GlaxoSmithKline plc and Theravance, Inc., announced initial results from the Study to Understand Mortality and MorbidITy in COPD (SUMMIT) for Relvar/Breo Ellipta 100/25mcg (fluticasone furoate ‘FF’/vilanterol ‘VI’ or ‘FF/VI’).

The study involved 16,485 patients from 43 countries who had chronic obstructive pulmonary disease (COPD) with moderate airflow limitation (FEV1 50-70 per cent predicted) and either a history or increased risk of cardiovascular disease (CVD).

For the primary endpoint of the study, the risk of dying on FF/VI 100/25mcg was 12.2 per cent lower than on placebo over the study period, which was not statistically significant (p=0.137).

For the first of two secondary endpoints, FF/VI 100/25mcg reduced the rate of lung function decline (as measured by forced expiratory volume in one second, ‘FEV1’) by 8mL per year compared with placebo (p=0.019). As the primary endpoint was not met, statistical significance cannot be inferred from this result. For the other secondary endpoint, the risk of experiencing an on-treatment cardiovascular (CV) event (CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack [TIA]) at any time was 7.4 per cent lower in patients taking FF/VI 100/25mcg versus placebo which was not statistically significant (p=0.475).

The study also formally analysed a number of additional COPD endpoints assessing the efficacy of FF/VI relative to placebo, which included FEV1 (post-bronchodilator), rate of moderate/severe exacerbations, time to first moderate/severe exacerbation, time to first severe (hospitalised) exacerbation, rate of severe (hospitalised) exacerbation, health related quality of life (as measured by the St George’s Respiratory Questionnaire-COPD total score at 12 months) and health status as measured using the COPD Assessment Tool (CAT) at 12 months. Against these endpoints FF/VI demonstrated an improvement compared to placebo with a nominal P-value of <0.002 for each. As the primary endpoint was not met, statistical significance cannot be inferred from these results.

The most frequently reported adverse events (greater than or equal to 3 per cent in FF/VI 100/25mcg and greater than placebo) were nasopharyngitis (FF/VI 100/25mcg 8.9 per cent, placebo 7.5 per cent), upper respiratory tract infection (FF/VI 100/25mcg 6.3 per cent, placebo 4.8 per cent), pneumonia (FF/VI 100/25mcg 5.0 per cent, placebo 4.6 per cent), back pain (FF/VI 100/25mcg 4.3 per cent, placebo 3.5 per cent), hypertension (FF/VI 100/25mcg 3.9 per cent, placebo 3.3 per cent) and influenza (FF/VI 100/25mcg 3.4 per cent, placebo 2.9 per cent.

The incidence of on-treatment serious adverse events (SAEs) were 23.2 per cent on FF/VI 100/25mcg and 22.2 per cent on placebo. Adverse events of special interest included all related terms for CV adverse events and pneumonia. The incidence of CV adverse events was 17.8 per cent on FF/VI 100/25mcg, 16.8 per cent on placebo and serious CV adverse events was 8.5 per cent on FF/VI100/25mcg, 7.7 per cent on placebo. The incidence of pneumonia was 5.7 per cent on FF/VI 100/25mcg and 5.2 per cent  on placebo and the incidence of serious pneumonia was 3.4 per cent on FF/VI 100/25mcg and 3.1 per cent on placebo.

The results will be the subject of future publications and presentations, including at the European Respiratory Society (ERS) International Congress in September.

Eric Dube, SVP and head, Global Respiratory Franchise, GSK said, “SUMMIT is an important study as this is the first time that survival has been studied in this under-researched co-morbid patient population. While we didn’t achieve statistical significance on the primary endpoint, we believe the full data set will be beneficial and informative to the respiratory and cardiovascular scientific community. Relvar/Breo 100/25mcg continues to play an important role in the treatment of appropriate patients with COPD and as leaders in respiratory, GSK remains committed to tackling the major challenges that physicians and patients face in the treatment of respiratory disease.”

