A Phase 3 interventional study of indacaterol and glycopyrronium (QVA149) and glycopyrronium (NVA237) in Chronic Obstructive Pulmonary Disease (COPD), sponsored by Novartis Pharmaceuticals. Completed at 166 sites in 19 countries. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2013-09-09.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
The purpose of this study is to provide pivotal efficacy and safety data for QVA149 in patients with moderate to severe COPD.
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Exclusion Criteria:
QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDPPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Drug: indacaterol and glycopyrronium (QVA149)
NVA237 50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Drug: glycopyrronium (NVA237)
QAB149 150 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Drug: indacaterol (QAB149)
Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Drug: tiotropium
Matching placebo capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDDPI) for 26 weeks. Participants remained on a stable dose of inhaled corticosteroid (ICS) and salbutamol/albuterol was available for use as rescue medication throughout the study.
Drug: placebo
Capsules for inhalation delivered via SDDPI.
Capsules for inhalation delivered via SDDPI.
Capsules for inhalation delivered via SDDPI.
Capsules for inhalation delivered via HandiHaler® device.
Placebo to match capsules for inhalation delivered via SDDPI.
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
Transitional Dyspnea Index (TDI) Focal Score at Week 26
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. 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. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: Week 26
St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 26
SGRQ is a health related quality of life questionnaire consisting of 51 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. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 26 weeks
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Over 26 Weeks
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: Baseline, Week 26
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149, QAB149 and NVA237 Compared to Placebo
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149 Compared to Tiotropium
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 23 hours 15 minutes and 23 hour 45 minute post-dose Week 26
Baseline Transitional Dyspnea Index (BDI/TDI) Focal Score at Week 12 and Week 26
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). BDI/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. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators as covariates and included baseline smoking status, baseline inhaled corticosteroids and region as fixed effects with center nested within region as a random effect.
Time frame: Baseline, Week 12, Week 26
Percentage of Patients With a Clinically Important Improvement of at Least 1 Point in TDI Focal Score After 26 Weeks of Treatment
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing) at Week 12 and Week 26. TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI (baseline) was measured at Day 1. The 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.
Time frame: Baseline, Week 26
St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 and 26 Weeks of Treatment
SGRQ is a health related quality of life questionnaire consisting of 51 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. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: Week 12, Week 26
Percentage of Patients With a Clinically Important Improvement From Baseline of at Least 4 Units in the SGRQ Total Score After 26 Weeks of Treatment
SGRQ is a health related quality of life questionnaire consisting of 51 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.
Time frame: Baseline, Week 26
Percentage of Nights With "No Night Time Awakenings" Over 26 Weeks
A day with no night time awakenings is defined from the diary data as any day where the patient did not wake up due to COPD symptoms. The percentage of nights is calculated by the number of days with no nighttime awakenings/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 26 Weeks
Percentage of Days With "No Daytime Symptoms" Over 26 Weeks
A day with no day time symptoms is defined from the diary data as any day where the patient recorded no coughing, no wheezing, no sputum production and no breathlessness during the previous 12 hours (approximately 8AM to 8PM). The percentage of days is calculated by the number of days with no daytime symptoms/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 26 Weeks
Percentage of "Days Able to Perform Usual Daily Activities" Over 26 Weeks
Patients answered the question "Did your respiratory symptoms stop you performing your usual activities today?-Not at all in their daily diary. The percentage of days is calculated by the number of days patient is able to perform daily activities/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of Days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 26 Weeks
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication at Week 12 and Week 26
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: Baseline, Week 12, Week 26
Change From Baseline (BL) in the Daytime and Night Time Rescue Medication Use (Number of Puffs) Over 26 Weeks
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs in the morning and evening were calculated and divided by the number of days with data to determine the mean daily number of daytime and nighttime puffs. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline (BL) ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: Baseline, Week 26
Percentage of "Days With no Rescue Medication Use" Over 26 Weeks
A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: 26 Weeks
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours at Day 1 and Week 26
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: From 5 minutes to 4 hours post-dose Day 1 and Week 26
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 12 Hours at Day 1 and Week 26
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: From 5 minutes to 12 hours post-dose Day 1 and Week 26
Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 23 Hours 45 Minutes at Week 26
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
Time frame: From 5 minutes to 23 hours 45 minutes post-dose Week 26
24 Hour Holter Monitoring in a Subset of Patients
24-hourly mean heart rate was performed using a Holter Monitor at Weeks 12 and 26 in a subgroup of patients. Mixed model: heart rate = treatment + baseline heart rate + baseline smoking status + baseline ICS use + region + center (region) + error. Center was included as a random effect nested within region. The 24-hourly mean heart rate is the mean heart rate over the 24 hour period, derived using hourly mean heart rate beats per minute.
Time frame: Week 12, Week 26
Rate of Moderate or Severe COPD Exacerbation
Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 26 Weeks
Percentage of Patients With at Least One Moderate or Severe COPD Exacerbation Over the 26 Week Treatment Period
Time frame: 26 Weeks
Percentage of Participants With COPD Exacerbations Requiring Hospitalization or Treatment With Systemic Corticosteroids and/or Antibiotics But no Hospitalization
Time frame: 26 Weeks
| Milestone | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Started | 475 | 477 | 475 | 483 | 234 |
| Safety set; received study drug | 474 | 476 | 473 | 480 | 232 |
| Completed | 437 | 421 | 422 | 441 | 189 |
| Not completed | 38 | 56 | 53 | 42 | 45 |
| Withdrew: Protocol deviation | 14 | 8 | 12 | 10 | 11 |
| Withdrew: Subject withdrew consent | 12 | 13 | 22 | 11 | 13 |
| Withdrew: Adverse event | 5 | 23 | 13 | 10 | 10 |
| Withdrew: Administrative problems | 3 | 2 | 1 | 1 | 2 |
| Withdrew: Unsatisfactory therapeutic effect | 2 | 8 | 2 | 5 | 8 |
| Withdrew: Lost to follow-up | 1 | 1 | 0 | 4 | 1 |
| Withdrew: Death | 1 | 1 | 1 | 1 | 0 |
| Withdrew: Abnormal test procedure result (s) | 0 | 0 | 2 | 0 | 0 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) |
|---|---|---|---|
| Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment | 1.45 ± 0.010 | 1.38 ± 0.010 | 1.36 ± 0.010 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. 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. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Score on a scale | Indacaterol and Glycopyrronium (QVA149) | Placebo |
|---|---|---|
| Transitional Dyspnea Index (TDI) Focal Score at Week 26 | 2.72 ± 0.170 | 1.63 ± 0.230 |
SGRQ is a health related quality of life questionnaire consisting of 51 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. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Score on a scale | Indacaterol and Glycopyrronium (QVA149) | Placebo |
|---|---|---|
| St. George's Respiratory Questionnaire (SGRQ) Total Score at Week 26 | 37.01 ± 0.679 | 40.02 ± 0.941 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Puffs per day | Indacaterol and Glycopyrronium (QVA149) | Placebo |
|---|---|---|
| Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication Over 26 Weeks | -1.88 ± 0.105 | -0.92 ± 0.147 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Placebo |
|---|---|---|---|---|
| Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149, QAB149 and NVA237 Compared to Placebo | 1.45 ± 0.010 | 1.38 ± 0.010 | 1.36 ± 0.010 | 1.25 ± 0.015 |
Spirometry was performed according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hour 15 minute and 23 hour 45 minute post-dose values. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Tiotropium |
|---|---|---|
| Trough Forced Expiratory Volume In One Second (FEV1) After 26 Weeks of Treatment With QVA149 Compared to Tiotropium | 1.46 ± 0.011 | 1.39 ± 0.011 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing). BDI/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. A mixed model was used with treatment as a fixed effect with Baseline Dyspnea Index Score and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators as covariates and included baseline smoking status, baseline inhaled corticosteroids and region as fixed effects with center nested within region as a random effect.
