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Comparison of Safety and Efficacy of the Combination Product QVA149A Against the Concurrent Administration of the Individual Components, QAB149 and NVA237, in Patients With Chronic Obstructive Pulmonary Disease (COPD) (BEACON)

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ClinicalTrials.gov Identifier: NCT01529632
Recruitment Status : Completed
First Posted : February 9, 2012
Results First Posted : February 12, 2014
Last Update Posted : February 12, 2014
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease
Interventions Drug: QVA149
Drug: NVA237
Drug: QAB149
Drug: Placebo
Enrollment 193
Recruitment Details 193 patients were randomized, with 187 of those completing the study. A total of 6 patients discontinued from the study.
Pre-assignment Details Open-label, active QAB149 and NVA237 were administered during a 14-day period prior to randomization in order to stabilize patients and standardize baseline lung function. The patients were then randomized to either the fixed dose combination or free combination arms of blinded treatment in a 1:1 ratio and received study drug for 28 days.
Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description QVA149 plus placebo once daily for 28 days. Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Period Title: Overall Study
Started 90 103
Completed 87 100
Not Completed 3 3
Reason Not Completed
Administrative problem             2             1
Protocol Violation             0             1
Adverse Event             1             1
Arm/Group Title QVA149 QAB149 + NVA237 Total
Hide Arm/Group Description QVA149 plus placebo once daily for 28 days. Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days. Total of all reporting groups
Overall Number of Baseline Participants 90 103 193
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 90 participants 103 participants 193 participants
65.6  (7.28) 64.2  (7.40) 64.9  (7.36)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 103 participants 193 participants
Female
32
  35.6%
44
  42.7%
76
  39.4%
Male
58
  64.4%
59
  57.3%
117
  60.6%
1.Primary Outcome
Title Trough Forced Expiratory Volume in 1 Second (FEV1) After 28 Days of Blinded Treatment
Hide Description Spirometry was conducted according to internationally accepted standards. Trough FEV1 is defined as the average of the 23 hour 15 minute and 23 hour 45 minute post-dose FEV1 readings measured at day 29, after 28 days of treatment. Mixed model: Trough FEV1 = treatment + baseline FEV1 + FEV1 reversibility components + baseline smoking status + baseline ICS use + country + center (country) + error. Center was included as a random effect nested within country.
Time Frame Day 29
Hide Outcome Measure Data
Hide Analysis Population Description

The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion.

Patients were analyzed according to the treatment to which they were randomized.

Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 81 96
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.459  (0.0196) 1.465  (0.0180)
2.Secondary Outcome
Title Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 0-4 Hours at Day 1
Hide Description Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 0-4h at Day 1 was measured via spirometry conducted according to internationally accepted standards. Measurements were made at 0, 5, 15, and 30 minutes; and 1, 2, 3 and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. Mixed model used: AUC FEV1 = treatment + baseline FEV1 + FEV1 reversibility components + baseline smoking status + baseline ICS use + country + center (country) + error. Center was included as a random effect nested within country.
Time Frame 0, 5, 15, and 30 minutes; and 1, 2, 3 and 4 hours post-dose at Day 1
Hide Outcome Measure Data
Hide Analysis Population Description

The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion.

Patients were analyzed according to the treatment to which they were randomized.

Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 83 97
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.597  (0.0125) 1.573  (0.0114)
3.Secondary Outcome
Title Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 0-4 Hours at Day 28
Hide Description Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) 0-4h at Day 28 was measured via spirometry conducted according to internationally accepted standards. Measurements were made at 0, 5, 15, and 30 minutes; and 1, 2, 3 and 4 hours post-dose. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. Mixed model used: AUC FEV1 = treatment + baseline FEV1 + FEV1 reversibility components + baseline smoking status + baseline ICS use + country + center (country) + error. Center was included as a random effect nested within country.
Time Frame 0, 5, 15, and 30 minutes; and 1, 2, 3 and 4 hours post-dose at Day 28
Hide Outcome Measure Data
Hide Analysis Population Description

The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion.

Patients were analyzed according to the treatment to which they were randomized.

Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 80 92
Least Squares Mean (Standard Error)
Unit of Measure: Liters
1.575  (0.0200) 1.587  (0.0184)
4.Secondary Outcome
Title Peak Forced Expiratory Volume in 1 Second (FEV1) on Days 1 and 28 Post-dose
Hide Description Spirometry was conducted according to internationally accepted standards. Peak FEV1 is the maximum FEV1 recorded in the period between 5 minutes and 4 hours post dose. Analysis of Covariance was carried out with a mixed model that used (period) baseline, defined as the value of FEV1 measured prior to the first study drug intake in the period, as a covariate.
Time Frame 5 min - 4 hr at Days 1 and 28
Hide Outcome Measure Data
Hide Analysis Population Description

The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion.

Patients were analyzed according to the treatment to which they were randomized.

Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 83 97
Least Squares Mean (Standard Error)
Unit of Measure: Liters
Day 1 (n=83, 97) 1.668  (0.0132) 1.646  (0.0120)
Day 28 (n= 80, 92) 1.643  (0.0210) 1.654  (0.0194)
5.Secondary Outcome
Title Time Course of Forced Expiratory Volume in One Second (FEV1) (Pre-dose to 4 Hours Post Dose) on Day 28
Hide Description Time course of Forced Expiratory Volume in 1 second (FEV1) was measured at -45 min, -15 min predose, 5 min, 30 min, 1 hr, 2hr, 3hr and 4 hr post-dose on Day 28. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Time Frame -45 min, -15 min predose, 5 min, 30 min, 1 hr, 2hr, 3hr and 4 hr post-dose on Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion. Patients were analyzed according to the treatment to which they were randomized.
Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 78 91
Least Squares Mean (Standard Error)
Unit of Measure: Liters
-45 min predose (n=76,90) 1.452  (0.0197) 1.460  (0.0184)
-15 predose (n=72,87) 1.449  (0.0239) 1.430  (0.0227)
5 min postdose (n=76,89) 1.491  (0.0222) 1.514  (0.0206)
30 min postdose (n=76,88) 1.529  (0.0181) 1.544  (0.0166)
1 hour postdose (n=77,90) 1.584  (0.0204) 1.604  (0.0189)
2 hours postdose (n=77,90) 1.601  (0.0219) 1.624  (0.0203)
3 hours postdose (n=78,91) 1.576  (0.0211) 1.587  (0.0195)
4 hours postdose (n=77,84) 1.554  (0.0236) 1.556  (0.0228)
6.Secondary Outcome
Title Change From Baseline in the Mean Daily, (Daytime and Nighttime Combined) Number of Puffs of Rescue Medication Used Over 28 Days of Treatment
Hide Description The number of puffs of rescue medication taken in the previous 12 hours was recorded in the Patient Diary in the morning and evening. The total number of puffs of rescue medication per day over the whole active treatment period was calculated and divided by the total number of days with non-missing rescue data to derive the mean daily number of puffs of rescue medication taken for the patient. If the number of puffs was missing for part of the day (either morning or evening) then a half day was used in the denominator.
Time Frame Baseline and 28 days
Hide Outcome Measure Data
Hide Analysis Population Description

The Per Protocol Set includes the Full analysis Set patients with available data and without any major protocol deviations or criteria causing exclusion.

Patients were analyzed according to the treatment to which they were randomized.

Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 84 95
Mean (Standard Deviation)
Unit of Measure: puffs
Baseline (day 1) 2.24  (2.437) 2.04  (2.585)
28 days after treatment 1.85  (2.283) 1.70  (2.338)
7.Secondary Outcome
Title Change From Baseline in Percentage of Days With 'no Daytime Symptoms' Over 28 Days of Treatment
Hide Description The mean total symptom scores and mean individual symptom scores for the patient were calculated for the whole study period. The mean change from baseline in the total scores and in the individual scores were summarized by treatment and were analyzed for the percentage of 'nights with no nighttime awakenings'. The symptom variables for the whole active treatment period was analyzed using the similar MIXED model as for the primary endpoint, with the baseline FEV1 term being replaced by the respective baseline symptom variables.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
The Modified per protocol set (PPS) was defined post-DBL and included all patients with available data and without any major protocol deviations or criteria or GCP finding causing exclusion. Patients were analyzed according to the treatment to which they were randomized.
Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description:
QVA149 plus placebo once daily for 28 days.
Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
Overall Number of Participants Analyzed 82 93
Mean (Standard Deviation)
Unit of Measure: percentage of days
Baseline (day 1) 6.2  (16.54) 3.9  (10.44)
After 28 days of treatment 9.3  (23.69) 6.0  (15.85)
Time Frame From day 1 to day 28 and additional 30 days follow up.
Adverse Event Reporting Description Safety Set included all patients who received at least one dose of study drug whether or not they were randomized.
 
