Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease
|Pulmonary Disease, Chronic Obstructive||Drug: fluticasone furoate/vilanterol Drug: fluticasone furoate Drug: vilanterol Other: Placebo||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Clinical Outcomes Study to Compare the Effect of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25mcg With Placebo on Survival in Subjects With Moderate Chronic Obstructive Pulmonary Disease (COPD) and a History of or at Increased Risk for Cardiovascular Disease|
- Number of Participants With Death (Both on and Off Treatment) Due to Any Cause, Time up to or on the Pre-determined Common End Date [ Time Frame: From the date of randomization until date of death due to any cause (average of 2 study years) ]Death from any cause: which occurred from the day of starting IP until the Commone End Date (CED). Common End Date (CED) is the study end date that was pre determined where approximately 1000 deaths would have occurred in the Intent-toTreat Efficacy (ITT-E) Population. Only deaths which occurred on or before the CED were used for the primary analysis. Those who had not died by CED, but who were known to be alive on or after the CED, were censored at the CED. Cox Proportional Hazards (PH) Model was adjusted for age, and gender, including all 4 arms. A hazard ratio of less than 1 indicates a lower death rate versus placebo or other arm. ITT-E Population consisted of all participants in the Safety Population (i.e. randomized to IP and who received at least one dose of IP), with the exception of those recruited at sites that were closed.
- Decline in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: From start date of IP until IP stop date + 1 (assessed up to 4 years) ]FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The effect of treatment on decline of post bronchodilator FEV1 recorded during the treatment period was analyzed using a particular form of a mixed effect model - a random coefficients model. FEV1 was fitted as the response variable with treatment group, age, gender, baseline FEV1 and time on treatment as fixed effects. Time on treatment was treated as a continuous variable. This model allowed for an initial increase in FEV1, but then tested the difference in slopes from the first post-baseline measurement which was at 3 months. A negative slope indicates a decline. A positive treatment difference indicates a slower rate of decline vs Placebo or Component. Only participants with at least one on-treatment post-bronchodilator FEV1 measurement were analyzed.
- Number of Participants With First On-treatment Cardiovascular (CV) Composite Events Occured on or Before Common End Date [ Time Frame: From the start of IP to first on treatment CV event till 7 days after the last dose of IP (average of 2 study years) ]On-treatment CV composite event is comprised of the first event that is adjudicated as on-treatment CV death, myocardial infarction, stroke, unstable angina, or transient ischemic attack experienced by a participant. The events that occurred no more than 7 days after the participants last dose of IP are considered as on-treatment adverse events. Common end date is the study end date where approximately 1000 deaths would have occurred in the ITT-E Population. Cox PH Model was used to assess time to first on-treatment CV composite event. Cox PH Model was adjusted for age, gender and indicators of ischemic and vascular disease, including all four treatment arms. A hazard ratio less than 1 indicates a lower risk of a first CV event rate versus placebo or any arm.
|Actual Study Start Date:||January 25, 2011|
|Study Completion Date:||July 15, 2015|
|Primary Completion Date:||July 15, 2015 (Final data collection date for primary outcome measure)|
Experimental: fluticasone furoate/vilanterol
Combination of both products in one inhaler
Drug: fluticasone furoate/vilanterol
100/25mcg given once daily via novel dry powder inhaler
Experimental: fluticasone furoate
comparator of individual component
Drug: fluticasone furoate
100mcg given once daily via novel dry powder inhaler
comparator of individual component
25mcg given once daily via novel dry powder inhaler
Placebo Comparator: placebo
once daily via inhaler
placebo comparator once daily via novel dry powder inhaler
Despite a potential link between the pathogenetic mechanisms involved in Chronic Obstructive Pulmonary Disease (COPD) and atherosclerotic cardiovascular disease, there are no currently approved therapies for patients with COPD that have clearly shown an additional beneficial effect in patients with cardiovascular comorbidities. The TOwards a Revolution in COPD Health (TORCH) study assessed the impact of the inhaled corticosteroid (ICS) fluticasone propionate (FP) in combination with the long-acting beta agonist (LABA), salmeterol (SAL), in reducing all-cause mortality. TORCH demonstrated a 17.5% reduction on all-cause mortality with salmeterol-fluticasone propionate combination (SFC) compared with placebo (HR=0.825, 95% CI (0.681, 1.002), p=0.052) in the entire COPD population with disease severity form moderate to very severe. A post hoc analysis of the data restricted to those subjects with an forced expiratory volume in 1 second (FEV1) >=50% predicted with an apparent history of cardiovascular co-morbidities (defined as use at baseline of beta-blockers, angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), HMG CoA reductase inhibitors (i.e. statins) or a prior MI recorded at baseline) demonstrated a 49% reduction in the risk of dying within 96 weeks for the comparison of SFC with placebo. These post hoc data suggest the possibility of an ICS/LABA combination product to be of substantial benefit in COPD subjects with less severe airflow obstruction yet with increased cardiovascular risk.
The mechanism by which SFC appears to be associated with a greater reduction in mortality in these less severe COPD subjects with concomitant cardiovascular comorbidities is speculative at present, but could potentially in part be related to a lessening of the degree of inflammation in the systemic circulation, potential plaque stabilization and/or amelioration of arterial stiffness.
ICS/LABA combinations that are currently available require twice daily administration. A once daily ICS/LABA combination has the potential to improve patient compliance and as a result, overall disease management.
The purpose of this study is to prospectively evaluate the effect of the once daily ICS/LABA combination Fluticasone Furoate (FF)/Vilanterol (VI) on survival in subjects with moderate COPD (>=50 and =<70 % predicted FEV1 ) and a history of, or at increased risk for cardiovascular disease.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01313676
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|Study Director:||GSK Clinical Trials||GlaxoSmithKline|