionnaire (SGRQ-C) after 26 weeks of treatment
Time frame: Baseline, week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis). | Baseline (n=452,441) | 44.70 Score on a scale | Standard Deviation 17.718 |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis). | Week 26 (n=475,456) | 41.30 Score on a scale | Standard Deviation 19.923 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis). | Baseline (n=452,441) | 45.68 Score on a scale | Standard Deviation 17.72 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | St. George's Respiratory Questionnaire (SGRQ-C) Total Score After 26 Weeks of Treatment (Superiority Analysis). | Week 26 (n=475,456) | 43.19 Score on a scale | Standard Deviation 19.284 |
Secondary
Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C
Part I of the SGRQ-C covers symptoms and is concerned with respiratory symptoms, their frequency and severity. Each questionnaire response has a unique empirically derived weight. A score was calculated from these weights. The lowest possible value is zero and the highest 100. A higher value corresponds to greater impairment of health status.
Time frame: Baseline, Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C | Baseline (n=473,457) | 64.10 Score on a scale | Standard Deviation 19.884 |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C | Week 26 (n=476,458) | 58.31 Score on a scale | Standard Deviation 21.764 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C | Baseline (n=473,457) | 64.29 Score on a scale | Standard Deviation 19.768 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Symptoms Score Reported by the Patients Using Part I Symptoms of SGRO-C | Week 26 (n=476,458) | 60.16 Score on a scale | Standard Deviation 20.678 |
Secondary
Time- Event Analysis, Number of Participants With at Least One COPD Exacerbation (Moderate or Severe) During the Treatment Period
The number of participants with at least one moderate or severe COPD exacerbation. COPD exacerbations are considered to be moderate if treatment with systemic corticosteroids and/or antibiotics was required. COPD exacerbations are considered to be severe if hospitalizations were required.
Time frame: Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Time- Event Analysis, Number of Participants With at Least One COPD Exacerbation (Moderate or Severe) During the Treatment Period | 62 Participants |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Time- Event Analysis, Number of Participants With at Least One COPD Exacerbation (Moderate or Severe) During the Treatment Period | 70 Participants |
Secondary
Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment.
Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. missing values were replaced by the latest observed value (LOCF)
Time frame: Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment. | 1.34 Units on a scale | Standard Deviation 3.44 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Transition Dyspnea Index (TDI) Focal Score After 26 Weeks of Treatment. | 0.87 Units on a scale | Standard Deviation 3.439 |
Secondary
Trough FEV1 at Baseline and Week 26
Trough FEV1 is the mean value of FEV1 (forced expiratory volume in one second) measured at 23:15h and 23:45h after the morning doses. The baseline value was measured at day 1 prior to the first dose.
Time frame: Baseline, Week 26
Population: Full analysis set (FAS): all randomized patients who received at least one dose of randomized study drug. Following the ITT principle, patients were analyzed according to the treatment they were assigned to. The FAS was used for all efficacy variables unless otherwise stated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Trough FEV1 at Baseline and Week 26 | Baseline | 1.329 Liters | Standard Deviation 0.4806 |
| QVA149 Plus Placebo to Tiotropium and Placebo to Formoterol | Trough FEV1 at Baseline and Week 26 | Week 26 | 1.495 Liters | Standard Deviation 0.506 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Trough FEV1 at Baseline and Week 26 | Baseline | 1.313 Liters | Standard Deviation 0.4525 |
| Tiotropium Plus Formoterol and Placebo to QVA149 | Trough FEV1 at Baseline and Week 26 | Week 26 | 1.409 Liters | Standard Deviation 0.4878 |