Arm/Group Title QVA149 QAB149 + NVA237
Hide Arm/Group Description QVA149 plus placebo once daily for 28 days. Indacaterol (QAB149) plus glycopyrronium bromide (NVA237) once daily for 28 days.
All-Cause Mortality
QVA149 QAB149 + NVA237
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
QVA149 QAB149 + NVA237
Affected / at Risk (%) Affected / at Risk (%)
Total   4/90 (4.44%)   6/103 (5.83%) 
Cardiac disorders     
Pericarditis  1  0/90 (0.00%)  1/103 (0.97%) 
Infections and infestations     
Pneumonia  1  2/90 (2.22%)  0/103 (0.00%) 
Pyelonephritis  1  0/90 (0.00%)  1/103 (0.97%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bronchial carcinoma  1  0/90 (0.00%)  2/103 (1.94%) 
Sarcoma  1  0/90 (0.00%)  1/103 (0.97%) 
Renal and urinary disorders     
Nephrolithiasis  1  0/90 (0.00%)  1/103 (0.97%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/90 (1.11%)  0/103 (0.00%) 
Pneumothorax  1  1/90 (1.11%)  0/103 (0.00%) 
Vascular disorders     
Aortic aneurysm  1  1/90 (1.11%)  0/103 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
QVA149 QAB149 + NVA237
Affected / at Risk (%) Affected / at Risk (%)
Total   20/90 (22.22%)   12/103 (11.65%) 
Gastrointestinal disorders     
Diarrhoea  1  1/90 (1.11%)  1/103 (0.97%) 
Oedema mouth  1  1/90 (1.11%)  0/103 (0.00%) 
Oral pain  1  1/90 (1.11%)  0/103 (0.00%) 
General disorders     
Chest discomfort  1  2/90 (2.22%)  0/103 (0.00%) 
Infections and infestations     
Influenza  1  2/90 (2.22%)  1/103 (0.97%) 
Nasopharyngitis  1  7/90 (7.78%)  6/103 (5.83%) 
Injury, poisoning and procedural complications     
Ligament injury  1  1/90 (1.11%)  0/103 (0.00%) 
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  1/90 (1.11%)  0/103 (0.00%) 
Myalgia  1  2/90 (2.22%)  0/103 (0.00%) 
Nervous system disorders     
Headache  1  1/90 (1.11%)  1/103 (0.97%) 
Neuropathy peripheral  1  1/90 (1.11%)  0/103 (0.00%) 
Somnolence  1  1/90 (1.11%)  0/103 (0.00%) 
Psychiatric disorders     
Depression  1  1/90 (1.11%)  0/103 (0.00%) 
Reproductive system and breast disorders     
Breast pain  1  1/90 (1.11%)  0/103 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  3/90 (3.33%)  2/103 (1.94%) 
Cough  1  4/90 (4.44%)  2/103 (1.94%) 
Dysphonia  1  1/90 (1.11%)  1/103 (0.97%) 
Dyspnoea  1  1/90 (1.11%)  2/103 (1.94%) 
Oropharyngeal pain  1  1/90 (1.11%)  1/103 (0.97%) 
Pharyngeal oedema  1  1/90 (1.11%)  0/103 (0.00%) 
Rhinorrhoea  1  1/90 (1.11%)  0/103 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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 pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01529632     History of Changes
Other Study ID Numbers: CQVA149A2326
2011-006050-91 ( EudraCT Number )
First Submitted: February 6, 2012
First Posted: February 9, 2012
Results First Submitted: December 2, 2013
Results First Posted: February 12, 2014
Last Update Posted: February 12, 2014