Chronic Obstructive Pulmonary Disease
Conditions
Keywords
QVA149, NVA237, COPD, exacerbation, combination bronchodilator
Brief summary
This study is designed to assess the effect of once-daily QVA149 on COPD exacerbations in patients with severe to very severe COPD.
Interventions
DRUGQVA149
QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).
DRUGNVA237
NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).
DRUGtiotropium
Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks).
As needed throughout the study
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: 1. Male or female adults aged ≥40 years, who had signed an informed consent form prior to initiation of any study-related procedure. 2. Patients with severe to very severe Chronic Obstructive Pulmonary Disease COPD (Stage III or IV) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines 2008. 3. Current or ex-smokers with a smoking history of at least 10 pack years (Ten pack-years were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years). 4. Patients with a post-bronchodilator Forced Expiratory Volume in one second ( FEV1) \<50% of the predicted normal value, and post-bronchodilator FEV1/ Forced Vital Capacity (FVC) \<0.70 at Visit 2 (day -14). (Post refers to 1 h after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol). 5. A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics.
Exclusion criteria
1. Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test). 2. Women of child-bearing potential 3. Patients requiring long term oxygen therapy (\> 15 h a day) on a daily basis for chronic hypoxemia. 4. Patients who had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to visit 1 or between visit 1 (Day -21) and Visit 3 (Day 1). 5. Patients who developed a COPD exacerbation during a period between visit 1 and 3 were ineligible but were permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. 6. Patients who had a respiratory tract infection within 4 weeks prior to visit 1 (Day -21) • Patients who developed an upper or lower respiratory tract infection during the screening period (up to visit 3 (Day 1) were not eligible, but were permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection 7. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension. 8. Patients with lung lobectomy, or lung volume reduction or lung transplantation. 9. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to): * Unstable ischemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable Atrial Fibrillation (AF). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study * history of malignancy of any organ system (including lung cancer), 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 * uncontrolled hypo- or hyperthyroidism, hypokalemia or hyper adrenergic state * narrow-angle glaucoma * Symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (Patients with a Transurethral Resection of Prostate (TURP) were excluded from the study. Patients who underwent full re-section of the prostate could be considered for the study, as well as patients who were asymptomatic and stable on pharmacological treatment for the condition). * any condition which might have compromised patient safety or compliance, interfered with evaluation, or precluded completion of the study 10. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count \> 600/mm3 (at visit 2), or onset of symptoms prior to 40 years. Patients without asthma were excluded if their eosinophil count was \>600/mm3 at visit 2. 11. Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids intermittently (treatment with a constant dose was permitted). 12. Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known positive skin prick test in the last 5 years. 13. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency. 14. Patients who were participating in the active phase of a supervised pulmonary rehabilitation program. 15. Patients with Type I or uncontrolled Type II diabetes. 16. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or drugs of a similar class or any component thereof: * anticholinergic agents * long and short acting beta-2 agonists * sympathomimetic amines. 17. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) measured at visit 2 (Day -14) (Fridericia method) was prolonged (\>450 ms for males and females) as confirmed by the central ECG assessor. 18. Patients with a clinically significant abnormality on the screening or baseline ECG who in the judgment of the investigator would be at potential risk if enrolled into the study. (These patients could not be re-screened). 19. Patients who needed treatments for COPD and allied conditions after the start of the study (visit 1) 20. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis) unless they had been stabilized 21. Patients taking other prohibited medications 22. Patients unable to use a dry powder inhaler (e.g. single dose dry powder inhaler (SDDPI), HandiHaler® device, or pressurized Metered Dose Inhaler (MDI) (rescue medication). 23. Patients unable to use an electronic patient diary. 24. Patients who were, in the opinion of the investigator known to be unreliable or non-compliant. 25. Patients who used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of visit 1 (day -21), whichever was longer. 26. Patients who had live attenuated vaccination within 30 days prior to the screening visit or during the run-in period. Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated vaccine was acceptable provided it was not administered within 48 hours prior to screening and randomization visits. No additional exclusions were applied by the investigator, in order to ensure that the study population was representative of all eligible patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period. | 64 weeks | A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period | 64 weeks | A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years |
| Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics | 64 weeks | Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years |
| Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | 64 weeks | The number of exacerbation days is defined as the sum of the duration of days recorded as an exacerbation for all exacerbations recorded per patient. |
| Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period. | 64 weeks | Time to Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase. |
| Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period | 64 weeks | Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase. |
| Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period. | 76 weeks | A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years |
| Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | 4, 12, 26, 38, 52 and 64 weeks | Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Spirometry measurements taken were FEV1 at -45 minutes and -15 minutes pre-dose. Three acceptable maneuvers had to be performed for each time point. The FEV1 values recorded had to be the highest values measured irrespective of whether or not they occurred on the same curve. The mixed model for analysis contained treatment as a fixed effect with average of the 45 minutes and 15 minutes pre dose FEV1 measurements at day 1 as the baseline measurement, FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at -14 Day) as covariates. |
| Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | 4, 12, 26, 38, 52 and 64 weeks | Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Pre-dose Forced Vital Capacity (FVC) is defined as the average of the -15 minutes and the -45 minutes FVC values. Baseline is defined as the average of the -45 minutes and -15 minutes FVC values taken on day 1 prior to first dose. FVC data taken within 6h of rescue medication or within 7 days of systemic corticosteroid is excluded from this analysis |
| Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Baseline (14 day run-in), 64 weeks | The severe or less FEV1 % predicted (post bronchodilator)\>=30%; very severe=\> FEV1 % predicted(the post bronchodilator)\<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded 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. |
| Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period | Baseline (14 day run-in), 64 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. |
| St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | 12, 26, 38, 52 and 64 weeks | St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, Forced Expiratory Volume in 1 Second (FEV1) prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. SGRQ total score is the sum of the scores from the three components; symptoms, activity and impacts. |
| Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 26, 52, 64, 76 weeks | Cumulative rates were estimated using Anderson and Gill method. Chronic Obstructive Pulmonary Disease (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 treatment for moderate severity and hospitalization were required. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years |
Countries
Argentina, Austria, Canada, Colombia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Mexico, Netherlands, Peru, Philippines, Poland, Puerto Rico, Russia, Slovakia, South Africa, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 3865 participants were screened of whom 2224 were randomized to 1 of the 3 treatment groups (QVA149, NVA237 or tiotropium) in a 1:1:1 ratio for at least 64 weeks (maximum 76 weeks) of treatment period.
Pre-assignment details
5 (QVA149), 2 (NVA237) and 3 (tiotropium) participants were randomized but did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| QVA149 QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study. | 729 |
| NVA237 NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period. Salbutamol/albuterol was available for rescue medication use throughout the study. | 740 |
| Open-label Tiotropium Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study. | 737 |
| Total | 2,206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 3 | 4 |
| Overall Study | Abnormal test procedure result(s) | 3 | 2 | 1 |
| Overall Study | Administrative problems | 15 | 8 | 9 |
| Overall Study | Adverse Event | 59 | 67 | 47 |
| Overall Study | Death | 21 | 22 | 24 |
| Overall Study | Lost to Follow-up | 5 | 6 | 4 |
| Overall Study | Patient's inability to use the device | 3 | 1 | 0 |
| Overall Study | Protocol deviation | 13 | 12 | 12 |
| Overall Study | Subject withdrew consent | 33 | 50 | 44 |
| Overall Study | Unsatisfactory therapeutic effect | 18 | 32 | 38 |
Baseline characteristics
| Characteristic | QVA149 | NVA237 | Open-label Tiotropium | Total |
|---|---|---|---|---|
| Age Continuous | 63.1 years STANDARD_DEVIATION 8.07 | 63.1 years STANDARD_DEVIATION 7.98 | 63.6 years STANDARD_DEVIATION 7.79 | 63.3 years STANDARD_DEVIATION 7.95 |
| Sex: Female, Male Female | 173 Participants | 198 Participants | 184 Participants | 555 Participants |
| Sex: Female, Male Male | 556 Participants | 542 Participants | 553 Participants | 1651 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 | 656 / 729 | 671 / 740 | 666 / 737 |
| serious Total, serious adverse events | 167 / 729 | 179 / 740 | 165 / 737 |
Outcome results
Primary
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period.