Lead investigator, Jørgen Vestbo, professor of respiratory medicine at the Centre for Respiratory Medicine and Allergy, University Hospital South Manchester NHS Foundation Trust and the University of Manchester, said, “We have long known that CVD often coexists with COPD and that each disease is a leading cause of death globally. The SUMMIT study is the first prospective study to investigate the interaction between these two diseases and set out to achieve the ambitious goal of demonstrating a reduction in death from any cause in patients with both COPD and CVD. While the study was unable to demonstrate a statistically significant improvement on this endpoint, it provides us with a wealth of data to help us as clinicians understand the interplay between these two conditions and insights on how to improve the management of these patients.”

Michael W. Aguiar, president and chief executive officer of Theravance, Inc., said, "While we were unable to demonstrate a statistically significant survival benefit in this population, the full data set from SUMMIT, the largest study with Relvar/Breo conducted to date, provides additional confidence in the safety and efficacy of Relvar/Breo 100/25mcg as a once-a-day treatment to improve lung function and reduce exacerbation risk in patients with COPD.”

The Study to Understand Mortality and MorbidITy (SUMMIT) in COPD is the first prospective study that aims to understand the effect of respiratory treatments in patients with COPD and a history or risk of CVD.

It is a placebo-controlled, double-blind, randomised, parallel group, multi-centre trial. COPD patients with moderate airflow limitation (>50 and <70 per cent predicted FEV1) and a history or risk of CVD were randomised 1:1:1:1 to one of four double-blind treatment groups: FF/VI 100/25mcg, FF 100mcg, VI 25mcg or placebo. All treatments were administered once daily via the Ellipta dry powder inhaler. All comparisons for the primary, secondary and other endpoints were performed at the two-sided 5 per cent level of significance.

In all arms of the study, patients were permitted to use study-supplied albuterol/salbutamol (short-acting beta-2 agonists, ‘SABA’). If subjects experienced multiple moderate COPD exacerbations or a severe COPD exacerbation during the study, a long-acting muscarinic antagonist (LAMA) or PDE IV inhibitor was permitted. Oral corticosteroids and antibiotics were also permitted for the short-term treatment of COPD exacerbations during the study. Patients were able to continue taking cardiovascular medications throughout the duration of the study. Use of any inhaled corticosteroid (ICS) or long-acting beta-2 agonist (LABA) while on double-blind treatment was not permitted.

The primary endpoint was time to death from any cause, to evaluate the effect of FF/VI 100/25mcg on survival compared with placebo. The secondary endpoints were: the effect of FF/VI 100/25mcg compared with placebo on the rate of decline in lung function, as measured by FEV1. This is the amount of air you can forcefully blow out of your lungs in one second and is used as a measure of disease progression that is associated with mortality and the effect of FF/VI 100/25mcg compared with placebo on a CV composite endpoint comprised of on-treatment CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack (TIA).

COPD is a disease of the lungs that includes chronic bronchitis, emphysema or both. COPD is characterised by obstruction to airflow that interferes with normal breathing. Cigarette smoke, breathing in second-hand smoke, air pollution including biomass fuels, chemical fumes and dust from the environment or workplace can all contribute to COPD.

COPD mortality is increasing and is the third leading cause of death globally. COPD often coexists with other chronic diseases and epidemiological data suggests that CVD or CV risk occurs in nearly half of all patients with COPD. CVD is the number one killer of mild to moderate COPD patients and patients with both COPD and CVD or CV risk were observed to have a mortality rate double that of COPD patients without CVD in studies of up to 15 years in duration.

FF/VI 100/25mcg, under the brand name Breo Ellipta 100/25mcg is licensed in the US for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with a history of exacerbations. Breo Ellipta 100/25mcg is the only strength indicated for the treatment of COPD.

Breo Ellipta100/25mcg is not indicated for the relief of acute bronchospasm.

FF/VI 100/25mcg, under the brand name Relvar Ellipta is approved in Europe for the symptomatic treatment of adults with COPD with a FEV1<70 per cent predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy.