A 28-day, randomized, double-blind, placebo-controlled, parallel group study of nebulized revefenacin in patients with chronic obstructive pulmonary disease

Abstract

Background: Revefenacin is a once-daily long-acting muscarinic antagonist (LAMA) in clinical development for the treatment of patients with chronic obstructive pulmonary disease (COPD). In a dose-ranging study, nebulized once-daily revefenacin had a long duration of action in patients after 7 days' administration of doses up to 700 μg. In this multiple-dose study, the bronchodilation efficacy and adverse events profile were characterized in patients administered nebulized revefenacin once daily for 28 days.

Methods: A total of 355 COPD patients (mean age 62 years, mean forced expiratory volume in 1 s [FEV1] 44% of predicted) were randomized in a double-blind, placebo-controlled parallel group study. Inhaled corticosteroids as well as short-acting bronchodilators were permitted. Once-daily treatments (44, 88, 175 or 350 μg revefenacin or matching placebo) were administered by a standard jet nebulizer, for 28 days. The primary endpoint was change from baseline in D28 trough FEV1, and secondary endpoints included weighted mean FEV1 over 0 to 24 h and rescue medication (albuterol) use. Safety evaluations included adverse events, laboratory assessments, electrocardiograms and 24-h Holter profiles.

Results: Revefenacin (88, 175 and 350 μg) significantly improved D28 trough FEV1 over placebo (187.4, 166.6 and 170.6 mL, respectively, all p < 0.001); 44 μg produced a sub-therapeutic response. At doses ≥88 μg, more than 80% of patients achieved at least a 100-mL increase from baseline FEV1 in the first 4 h post dose compared with 33% of placebo patients. For doses ≥88 μg, D28 24 h weighted mean differences from placebo for FEV1 were numerically similar to respective trough FEV1 values, indicating bronchodilation was sustained for 24 h post dose. Doses ≥88 μg reduced the average number of albuterol puffs/day by more than one puff/day. The 350 μg dose did not demonstrate additional efficacy over that observed with 175 μg revefenacin. Revefenacin was generally well tolerated, with minimal reports of systemic anti-cholinergic effects.

Conclusions: These data suggest that 88 and 175 μg revefenacin are appropriate doses for use in longer-term safety and efficacy trials. Revefenacin offers the potential for the first once-daily LAMA for nebulization in patients with COPD who require or prefer a nebulized drug delivery option.

Trial registration: ClinicalTrials.gov NCT02040792 . Registered January 16, 2014.

Conflict of interest statement

Ethics approval and consent to participate

The protocol and all amendments were approved by local review boards, ethics committees and health authorities at each of the 41 study centers. All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

KP has no disclosures. CB, EM and BH are employees of the Theravance Biopharma group of companies. EK is a consultant for Amphastar, Astra Zeneca, Forest, Mylan, Novartis, Sunovion, Teva and Theravance Biopharma.

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Figures

Fig. 1

Patient disposition (ITT population). aOne patient, identified as participating in another clinical study during this study, was removed from all efficacy analyses (n = 354) but retained in all safety analyses (n = 355). bOne patient receiving revefenacin 350 μg was withdrawn from the study by the investigator on D6 due to a non-treatment–emergent prolonged QTcF (>500 msc) during the screening electrocardiogram. The subject is included in both the ITT and safety populations though the prolonged QTcF adverse event is not contained in the treatment-emergent AE summaries. Abbreviations: AE: adverse event; ITT: intent to treat; QTcF: Fridericia formula for QT interval correction

Fig. 2

Change from baseline in trough FEV1. a D28a trough FEV1 and b trough FEV1 on D1, D15, D16 and D28. Data presented as LS mean ± SE. *p < 0.001 versus placebo. Abbreviations: FEV1: forced expiratory volume in 1 s; LS: least squares; Rev.: revefenacin; SE: standard error. aD28 trough FEV1 measured on D29

Fig. 3

Change from baseline in serial FEV1 on Day 1 (a) and Day 28 (b). Data presented as LS mean ± SE. Abbreviations: FEV1: forced expiratory volume in 1 s; h: hours; LS: least squares, Rev.: revefenacin; SE: standard error

Fig. 4

Effect of revefenacin on rescue medication use. a albuterol puffs per day; data presented as LS mean ± SE. b percent of albuterol-free 24-h periods over the entire treatment period; data presented as LS mean difference from placebo ± SE. *p < 0.05; **p < 0.005. Abbreviations: LS: least squares; SE: standard error

Fig. 5

Effect of revefenacin on daily peak expiratory flow rate. a morning PEF (representative of the trough PEF of the prior day’s dosing). b evening PEF, assessed ≈12 h after daily study medication dosing. Data presented as placebo-adjusted LS mean; dotted line (·········) = zero L/min; dashed line (−·­·­·­·­) represents LS mean placebo–adjusted increases in AM and PM PEF for revefenacin doses ≥88 μg, which were similar across the treatment period and centered at approximately 27 L/min and 29 L/min, respectively. Abbreviations: LS: least squares; PEFR: peak expiratory flow rate