Trial Outcomes & Findings for Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation (NCT NCT01610037)
NCT ID: NCT01610037
Last Updated: 2016-06-15
Results Overview
The overall rate of serious adverse events reported from initiation through 30 days post last dose.
COMPLETED
PHASE3
1215 participants
Week 52
2016-06-15
Participant Flow
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.
One patient of the 1216 was randomized but did not receive treatment
Participant milestones
| Measure |
QVA149
110/50 µg capsules for inhalation, o.d
|
Tiotropium
18 μg capsules for inhalation, o.d
|
Placebo
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
All Patients
STARTED
|
407
|
405
|
404
|
|
All Patients
Randomized Set (RAN)
|
407
|
405
|
404
|
|
All Patients
Full Analysis Set (FAS)
|
407
|
405
|
403
|
|
All Patients
COMPLETED
|
348
|
354
|
320
|
|
All Patients
NOT COMPLETED
|
59
|
51
|
84
|
|
Treatment and Follow up Period
STARTED
|
407
|
405
|
404
|
|
Treatment and Follow up Period
COMPLETED
|
382
|
377
|
378
|
|
Treatment and Follow up Period
NOT COMPLETED
|
25
|
28
|
26
|
Reasons for withdrawal
| Measure |
QVA149
110/50 µg capsules for inhalation, o.d
|
Tiotropium
18 μg capsules for inhalation, o.d
|
Placebo
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
All Patients
Adverse Event
|
27
|
22
|
26
|
|
All Patients
Withdrawal by Subject
|
12
|
10
|
20
|
|
All Patients
Unsatisfactory therapeutic effect
|
9
|
8
|
27
|
|
All Patients
Death
|
4
|
2
|
1
|
|
All Patients
Protocol deviation
|
4
|
3
|
3
|
|
All Patients
Abnormal laboratory value
|
1
|
1
|
0
|
|
All Patients
Administrative problems
|
1
|
4
|
4
|
|
All Patients
Lost to Follow-up
|
1
|
0
|
0
|
|
All Patients
Abnormal test procedure result(s)
|
0
|
1
|
3
|
|
Treatment and Follow up Period
Subject withdrew consent
|
13
|
14
|
16
|
|
Treatment and Follow up Period
Death
|
10
|
5
|
4
|
|
Treatment and Follow up Period
Administrative problems
|
1
|
3
|
2
|
|
Treatment and Follow up Period
Lost to Follow-up
|
1
|
6
|
4
|
Baseline Characteristics
Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation
Baseline characteristics by cohort
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=404 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
Total
n=1216 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
64.6 Years
STANDARD_DEVIATION 7.89 • n=5 Participants
|
64.1 Years
STANDARD_DEVIATION 8.57 • n=7 Participants
|
64.9 Years
STANDARD_DEVIATION 7.95 • n=5 Participants
|
64.5 Years
STANDARD_DEVIATION 8.14 • n=4 Participants
|
|
Sex: Female, Male
Female
|
119 Participants
n=5 Participants
|
105 Participants
n=7 Participants
|
94 Participants
n=5 Participants
|
318 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
288 Participants
n=5 Participants
|
300 Participants
n=7 Participants
|
310 Participants
n=5 Participants
|
898 Participants
n=4 Participants
|
PRIMARY outcome
Timeframe: Week 52Population: 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.
The overall rate of serious adverse events reported from initiation through 30 days post last dose.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=403 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=402 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Number of Patients With Serious Adverse Events
|
55 Participants
|
55 Participants
|
50 Participants
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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.
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events.
|
3.9 Percentage of participants
|
2 Percentage of participants
|
1 Percentage of participants
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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.
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE
|
1 Percentage of participants
|
0.7 Percentage of participants
|
0.7 Percentage of participants
|
SECONDARY outcome
Timeframe: Day 22, 43, 85, 183, 274 and 364Population: 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
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=379 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
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
|
0.0750 Liters
Standard Error 0.21489
|
-0.0601 Liters
Standard Error 0.20936
|
|
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
|
0.1018 Liters
Standard Error 0.18389
|
-0.0148 Liters
Standard Error 0.16758
|
|
Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1)
Day 43 (n=380, 375, 345)
|
0.1751 Liters
Standard Error 0.20800
|
0.0961 Liters
Standard Error 0.18261
|
-0.0196 Liters
Standard Error 0.18178
|
|
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
|
0.0785 Liters
Standard Error 0.19606
|
-0.0506 Liters
Standard Error 0.19369
|
|
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
|
0.0714 Liters
Standard Error 0.20358
|
-0.0583 Liters
Standard Error 0.20305
|
|
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
|
0.0559 Liters
Standard Error 0.22433
|
-0.0826 Liters
Standard Error 0.21443
|
SECONDARY outcome
Timeframe: Measurment at day 364Population: 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
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.
Outcome measures
| Measure |
QVA149
n=343 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=349 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=314 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
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
|
-6.12 Score
Standard Deviation 13.695
|
-2.18 Score
Standard Deviation 13.311
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
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
|
-1.2283 Score
Standard Deviation 1.93241
|
-0.7683 Score
Standard Deviation 1.73598
|
|
Change From Baseline in Daily, Morning and Evening Symptom Scores
Daytime total symptom score (n= 380, 385, 374)
|
-1.1688 Score
Standard Deviation 1.93350
|
-1.0669 Score
Standard Deviation 1.90366
|
-0.5641 Score
Standard Deviation 1.62577
|
|
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
|
-0.9532 Score
Standard Deviation 1.78168
|
-0.5984 Score
Standard Deviation 1.73356
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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
A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms.
Outcome measures
| Measure |
QVA149
n=387 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=388 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=375 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings
|
11.34 Percentage of nights
Standard Deviation 30.115
|
10.66 Percentage of nights
Standard Deviation 26.579
|
8.21 Percentage of nights
Standard Deviation 28.002
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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
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).
Outcome measures
| Measure |
QVA149
n=380 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=385 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=374 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Change From Baseline in Percentage of no Daytime Symptoms
|
5.56 Percentage of days
Standard Deviation 19.670
|
4.72 Percentage of days
Standard Deviation 15.942
|
1.78 Percentage of days
Standard Deviation 15.733
|
SECONDARY outcome
Timeframe: 52 weeksPopulation: 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
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.
Outcome measures
| Measure |
QVA149
n=380 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=385 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=374 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities.
|
10.79 Percentage of days
Standard Deviation 31.006
|
6.54 Percentage of days
Standard Deviation 30.215
|
1.13 Percentage of days
Standard Deviation 25.039
|
SECONDARY outcome
Timeframe: Day 1, 22, 43, 85, 183, 274 and 364Population: 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
Pulmonary function assessments were performed using centralized spirometry according to international standards
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
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
|
0.2822 Liters
Standard Deviation 0.39781
|
-0.0283 Liters
Standard Deviation 0.36919
|
|
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
|
0.2821 Liters
Standard Deviation 0.40546
|
-0.0404 Liters
Standard Deviation 0.37777
|
|
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
|
0.2806 Liters
Standard Deviation 0.28293
|
0.0630 Liters
Standard Deviation 0.22884
|
|
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
|
0.3123 Liters
Standard Deviation 0.36755
|
0.0178 Liters
Standard Deviation 0.33624
|
|
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
|
0.2966 Liters
Standard Deviation 0.37124
|
0.0274 Liters
Standard Deviation 0.35681
|
|
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
|
0.2867 Liters
Standard Deviation 0.40131
|
0.0035 Liters
Standard Deviation 0.36897
|
|
Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements
Day 364 (n= 336, 347, 302)
|
0.3153 Liters
Standard Deviation 0.46560
|
0.2224 Liters
Standard Deviation 0.40778
|
-0.0498 Liters
Standard Deviation 0.39908
|
SECONDARY outcome
Timeframe: Time varied from 5 - 407 daysPopulation: 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.
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Time to Premature Discontinuation
|
NA Days
NA - insufficient number of participants with events
|
NA Days
Interval 378.0 to
NA - insufficient number of participants with events
|
NA Days
NA - insufficient number of participants with events
|
SECONDARY outcome
Timeframe: Day 1, 22, 43, 85, 183, 274 and 364Population: 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
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.
