Background Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β(2) agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0-4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV(1)) (23-24 h postdose; day 29) and wm FEV(1) (0-4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV(1) per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0-4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI -3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV(1) (mean difference 183 ml) and 0-4 h postdose wm FEV(1) (mean difference 236 ml). Conclusion FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov-NCT00731822.

Background Previous studies have shown a reduction in cough response to inhaled citric acid after blocking NK1, NK2 and also NK3 receptors in guinea pigs. NK3 receptor may be more relevant to study the role of tachykinins in cough due to their greater specificity for its agonist neurokinin B. We studied a specific NK3 receptor antagonist Talnetant to determine the effect on the human cough reflex sensitivity to citric acid in healthy individuals. Oral codeine and placebo were included as comparators. Methods Double-blind, randomised, placebo-controlled, 4-period cross-over study in non-smoking healthy adult volunteers. A total of 28 subjects (12M, 16F) with mean age of 33 years (SD 10.5, range 22–55) were studied. Each subject received A. matched placebos; B. Talnetant 200 mg; C.Talnetant 25 mg; D. Codeine 60 mg, in a double blind double dummy manner. Subjects were randomly assigned to one of four treatment sequences (ABCD, BCDA, DCAB, BDCA). Each study period was 24 h with citric-acid challenges performed at 2, 6, 10 and 24 h post dose and a 7 day washout period between treatments. Results There was no significant difference in logC5 Citric acid between Talnetant 25 mgs, 200 mgs and placebo at any time point (see Abstract S114 Figure 1). The ‘positive’ control codeine had a non-significant trend for improvement in logC5 compared to placebo (all confidence intervals contained unity). Talantent was adequately absorbed with sustained blood levels at time points designed to coincide with the cough challenges. Conclusions In healthy volunteers, Talnetant had no significant effect on cough reflex sensitivity to citric acid despite an adequately powered study and sufficient systemic drug exposure. Possible explanations for this lack of efficacy are (1) NK3 receptors do not play an appreciable role in the healthy human cough reflex or (2) the role of NK3 receptors may be limited to the central nervous system where Talnetant has limited penetrance and receptor occupancy. Whilst this study suggests predominantly peripherally acting NK3 receptor antagonists do not influence the cough reflex in healthy volunteers, a significant effect in patients with a hypersensitive cough reflex cannot be excluded and this class of drugs may yet prove to have anti-tussive properties, especially with improved central activity.