A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 64 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site , which had major issues with Good Clinical Practice (GCP) compliance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period. | 0.94 Exacerbations per year |
| NVA237 | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and NVA237 Treatment Arms During the Treatment Period. | 1.07 Exacerbations per year |
Secondary
Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period
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: Baseline (14 day run-in), 64 weeks
Population: Modified Full Analysis Set(mFAS)included all patients in the Full analysis set except patients from a site,which had major issues with GCP compliance. The Full Analysis Set includes all randomized patients who received at least one dose of study drug and data was available for analysis. Patients with evaluable data were included in this analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period | 29.36 percentage of days | Standard Error 1.445 |
| NVA237 | Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period | 21.65 percentage of days | Standard Error 1.41 |
| Open-label Tiotropium | Change From Baseline of Percentage of Days Without Rescue Therapy Use Between QVA149,NVA237 and Open Label Tiotropium Over the 64 Week Treatment Period | 23.86 percentage of days | Standard Error 1.422 |
Secondary
Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period
The severe or less FEV1 % predicted (post bronchodilator)\>=30%; very severe=\> FEV1 % predicted(the post bronchodilator)\<30%.Number of puffs of rescue medication taken in the previous 12 hours was recorded 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.
Time frame: Baseline (14 day run-in), 64 weeks
Population: Modified Full Analysis Set mFAS included all patients in the Full analysis set except patients from a site,which had major issues with GCP compliance. The Full Analysis Set includes all randomized patients who received at least one dose of study drug and data was available for analysis. Patients with evaluable data were included in this analysis
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Severe or Less(n=565,575,561) | -2.3 # puffs | Standard Error 0.137 |
| QVA149 | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Very Severe (n=143,149,148) | -2.1 # puffs | Standard Error 0.234 |
| NVA237 | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Severe or Less(n=565,575,561) | -1.5 # puffs | Standard Error 0.135 |
| NVA237 | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Very Severe (n=143,149,148) | -1.1 # puffs | Standard Error 0.228 |
| Open-label Tiotropium | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Severe or Less(n=565,575,561) | -1.6 # puffs | Standard Error 0.136 |
| Open-label Tiotropium | Change in Mean Daily Use (Number of Puffs) of Rescue Therapy Between QVA149, NVA237 and Open Label Tiotropium From Baseling Over the 64 Week Treatment Period | Mean Daily # puffs Very Severe (n=143,149,148) | -1.0 # puffs | Standard Error 0.228 |
Secondary
Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points
Cumulative rates were estimated using Anderson and Gill method. Chronic Obstructive Pulmonary Disease (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 treatment for moderate severity and hospitalization were required. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 26, 52, 64, 76 weeks
Population: Modified Full Analysis Set(mFAS) included all patients in the Full Analysis Set (FAS) except patients from a site, which had major issues with GCP compliance. FAS include all randomized patients who received at least one dose of study drug and data was available for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| QVA149 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 26 weeks | 0.57 exacerbations per year |
| QVA149 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 52 weeks | 0.99 exacerbations per year |
| QVA149 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 64 weeks | 1.19 exacerbations per year |
| QVA149 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 76 weeks | 1.39 exacerbations per year |
| NVA237 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 76 weeks | 1.59 exacerbations per year |
| NVA237 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 26 weeks | 0.65 exacerbations per year |
| NVA237 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 64 weeks | 1.36 exacerbations per year |
| NVA237 | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 52 weeks | 1.13 exacerbations per year |
| Open-label Tiotropium | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 76 weeks | 1.55 exacerbations per year |
| Open-label Tiotropium | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 52 weeks | 1.11 exacerbations per year |
| Open-label Tiotropium | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 64 weeks | 1.31 exacerbations per year |
| Open-label Tiotropium | Cumulative Rates of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations for Multiple COPD Exacerbation at Different Time Points | 26 weeks | 0.63 exacerbations per year |
Secondary
Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics
The number of exacerbation days is defined as the sum of the duration of days recorded as an exacerbation for all exacerbations recorded per patient.
Time frame: 64 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site with GCP non-compliance. This is a sub-group analysis with mutually exclusive population in each category for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | antibiotics [n= 195, 177, 177] | 25.08 Days | Standard Deviation 47.035 |
| QVA149 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | systemic corticosteroids [n= 97, 108, 109] | 20.49 Days | Standard Deviation 25.426 |
| QVA149 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | corticosteroids and antibiotic [n= 266, 290, 270] | 22.10 Days | Standard Deviation 49.999 |
| NVA237 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | antibiotics [n= 195, 177, 177] | 18.10 Days | Standard Deviation 21.79 |
| NVA237 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | systemic corticosteroids [n= 97, 108, 109] | 25.22 Days | Standard Deviation 42.674 |
| NVA237 | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | corticosteroids and antibiotic [n= 266, 290, 270] | 26.18 Days | Standard Deviation 52.336 |
| Open-label Tiotropium | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | systemic corticosteroids [n= 97, 108, 109] | 17.57 Days | Standard Deviation 17.797 |
| Open-label Tiotropium | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | corticosteroids and antibiotic [n= 266, 290, 270] | 22.03 Days | Standard Deviation 42.513 |
| Open-label Tiotropium | Number of Days With Moderate or Severe Exacerbation That Required Treatment With Systemic Corticosteroids and Antibiotics | antibiotics [n= 195, 177, 177] | 25.94 Days | Standard Deviation 50.007 |
Secondary
Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period
Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.
Time frame: 64 weeks
Population: Modified safety set (mSAF set) includes all patients in the safety set except patients from a site who had major GCP issues. The Safety set includes all patients who received at least one dose of study drug whether or not being randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period | 21.8 percentage of participants |
| NVA237 | Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period | 27.3 percentage of participants |
| Open-label Tiotropium | Percentage of Patients With Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.)During the Treatment Period | 24.2 percentage of participants |
Secondary
Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium
Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Spirometry measurements taken were FEV1 at -45 minutes and -15 minutes pre-dose. Three acceptable maneuvers had to be performed for each time point. The FEV1 values recorded had to be the highest values measured irrespective of whether or not they occurred on the same curve. The mixed model for analysis contained treatment as a fixed effect with average of the 45 minutes and 15 minutes pre dose FEV1 measurements at day 1 as the baseline measurement, FEV1 prior to inhalation and FEV1 60 minutes post inhalation of two short acting bronchodilators (components of reversibility at -14 Day) as covariates.
Time frame: 4, 12, 26, 38, 52 and 64 weeks
Population: Modified Full Analysis Set(mFAS) included all patients in the Full Analysis Set (FAS) except patients from a site, which had major issues with GCP compliance. FAS include all randomized patients who received at least one dose of study drug and data was available for analysis. Each category has patients with assessable data at that particular time.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 4 (n= 656,654,630) | 1.08 L (liters) | Standard Error 0.009 |
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 12 (n= 666,663,653) | 1.08 L (liters) | Standard Error 0.01 |
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 26 (n= 604,577,599) | 1.07 L (liters) | Standard Error 0.01 |
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 38 (n= 593,549,583) | 1.08 L (liters) | Standard Error 0.011 |
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 52 (n= 557,538,548) | 1.05 L (liters) | Standard Error 0.011 |
| QVA149 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 64 (n= 549,504,530) | 1.05 L (liters) | Standard Error 0.011 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 64 (n= 549,504,530) | 0.98 L (liters) | Standard Error 0.011 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 4 (n= 656,654,630) | 0.99 L (liters) | Standard Error 0.009 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 38 (n= 593,549,583) | 1.00 L (liters) | Standard Error 0.011 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 52 (n= 557,538,548) | 0.98 L (liters) | Standard Error 0.011 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 12 (n= 666,663,653) | 1.01 L (liters) | Standard Error 0.009 |
| NVA237 | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 26 (n= 604,577,599) | 0.99 L (liters) | Standard Error 0.01 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 12 (n= 666,663,653) | 1.01 L (liters) | Standard Error 0.009 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 26 (n= 604,577,599) | 1.00 L (liters) | Standard Error 0.01 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 64 (n= 549,504,530) | 0.99 L (liters) | Standard Error 0.011 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 38 (n= 593,549,583) | 1.00 L (liters) | Standard Error 0.011 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 4 (n= 656,654,630) | 1.00 L (liters) | Standard Error 0.009 |
| Open-label Tiotropium | Pre-dose Forced Expiratory Volume in 1 Second (FEV-1) After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FEV1 Week 52 (n= 557,538,548) | 0.99 L (liters) | Standard Error 0.011 |
Secondary
Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium
Pulmonary function assessments were performed using centralized spirometry. The spirometer was customized and programmed according to the requirements of the study protocol in accordance with American Thoracic Society (ATS) standards. Pre-dose Forced Vital Capacity (FVC) is defined as the average of the -15 minutes and the -45 minutes FVC values. Baseline is defined as the average of the -45 minutes and -15 minutes FVC values taken on day 1 prior to first dose. FVC data taken within 6h of rescue medication or within 7 days of systemic corticosteroid is excluded from this analysis
Time frame: 4, 12, 26, 38, 52 and 64 weeks
Population: Modified Full Analysis Set(mFAS) included all patients in the Full Analysis Set (FAS) except patients from a site, which had major issues with GCP compliance. FAS include all randomized patients who received at least one dose of study drug and data was available for analysis. Each category has patients with assessable data at that particular time.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 4 (n= 656,654,630) | 2.74 L (liters) | Standard Error 0.02 |
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 12 (n= 623,621,619) | 2.77 L (liters) | Standard Error 0.021 |
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 26 (n= 604,577,599) | 2.73 L (liters) | Standard Error 0.023 |
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 38 (n= 592,548,580) | 2.76 L (liters) | Standard Error 0.025 |
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 52 (n= 557,538,547) | 2.68 L (liters) | Standard Error 0.025 |
| QVA149 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 64 (n= 549,502,526) | 2.67 L (liters) | Standard Error 0.025 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 64 (n= 549,502,526) | 2.57 L (liters) | Standard Error 0.025 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 4 (n= 656,654,630) | 2.59 L (liters) | Standard Error 0.019 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 38 (n= 592,548,580) | 2.65 L (liters) | Standard Error 0.025 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 52 (n= 557,538,547) | 2.58 L (liters) | Standard Error 0.025 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 12 (n= 623,621,619) | 2.63 L (liters) | Standard Error 0.021 |
| NVA237 | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 26 (n= 604,577,599) | 2.60 L (liters) | Standard Error 0.022 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 12 (n= 623,621,619) | 2.65 L (liters) | Standard Error 0.021 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 26 (n= 604,577,599) | 2.61 L (liters) | Standard Error 0.022 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 64 (n= 549,502,526) | 2.59 L (liters) | Standard Error 0.025 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 38 (n= 592,548,580) | 2.63 L (liters) | Standard Error 0.025 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 4 (n= 656,654,630) | 2.60 L (liters) | Standard Error 0.019 |
| Open-label Tiotropium | Pre-dose Forced Vital Capacity (FVC)After 4, 12, 26, 38, 52 and 64 Weeks of Treatment Between QVA149, NVA237 and Open Label Tiotropium | predose FVC Week 52 (n= 557,538,547) | 2.58 L (liters) | Standard Error 0.025 |
Secondary
Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics
Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 64 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance. The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study drug and data was available for analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics | 0.46 exacerbations per year |
| NVA237 | Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics | 0.58 exacerbations per year |
| Open-label Tiotropium | Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Requiring the Use of Both Systemic Glucocorticosteroids and Antibiotics | 0.54 exacerbations per year |
Secondary
Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period.
A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 76 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period. | 0.94 Exacerbations per year |
| NVA237 | Rate of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in QVA149 and Open-label Tiotropium Treatment Arms During the Treatment Period. | 1.06 Exacerbations per year |
Secondary
St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment
St. George's Respiratory Questionnaire (SGRQ) is a health related quality of life questionnaire consisting of 51 items in three components: symptoms, activity, and impacts. The lowest possible value is zero and the highest 100. Higher values correspond to greater impairment in quality of life. Mixed model used baseline SGRQ, baseline inhaled corticosteroid (ICS) use, Forced Expiratory Volume in 1 Second (FEV1) prior to inhalation of short acting beta-agonist (SABA), and FEV1 45 minutes post-inhalation of SABA as covariates. SGRQ total score is the sum of the scores from the three components; symptoms, activity and impacts.