Outcome measures
| Measure |
QVA149
n=407 Participants
110/50 µg capsules for inhalation, o.d
|
Tiotropium 18 µg o.d
n=405 Participants
18 μg capsules for inhalation, o.d
|
Placebo
n=403 Participants
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 85 (n=376, 371, 345)
|
0.3026 Liters
Standard Deviation 0.23260
|
0.1913 Liters
Standard Deviation 0.23274
|
-0.0217 Liters
Standard Deviation 0.20195
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 1 (n=403, 402, 399)
|
0.2064 Liters
Standard Deviation 0.14248
|
0.1567 Liters
Standard Deviation 0.13349
|
0.0281 Liters
Standard Deviation 0.11123
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 22 (n=384, 381, 362)
|
0.2883 Liters
Standard Deviation 0.21074
|
0.2077 Liters
Standard Deviation 0.20027
|
1.5827 Liters
Standard Deviation 15.69990
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 43 (n=380, 373, 351)
|
0.2904 Liters
Standard Deviation 0.23377
|
0.2008 Liters
Standard Deviation 0.20752
|
1.6209 Liters
Standard Deviation 16.89209
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 183 (n=364, 359, 317)
|
0.2860 Liters
Standard Deviation 0.24351
|
0.1842 Liters
Standard Deviation 0.22851
|
-0.0253 Liters
Standard Deviation 0.21129
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 274 (n=349, 352, 306)
|
0.2749 Liters
Standard Deviation 0.24314
|
0.1681 Liters
Standard Deviation 0.23626
|
-0.0360 Liters
Standard Deviation 0.21854
|
|
Change From Baseline in 1 Hour Post-dose FEV1 Measurements
Day 364 (n= 336, 347, 302)
|
0.2619 Liters
Standard Deviation 0.25967
|
0.1621 Liters
Standard Deviation 0.23922
|
-0.0533 Liters
Standard Deviation 0.21560
|
Adverse Events
QVA 149
Tiotropium
Placebo
Serious adverse events
| Measure |
QVA 149
n=407 participants at risk
110/50 µg capsules for inhalation, o.d
|
Tiotropium
n=405 participants at risk
18 μg capsules for inhalation, o.d
|
Placebo
n=403 participants at risk
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Hepatobiliary disorders
Cholecystitis acute
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Hepatobiliary disorders
Hepatic mass
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Hepatobiliary disorders
Liver injury
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Acute sinusitis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Infections and infestations
Arthritis bacterial
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Breast abscess
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Infections and infestations
Bronchitis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Infections and infestations
Bronchitis bacterial
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Bronchopneumonia
|
0.00%
0/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Infections and infestations
Cellulitis
|
0.25%
1/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Diverticulitis
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Influenza
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Infections and infestations
Lobar pneumonia
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Infections and infestations
Lower respiratory tract infection
|
0.00%
0/407
|
0.49%
2/405
|
0.50%
2/403
|
|
Infections and infestations
Pneumonia
|
0.74%
3/407
|
1.5%
6/405
|
0.50%
2/403
|
|
Infections and infestations
Pneumonia bacterial
|
0.49%
2/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Infections and infestations
Respiratory tract infection
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Infections and infestations
Skin infection
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Infections and infestations
Upper respiratory tract infection
|
0.25%
1/407
|
0.00%
0/405
|
0.50%
2/403
|
|
Infections and infestations
Upper respiratory tract infection bacterial
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Infections and infestations
Gastroenteritis salmonella
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Blood and lymphatic system disorders
Anaemia
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Cardiac disorders
Acute myocardial infarction
|
0.25%
1/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Cardiac disorders
Angina unstable
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Cardiac disorders
Atrial fibrillation
|
0.74%
3/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Cardiac disorders
Cardiac arrest
|
0.49%
2/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Cardiac disorders
Cardiac failure
|
0.25%
1/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Cardiac disorders
Cardiac failure acute
|
0.49%
2/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Cardiac disorders
Cardio-respiratory arrest
|
0.25%
1/407
|
0.74%
3/405
|
0.00%
0/403
|
|
Cardiac disorders
Cardiopulmonary failure
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Cardiac disorders
Cor pulmonale
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Cardiac disorders
Mitral valve incompetence
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Cardiac disorders
Myocardial infarction
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Cardiac disorders
Ventricular extrasystoles
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Ear and labyrinth disorders
Sudden hearing loss
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Eye disorders
Cataract
|
0.00%
0/407
|
0.49%
2/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Abdominal mass
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Gastrointestinal disorders
Abdominal pain
|
0.25%
1/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Gastrointestinal inflammation
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Inguinal hernia
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Gastrointestinal disorders
Intestinal obstruction
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Mesenteric artery thrombosis
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Pancreatitis haemorrhagic
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Small intestinal obstruction
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Gastrointestinal disorders
Umbilical hernia
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
General disorders
Chest pain
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
General disorders
Hypothermia
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Hepatobiliary disorders
Bile duct stone
|
0.25%
1/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Hepatobiliary disorders
Cholangitis
|
0.00%
0/407
|
0.00%
0/405
|
0.50%
2/403
|
|
Infections and infestations
Urinary tract infection
|
0.49%
2/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Infections and infestations
Viral upper respiratory tract infection
|
0.00%
0/407
|
0.49%
2/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Acetabulum fracture
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Injury, poisoning and procedural complications
Alcohol poisoning
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Injury, poisoning and procedural complications
Concussion
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Femoral neck fracture
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Fibula fracture
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Laceration
