Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
chronic obstructive pulmonary disease, COPD, QVA149, QAB149, NVA237, Indacaterol maleate, Glycopyronnium bromide
Brief summary
The study will assess the long-term safety of the fixed combination product QVA149 versus placebo and a standard of care treatment (tiotropium) in Chronic Obstructive Pulmonary Disease (COPD) patients with moderate to severe airflow limitation.
Interventions
DRUGplacebo
placebo to QVA149A and Tiotropium will be supplied in the appropriate capsule in blister packs for use in either the Novartis Concept1 SDDPI or the HandiHaler SDDPI
DRUGQVA149
QVA149 110/50 µg will be supplied as capsules in blister packs for once daily inhalation using the Novartis Concept1 SDDPI
DRUGTiotropium
Tiotropium 18 µg will be supplied as capsules in blister packs for once daily inhalation using the HandiHaler SDDPI
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female adults aged ≥40 years. * Patients with stable COPD according to GOLD strategy (GOLD 2011). * Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30% and \<80% of the predicted normal, and a post-bronchodilator. * FEV1/FVC \< 0.70. * Current or ex-smokers who have a smoking history of at least 10 pack years. * Patients with an mMRC ≥ grade 2
Exclusion criteria
* History of long QT syndrome or prolonged QTc. * Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to Visit 1. * Patients with Type I or uncontrolled Type II diabetes. * Patients with a history of asthma or have concomitant pulmonary disease. * Patients with paroxysmal (e.g. intermittent) atrial fibrillation. Only patients with persistent atrial fibrillation and controlled with a rate control strategy for at least six months could be eligible. * Patients who have clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities which could interfere with the assessment of safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Serious Adverse Events | Week 52 | The overall rate of serious adverse events reported from initiation through 30 days post last dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE | 52 weeks | The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug. |
| Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 22, 43, 85, 183, 274 and 364 | Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. |
| Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) | Measurment at day 364 | The SGRQ-C contains 40 items divided into two parts covering three aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score will be calculated for each of these three subscales and a Total score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. |
| Change From Baseline in Daily, Morning and Evening Symptom Scores | 52 weeks | Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline. |
| Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings | 52 weeks | A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms. |
| Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. | 52 weeks | The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug. |
| Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. | 52 weeks | A day able to perform usual daily activities' is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms. |
| Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 1, 22, 43, 85, 183, 274 and 364 | Pulmonary function assessments were performed using centralized spirometry according to international standards |
| Time to Premature Discontinuation | Time varied from 5 - 407 days | Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the 'time to treatment discontinuation' varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks. |
| Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 1, 22, 43, 85, 183, 274 and 364 | The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed. |
| Change From Baseline in Percentage of no Daytime Symptoms | 52 weeks | A day with 'no daytime symptoms' is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm). |
Countries
Argentina, Colombia, Croatia, Estonia, Hungary, India, Israel, Latvia, Mexico, Panama, Poland, Russia, Serbia, Slovenia, South Korea, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
A total of 2064 patients were screened, of whom 1216 patients were randomized to QVA149 110/50 µg o.d., tiotropium 18 µg o.d., or placebo. Of the 1216, one patient was randomized but not treated.
Pre-assignment details
One patient of the 1216 was randomized but did not receive treatment
Participants by arm
| Arm | Count |
|---|---|
| QVA149 110/50 µg capsules for inhalation, o.d | 407 |
| Tiotropium 18 μg capsules for inhalation, o.d | 405 |
| Placebo To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d | 404 |
| Total | 1,216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| All Patients | Abnormal laboratory value | 1 | 1 | 0 |
| All Patients | Abnormal test procedure result(s) | 0 | 1 | 3 |
| All Patients | Administrative problems | 1 | 4 | 4 |
| All Patients | Adverse Event | 27 | 22 | 26 |
| All Patients | Death | 4 | 2 | 1 |
| All Patients | Lost to Follow-up | 1 | 0 | 0 |
| All Patients | Protocol deviation | 4 | 3 | 3 |
| All Patients | Unsatisfactory therapeutic effect | 9 | 8 | 27 |
| All Patients | Withdrawal by Subject | 12 | 10 | 20 |
| Treatment and Follow up Period | Administrative problems | 1 | 3 | 2 |
| Treatment and Follow up Period | Death | 10 | 5 | 4 |
| Treatment and Follow up Period | Lost to Follow-up | 1 | 6 | 4 |
| Treatment and Follow up Period | Subject withdrew consent | 13 | 14 | 16 |
Baseline characteristics
| Characteristic | QVA149 | Tiotropium | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 64.6 Years STANDARD_DEVIATION 7.89 | 64.1 Years STANDARD_DEVIATION 8.57 | 64.9 Years STANDARD_DEVIATION 7.95 | 64.5 Years STANDARD_DEVIATION 8.14 |
| Sex: Female, Male Female | 119 Participants | 105 Participants | 94 Participants | 318 Participants |
| Sex: Female, Male Male | 288 Participants | 300 Participants | 310 Participants | 898 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 | 294 / 407 | 294 / 405 | 309 / 403 |
| serious Total, serious adverse events | 55 / 407 | 55 / 405 | 50 / 403 |
Outcome results
Primary
Number of Patients With Serious Adverse Events
The overall rate of serious adverse events reported from initiation through 30 days post last dose.
Time frame: Week 52
Population: The safety set included all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. Patients were analyzed according to treatment received. A patient who had no adverse events also constitutes a safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Number of Patients With Serious Adverse Events | 55 Participants |
| Tiotropium 18 µg o.d | Number of Patients With Serious Adverse Events | 55 Participants |
| Placebo | Number of Patients With Serious Adverse Events | 50 Participants |
Secondary
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed.
Time frame: Day 1, 22, 43, 85, 183, 274 and 364
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 22 (n=384, 381, 362) | 0.2883 Liters | Standard Deviation 0.21074 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 183 (n=364, 359, 317) | 0.2860 Liters | Standard Deviation 0.24351 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 85 (n=376, 371, 345) | 0.3026 Liters | Standard Deviation 0.2326 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 1 (n=403, 402, 399) | 0.2064 Liters | Standard Deviation 0.14248 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 364 (n= 336, 347, 302) | 0.2619 Liters | Standard Deviation 0.25967 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 274 (n=349, 352, 306) | 0.2749 Liters | Standard Deviation 0.24314 |
| QVA149 | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 43 (n=380, 373, 351) | 0.2904 Liters | Standard Deviation 0.23377 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 85 (n=376, 371, 345) | 0.1913 Liters | Standard Deviation 0.23274 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 1 (n=403, 402, 399) | 0.1567 Liters | Standard Deviation 0.13349 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 22 (n=384, 381, 362) | 0.2077 Liters | Standard Deviation 0.20027 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 43 (n=380, 373, 351) | 0.2008 Liters | Standard Deviation 0.20752 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 183 (n=364, 359, 317) | 0.1842 Liters | Standard Deviation 0.22851 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 274 (n=349, 352, 306) | 0.1681 Liters | Standard Deviation 0.23626 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 364 (n= 336, 347, 302) | 0.1621 Liters | Standard Deviation 0.23922 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 183 (n=364, 359, 317) | -0.0253 Liters | Standard Deviation 0.21129 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 22 (n=384, 381, 362) | 1.5827 Liters | Standard Deviation 15.6999 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 364 (n= 336, 347, 302) | -0.0533 Liters | Standard Deviation 0.2156 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 274 (n=349, 352, 306) | -0.0360 Liters | Standard Deviation 0.21854 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 85 (n=376, 371, 345) | -0.0217 Liters | Standard Deviation 0.20195 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 43 (n=380, 373, 351) | 1.6209 Liters | Standard Deviation 16.89209 |
| Placebo | Change From Baseline in 1 Hour Post-dose FEV1 Measurements | Day 1 (n=403, 402, 399) | 0.0281 Liters | Standard Deviation 0.11123 |
Secondary
Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements
Pulmonary function assessments were performed using centralized spirometry according to international standards
Time frame: Day 1, 22, 43, 85, 183, 274 and 364
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 364 (n= 336, 347, 302) | 0.3153 Liters | Standard Deviation 0.4656 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 1(n=403, 402, 399) | 0.3331 Liters | Standard Deviation 0.30312 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 22 (n=384, 381, 362) | 0.3971 Liters | Standard Deviation 0.40009 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 43 (n=380, 373, 351) | 0.4021 Liters | Standard Deviation 0.42797 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 85 (376, 371, 345) | 0.4169 Liters | Standard Deviation 0.42175 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 183 (n=364, 359, 317) | 0.3880 Liters | Standard Deviation 0.45342 |
| QVA149 | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 274 (n=349, 352, 306) | 0.3582 Liters | Standard Deviation 0.43072 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 274 (n=349, 352, 306) | 0.2821 Liters | Standard Deviation 0.40546 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 43 (n=380, 373, 351) | 0.2966 Liters | Standard Deviation 0.37124 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 85 (376, 371, 345) | 0.2867 Liters | Standard Deviation 0.40131 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 364 (n= 336, 347, 302) | 0.2224 Liters | Standard Deviation 0.40778 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 183 (n=364, 359, 317) | 0.2822 Liters | Standard Deviation 0.39781 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 1(n=403, 402, 399) | 0.2806 Liters | Standard Deviation 0.28293 |
| Tiotropium 18 µg o.d | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 22 (n=384, 381, 362) | 0.3123 Liters | Standard Deviation 0.36755 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 364 (n= 336, 347, 302) | -0.0498 Liters | Standard Deviation 0.39908 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 183 (n=364, 359, 317) | -0.0283 Liters | Standard Deviation 0.36919 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 43 (n=380, 373, 351) | 0.0274 Liters | Standard Deviation 0.35681 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 274 (n=349, 352, 306) | -0.0404 Liters | Standard Deviation 0.37777 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 22 (n=384, 381, 362) | 0.0178 Liters | Standard Deviation 0.33624 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 85 (376, 371, 345) | 0.0035 Liters | Standard Deviation 0.36897 |
| Placebo | Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements | Day 1(n=403, 402, 399) | 0.0630 Liters | Standard Deviation 0.22884 |
Secondary
Change From Baseline in Daily, Morning and Evening Symptom Scores
Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline.
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daytime total symptom score (n= 380, 385, 374) | -1.1688 Score | Standard Deviation 1.9335 |
| QVA149 | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daily total symptom score (n=395, 395, 385) | -1.3478 Score | Standard Deviation 1.91692 |
| QVA149 | Change From Baseline in Daily, Morning and Evening Symptom Scores | Nighttime total symptom score (n= 387, 388, 375) | -0.9731 Score | Standard Deviation 1.96898 |
| Tiotropium 18 µg o.d | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daytime total symptom score (n= 380, 385, 374) | -1.0669 Score | Standard Deviation 1.90366 |
| Tiotropium 18 µg o.d | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daily total symptom score (n=395, 395, 385) | -1.2283 Score | Standard Deviation 1.93241 |
| Tiotropium 18 µg o.d | Change From Baseline in Daily, Morning and Evening Symptom Scores | Nighttime total symptom score (n= 387, 388, 375) | -0.9532 Score | Standard Deviation 1.78168 |
| Placebo | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daily total symptom score (n=395, 395, 385) | -0.7683 Score | Standard Deviation 1.73598 |
| Placebo | Change From Baseline in Daily, Morning and Evening Symptom Scores | Nighttime total symptom score (n= 387, 388, 375) | -0.5984 Score | Standard Deviation 1.73356 |
| Placebo | Change From Baseline in Daily, Morning and Evening Symptom Scores | Daytime total symptom score (n= 380, 385, 374) | -0.5641 Score | Standard Deviation 1.62577 |
Secondary
Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C)
The SGRQ-C contains 40 items divided into two parts covering three aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score will be calculated for each of these three subscales and a Total score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
Time frame: Measurment at day 364
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) | -6.79 Score | Standard Deviation 12.611 |
| Tiotropium 18 µg o.d | Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) | -6.12 Score | Standard Deviation 13.695 |
| Placebo | Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) | -2.18 Score | Standard Deviation 13.311 |
Secondary
Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities.
A day able to perform usual daily activities' is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms.