Time frame: 12, 26, 38, 52 and 64 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance. The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study drug and data was available for analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 52 (n= 625,593,613) | 43.38 units on a scale | Standard Error 0.722 |
| QVA149 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 38 (n= 648,626,635) | 42.72 units on a scale | Standard Error 0.667 |
| QVA149 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 12 (n= 694,694,676) | 44.69 units on a scale | Standard Error 0.612 |
| QVA149 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 26 (n= 684,677,658) | 44.06 units on a scale | Standard Error 0.655 |
| QVA149 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 64 (n= 600,564,579) | 43.39 units on a scale | Standard Error 0.778 |
| NVA237 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 38 (n= 648,626,635) | 45.53 units on a scale | Standard Error 0.663 |
| NVA237 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 12 (n= 694,694,676) | 47.13 units on a scale | Standard Error 0.603 |
| NVA237 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 26 (n= 684,677,658) | 45.93 units on a scale | Standard Error 0.647 |
| NVA237 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 52 (n= 625,593,613) | 45.96 units on a scale | Standard Error 0.723 |
| NVA237 | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 64 (n= 600,564,579) | 45.46 units on a scale | Standard Error 0.78 |
| Open-label Tiotropium | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 64 (n= 600,564,579) | 46.08 units on a scale | Standard Error 0.778 |
| Open-label Tiotropium | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 52 (n= 625,593,613) | 46.21 units on a scale | Standard Error 0.714 |
| Open-label Tiotropium | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 12 (n= 694,694,676) | 47.62 units on a scale | Standard Error 0.607 |
| Open-label Tiotropium | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 38 (n= 648,626,635) | 45.86 units on a scale | Standard Error 0.66 |
| Open-label Tiotropium | St. George's Respiratory Questionnaire (SGRQ) Scores Between QVA149, NVA237 and Open Label Tiotropium Over 12, 26, 38, 52 and 64 Weeks of Treatment | Week 26 (n= 684,677,658) | 45.77 units on a scale | Standard Error 0.651 |
Secondary
Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period
A Chronic Obstructive Pulmonary Disease (COPD) exacerbation was defined as a worsening of two or more of the following major symptoms for at least 2 consecutive days: dyspnea, sputum volume or sputum purulence OR a worsening of any 1 major symptom together with an increase in any 1 of the following minor symptoms for at least 2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, cough or wheezing. A COPD exacerbation was considered of moderate severity if treatment with systemic glucocorticosteroids or antibiotics or both was required and severe if hospitalization was required. An emergency room (ER) visit of longer than 24 hours was considered a hospitalization. Rate of moderate or severe exacerbations per year = total number of moderate or severe exacerbations / total number of treatment years
Time frame: 64 weeks
Population: Modified Full Analysis Set (mFAS) included all patients in the Full analysis set except patients from a site, which had major issues with GCP compliance. Only patients with a moderate or severe COPD exacerbation were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| QVA149 | Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period | 296 days |
| NVA237 | Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period | 287 days |
| Open-label Tiotropium | Time to First Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Between QVA149, NVA237 and Open Label Tiotropium During the Treatment Period | 331 days |
Secondary
Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period.
Time to Study Withdrawal or Premature Discontinuation for Any Reason was analyzed for each treatment group using a Kaplan-Meier estimation for the modified safety set. Patients who did not discontinue early were censored at the final visit of the treatment phase.
Time frame: 64 weeks
Population: Modified safety set (mSAF set) includes all patients in the safety set except patients from a site who had major GCP issues. The Safety set includes all patients who received at least one dose of study drug whether or not being randomized. Analysis population included patients with study withdrawal or premature discontinuation for any reason.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| QVA149 | Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period. | NA days |
| NVA237 | Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period. | NA days |
| Open-label Tiotropium | Time to Study Withdrawal or Premature Discontinuation for Any Reason Between QVA149 (110/50 µg q.d.), NVA237 (50 µg q.d.) and Open Label Tiotropium (18 µg q.d.) During the Treatment Period. | NA days |