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Ligament sprain
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Lower limb fracture
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Pneumothorax traumatic
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Rib fracture
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Road traffic accident
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Thoracic vertebral fracture
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Tibia fracture
|
0.00%
0/407
|
0.49%
2/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Toxicity to various agents
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Injury, poisoning and procedural complications
Traumatic haemothorax
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Injury, poisoning and procedural complications
Upper limb fracture
|
0.49%
2/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Investigations
Arteriogram coronary
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Investigations
Hepatic enzyme increased
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Investigations
Transaminases increased
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
0.49%
2/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Metabolism and nutrition disorders
Malnutrition
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Metabolism and nutrition disorders
Type 2 diabetes mellitus
|
0.25%
1/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Musculoskeletal and connective tissue disorders
Synovitis
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenolipoma
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse large B-cell lymphoma
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cancer
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hypopharyngeal cancer
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma
|
0.00%
0/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant
|
0.25%
1/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant mediastinal neoplasm
|
0.00%
0/407
|
0.49%
2/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mantle cell lymphoma
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to lymph nodes
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic neoplasm
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
|
0.49%
2/407
|
0.49%
2/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Nervous system disorders
Carotid artery stenosis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Nervous system disorders
Cerebral haemorrhage
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Nervous system disorders
Cerebrovascular accident
|
0.25%
1/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Nervous system disorders
Optic neuritis
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Nervous system disorders
Radiculitis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Nervous system disorders
Syncope
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Nervous system disorders
Transient ischaemic attack
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Nervous system disorders
VIth nerve paresis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Nervous system disorders
Vertebrobasilar insufficiency
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Psychiatric disorders
Aggression
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Psychiatric disorders
Alcoholism
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Psychiatric disorders
Depression
|
0.00%
0/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Psychiatric disorders
Suicide attempt
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Renal and urinary disorders
Calculus ureteric
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Renal and urinary disorders
Renal failure acute
|
0.25%
1/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Renal and urinary disorders
Urinary retention
|
0.25%
1/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Respiratory, thoracic and mediastinal disorders
Bronchial disorder
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
4.9%
20/407
|
4.4%
18/405
|
5.7%
23/403
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Haemoptysis
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Hypoxia
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Respiratory, thoracic and mediastinal disorders
Nasal polyps
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
0.00%
0/407
|
0.74%
3/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax spontaneous
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory distress
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.74%
3/407
|
0.25%
1/405
|
0.25%
1/403
|
|
Skin and subcutaneous tissue disorders
Decubitus ulcer
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Surgical and medical procedures
Hip arthroplasty
|
0.00%
0/407
|
0.25%
1/405
|
0.00%
0/403
|
|
Vascular disorders
Aortic aneurysm
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Vascular disorders
Hypertension
|
0.74%
3/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Vascular disorders
Hypertensive crisis
|
0.25%
1/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Vascular disorders
Iliac artery occlusion
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Vascular disorders
Ischaemia
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
|
Vascular disorders
Jugular vein distension
|
0.25%
1/407
|
0.00%
0/405
|
0.00%
0/403
|
|
Vascular disorders
Peripheral artery thrombosis
|
0.00%
0/407
|
0.00%
0/405
|
0.25%
1/403
|
Other adverse events
| Measure |
QVA 149
n=407 participants at risk
110/50 µg capsules for inhalation, o.d
|
Tiotropium
n=405 participants at risk
18 μg capsules for inhalation, o.d
|
Placebo
n=403 participants at risk
To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
|
|---|---|---|---|
|
Infections and infestations
Influenza
|
1.7%
7/407
|
2.7%
11/405
|
4.5%
18/403
|
|
Infections and infestations
Lower respiratory tract infection
|
5.4%
22/407
|
3.5%
14/405
|
4.7%
19/403
|
|
Infections and infestations
Nasopharyngitis
|
8.1%
33/407
|
7.7%
31/405
|
6.5%
26/403
|
|
Infections and infestations
Respiratory tract infection viral
|
0.98%
4/407
|
2.7%
11/405
|
1.7%
7/403
|
|
Infections and infestations
Upper respiratory tract infection
|
4.4%
18/407
|
5.4%
22/405
|
4.5%
18/403
|
|
Infections and infestations
Upper respiratory tract infection bacterial
|
6.6%
27/407
|
6.9%
28/405
|
6.2%
25/403
|
|
Infections and infestations
Viral upper respiratory tract infection
|
4.7%
19/407
|
3.2%
13/405
|
4.2%
17/403
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
2.5%
10/407
|
1.5%
6/405
|
1.5%
6/403
|
|
Nervous system disorders
Headache
|
2.2%
9/407
|
3.2%
13/405
|
2.7%
11/403
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
66.1%
269/407
|
67.7%
274/405
|
71.2%
287/403
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
4.2%
17/407
|
5.2%
21/405
|
4.5%
18/403
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
2.0%
8/407
|
1.7%
7/405
|
3.0%
12/403
|
|
Vascular disorders
Hypertension
|
2.2%
9/407
|
2.5%
10/405
|
3.2%
13/403
|
Additional Information
Study Director
Novartis Pharmaceuticals
Results disclosure agreements
- Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
- Publication restrictions are in place
Restriction type: OTHER