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. | 10.79 Percentage of days | Standard Deviation 31.006 |
| Tiotropium 18 µg o.d | Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. | 6.54 Percentage of days | Standard Deviation 30.215 |
| Placebo | Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. | 1.13 Percentage of days | Standard Deviation 25.039 |
Secondary
Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings
A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms.
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings | 11.34 Percentage of nights | Standard Deviation 30.115 |
| Tiotropium 18 µg o.d | Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings | 10.66 Percentage of nights | Standard Deviation 26.579 |
| Placebo | Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings | 8.21 Percentage of nights | Standard Deviation 28.002 |
Secondary
Change From Baseline in Percentage of no Daytime Symptoms
A day with 'no daytime symptoms' is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm).
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in Percentage of no Daytime Symptoms | 5.56 Percentage of days | Standard Deviation 19.67 |
| Tiotropium 18 µg o.d | Change From Baseline in Percentage of no Daytime Symptoms | 4.72 Percentage of days | Standard Deviation 15.942 |
| Placebo | Change From Baseline in Percentage of no Daytime Symptoms | 1.78 Percentage of days | Standard Deviation 15.733 |
Secondary
Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1)
Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1.
Time frame: Day 22, 43, 85, 183, 274 and 364
Population: The full analysis set (FAS) included all randomized patients who eceived at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 274 (n=343, 351, 303) | 0.1463 Liters | Standard Error 0.21424 |
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 85 (n=373, 373, 340) | 0.1752 Liters | Standard Error 0.20198 |
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 364 (n=333, 346, 297) | 0.1468 Liters | Standard Error 0.22933 |
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 22 (n=378, 383, 361) | 0.1733 Liters | Standard Error 0.18537 |
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 183 (n=356, 358, 314) | 0.1557 Liters | Standard Error 0.21754 |
| QVA149 | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 43 (n=380, 375, 345) | 0.1751 Liters | Standard Error 0.208 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 183 (n=356, 358, 314) | 0.0714 Liters | Standard Error 0.20358 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 274 (n=343, 351, 303) | 0.0750 Liters | Standard Error 0.21489 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 43 (n=380, 375, 345) | 0.0961 Liters | Standard Error 0.18261 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 364 (n=333, 346, 297) | 0.0559 Liters | Standard Error 0.22433 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 22 (n=378, 383, 361) | 0.1018 Liters | Standard Error 0.18389 |
| Tiotropium 18 µg o.d | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 85 (n=373, 373, 340) | 0.0785 Liters | Standard Error 0.19606 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 364 (n=333, 346, 297) | -0.0826 Liters | Standard Error 0.21443 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 22 (n=378, 383, 361) | -0.0148 Liters | Standard Error 0.16758 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 43 (n=380, 375, 345) | -0.0196 Liters | Standard Error 0.18178 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 85 (n=373, 373, 340) | -0.0506 Liters | Standard Error 0.19369 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 183 (n=356, 358, 314) | -0.0583 Liters | Standard Error 0.20305 |
| Placebo | Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) | Day 274 (n=343, 351, 303) | -0.0601 Liters | Standard Error 0.20936 |
Secondary
Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events.
The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug.
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. | 3.9 Percentage of participants |
| Tiotropium 18 µg o.d | Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. | 2 Percentage of participants |
| Placebo | Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. | 1 Percentage of participants |
Secondary
Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE
The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug.
Time frame: 52 weeks
Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they were assigned to at randomization. If the patient was assigned to the wrong stratum for randomization, the patient was analyzed according to the actual (rather than assigned) stratum.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE | 1 Percentage of participants |
| Tiotropium 18 µg o.d | Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE | 0.7 Percentage of participants |
| Placebo | Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE | 0.7 Percentage of participants |
Secondary
Time to Premature Discontinuation
Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the 'time to treatment discontinuation' varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks.
Time frame: Time varied from 5 - 407 days
Population: The Safety set consisted of all patients that received at least one dose of study medication and had at least one post-baseline safety assessment. Patients were analyzed according to treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| QVA149 | Time to Premature Discontinuation | NA Days |
| Tiotropium 18 µg o.d | Time to Premature Discontinuation | NA Days |
| Placebo | Time to Premature Discontinuation | NA Days |