| Score on a scale | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| BDI_ baseline for Week 12 | 6.45 ± 0.100 | 6.28 ± 0.096 | 6.21 ± 0.097 | 6.43 ± 0.094 | 6.53 ± 0.154 |
| TDI Week 12 | 2.44 ± 0.158 | 2.18 ± 0.157 | 2.04 ± 0.158 | 1.81 ± 0.158 | 1.22 ± 0.215 |
| BDI_baseline for Week 26 (n=439,440,424,441,193) | 6.45 ± 0.101 | 6.28 ± 0.097 | 6.22 ± 0.097 | 6.46 ± 0.095 | 6.56 ± 0.157 |
| TDI Week 26 (n=439,440,424,441,193) | 2.72 ± 0.170 | 2.47 ± 0.171 | 2.52 ± 0.172 | 2.21 ± 0.171 | 1.63 ± 0.230 |
A trained assessor interviewed the patient and graded the degree of impairment due to dyspnea (difficulty breathing) at Week 12 and Week 26. TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. The BDI (baseline) was measured at Day 1. The 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.
| Percentage of participants | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of Patients With a Clinically Important Improvement of at Least 1 Point in TDI Focal Score After 26 Weeks of Treatment | 68.1 | 64.6 | 63.7 | 59.2 | 57.5 |
SGRQ is a health related quality of life questionnaire consisting of 51 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. A mixed model was used with treatment as a fixed effect with Baseline SGRQ and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Score on a scale | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| 12 Weeks | 37.56 ± 0.659 | 38.55 ± 0.662 | 39.40 ± 0.663 | 39.94 ± 0.658 | 41.55 ± 0.900 |
| 26 Weeks (n=441,443,430,450,196) | 37.01 ± 0.679 | 38.10 ± 0.680 | 38.19 ± 0.686 | 39.14 ± 0.677 | 40.02 ± 0.941 |
SGRQ is a health related quality of life questionnaire consisting of 51 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.
| Percentage of participants | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of Patients With a Clinically Important Improvement From Baseline of at Least 4 Units in the SGRQ Total Score After 26 Weeks of Treatment | 63.7 | 63.0 | 60.5 | 56.4 | 56.6 |
A day with no night time awakenings is defined from the diary data as any day where the patient did not wake up due to COPD symptoms. The percentage of nights is calculated by the number of days with no nighttime awakenings/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Percentage of nights | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of Nights With "No Night Time Awakenings" Over 26 Weeks | 63.68 ± 1.473 | 62.48 ± 1.479 | 58.64 ± 1.500 | 60.00 ± 1.469 | 53.67 ± 2.047 |
A day with no day time symptoms is defined from the diary data as any day where the patient recorded no coughing, no wheezing, no sputum production and no breathlessness during the previous 12 hours (approximately 8AM to 8PM). The percentage of days is calculated by the number of days with no daytime symptoms/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Percentage of days | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of Days With "No Daytime Symptoms" Over 26 Weeks | 7.49 ± 0.931 | 9.17 ± 0.933 | 6.40 ± 0.948 | 5.54 ± 0.928 | 4.44 ± 1.294 |
Patients answered the question "Did your respiratory symptoms stop you performing your usual activities today?-Not at all in their daily diary. The percentage of days is calculated by the number of days patient is able to perform daily activities/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline Percent of Days and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Percentage of days | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of "Days Able to Perform Usual Daily Activities" Over 26 Weeks | 45.97 ± 1.578 | 40.94 ± 1.582 | 40.10 ± 1.607 | 37.52 ± 1.572 | 34.49 ± 2.197 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs per day was calculated and divided by the number of days with data to determine the mean daily number of puffs of rescue medication for each patient. Rescue medication data recorded during the 14 day run-in was used to calculate the baseline. A negative change from baseline indicates improvement. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Puffs per day | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Change from Baseline (BL) at Week 12 | -1.82 ± 0.102 | -1.46 ± 0.102 | -1.22 ± 0.103 | -1.28 ± 0.102 | -0.83 ± 0.141 |
| Change from BL at Week 26 (n=419,416,403,424,199) | -1.88 ± 0.105 | -1.57 ± 0.106 | -1.22 ± 0.107 | -1.34 ± 0.105 | -0.92 ± 0.147 |
The number of puffs of rescue medication taken in the previous 12 hours was record in patient diary in the morning and in the evening for 26 weeks. The total number of puffs in the morning and evening were calculated and divided by the number of days with data to determine the mean daily number of daytime and nighttime puffs. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline (BL) ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Puffs | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Daytime Change from BL (n=415,410,395,418,195) | -1.11 ± 0.061 | -0.96 ± 0.062 | -0.75 ± 0.063 | -0.83 ± 0.061 | -0.58 ± 0.086 |
| Nighttime Change from BL (n=418,413,399,422,198) | -0.78 ± 0.049 | -0.63 ± 0.049 | -0.48 ± 0.050 | -0.52 ± 0.049 | -0.34 ± 0.069 |
A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. The percentage of days is calculated by the number of days with no rescue medicine use/total number of days with evaluable data X 100. A mixed model was used with treatment as a fixed effect with baseline number of puffs and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Percentage of days | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of "Days With no Rescue Medication Use" Over 26 Weeks | 47.09 ± 1.752 | 44.81 ± 1.764 | 37.74 ± 1.790 | 36.51 ± 1.752 | 34.76 ± 2.437 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Day 1 | 1.52 ± 0.006 | 1.46 ± 0.006 | 1.49 ± 0.006 | 1.44 ± 0.006 | 1.30 ± 0.008 |
| Week 26 (n=433,418,412,435,186) | 1.57 ± 0.010 | 1.46 ± 0.010 | 1.43 ± 0.010 | 1.44 ± 0.010 | 1.23 ± 0.015 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Day1 | 1.50 ± 0.017 | 1.40 ± 0.017 | 1.42 ± 0.018 | 1.38 ± 0.017 | 1.24 ± 0.023 |
| Week 26 (n=60,55,58,67,27) | 1.52 ± 0.027 | 1.39 ± 0.027 | 1.39 ± 0.028 | 1.39 ± 0.027 | 1.18 ± 0.036 |
FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5, 15, and 30 minutes; and 1, 2, 4, 8, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. A mixed model was used with treatment as a fixed effect with baseline FEV1 and FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at Day -14) as covariates. The model also included baseline smoking status (current/ex-smoker), baseline ICS use (Yes/No) and region as fixed effects with center nested within region as a random effect.
| Liters | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Standardized FEV1 (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 23 Hours 45 Minutes at Week 26 | 1.46 ± 0.026 | 1.35 ± 0.027 | 1.35 ± 0.027 | 1.36 ± 0.026 | 1.15 ± 0.036 |
24-hourly mean heart rate was performed using a Holter Monitor at Weeks 12 and 26 in a subgroup of patients. Mixed model: heart rate = treatment + baseline heart rate + baseline smoking status + baseline ICS use + region + center (region) + error. Center was included as a random effect nested within region. The 24-hourly mean heart rate is the mean heart rate over the 24 hour period, derived using hourly mean heart rate beats per minute.
| beats per minute | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Placebo |
|---|---|---|---|---|
| Week 12 (n=35,38,27,15) | 80.8 ± 1.5 | 79.9 ± 1.35 | 79.4 ± 1.57 | 78.9 ± 1.95 |
| Week 26 (n=36,36,26,16) | 79.8 ± 1.68 | 78.6 ± 1.57 | 80.5 ± 1.75 | 77.0 ± 2.09 |
Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
| Exacerbations per year | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Rate of Moderate or Severe COPD Exacerbation | 0.46 | 0.59 | 0.52 | 0.45 | 0.75 |
| Percentage of participants | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Percentage of Patients With at Least One Moderate or Severe COPD Exacerbation Over the 26 Week Treatment Period | 17.9 | 21.6 | 18.8 | 17.7 | 25.8 |
| Percentage of participants | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Requiring hospitalization | 2.1 | 2.5 | 1.9 | 1.0 | 3.0 |
| Corticosteroids_Antibiotics-No hospitalization | 16.7 | 19.7 | 17.8 | 16.9 | 23.3 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Indacaterol and Glycopyrronium (QVA149) | — | 22/474 (4.6%) | 166/474 (35%) |
| Indacaterol (QAB149) | — | 26/476 (5.5%) | 189/476 (39.7%) |
| Glycopyrronium (NVA237) | — | 29/473 (6.1%) | 185/473 (39.1%) |
| Tiotropium | — | 19/480 (4%) | 172/480 (35.8%) |
| Placebo | — | 13/232 (5.6%) | 102/232 (44%) |
| Event | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 10/474 | 15/476 | 9/473 | 7/480 | 7/232 |
| PneumoniaInfections and infestations | 2/474 | 2/476 | 3/473 | 3/480 | 3/232 |
| BronchitisInfections and infestations | 1/474 | 2/476 | 3/473 | 1/480 | 0/232 |
| Cardiac failureCardiac disorders | 0/474 | 3/476 | 0/473 | 0/480 | 0/232 |
| Angina unstableCardiac disorders | 0/474 | 0/476 | 0/473 | 0/480 | 1/232 |
| Left ventricular dysfunctionCardiac disorders | 0/474 | 1/476 | 0/473 | 0/480 | 1/232 |
| Temperature intoleranceGeneral disorders | 0/474 | 0/476 | 0/473 | 0/480 | 1/232 |
| Injection site abscessInfections and infestations | 0/474 | 0/476 | 0/473 | 0/480 | 1/232 |
| Lower respiratory tract infectionInfections and infestations | 0/474 | 1/476 | 0/473 | 0/480 | 1/232 |
| ContusionInjury, poisoning and procedural complications | 0/474 | 0/476 | 0/473 | 0/480 | 1/232 |
| Event | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo |
|---|---|---|---|---|---|
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 131/474 | 144/476 | 146/473 | 133/480 | 87/232 |
| NasopharyngitisInfections and infestations | 31/474 | 35/476 | 46/473 | 40/480 | 23/232 |
| CoughRespiratory, thoracic and mediastinal disorders | 26/474 | 38/476 | 18/473 | 21/480 | 8/232 |
| Upper respiratory tract infectionInfections and infestations | 20/474 | 31/476 | 20/473 | 24/480 | 13/232 |
| Upper respiratory tract infection bacterialInfections and infestations | 10/474 | 12/476 | 15/473 | 22/480 | 13/232 |
Baseline measures are based on the Safety Set that includes all participants who received study drug.
| Age Continuous(years) | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo | Total |
|---|---|---|---|---|---|---|
| Mean | 64.0 ± 8.88 | 63.6 ± 8.78 | 64.3 ± 9.04 | 63.5 ± 8.73 | 64.4 ± 8.58 | 63.9 ± 8.83 |
| Sex: Female, Male(Participants) | Indacaterol and Glycopyrronium (QVA149) | Indacaterol (QAB149) | Glycopyrronium (NVA237) | Tiotropium | Placebo | Total |
|---|---|---|---|---|---|---|
| Female | 112 | 122 | 108 | 120 | 63 | 525 |
| Male | 362 | 354 | 365 | 360 | 169 | 1610 |
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Novartis Pharmaceuticals