A randomized controlled trial of glycopyrrolate administered by metered dose inhaler in patients with uncontrolled asthma despite ICS/LABA treatment

Abstract

Objective: To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting β 2 -agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy. Method: This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 µg, 18 µg, 9 µg, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 µg. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV 1 ) area under the curve from 0 − 4 h (AUC 0 − 4 ) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed. Results: The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV 1 AUC 0 − 4 at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 µg, GP MDI 18 µg, GP MDI 9 µg, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV 1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments. Conclusion: Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV 1 were used in the analyses.

Optimizing asthma management: Role of long-acting muscarinic antagonists

“…A subgroup of patients received open-label TioR (2.5 mg once daily) as an add-on to ICS plus LABA. 48 The primary end point of change from baseline in FEV 1 area under the curve from 0 to 4 hours at week 24 was nominally significant in the 9-mg glycopyrronium group versus the placebo group and the open-label tiotropium group. A post hoc analysis identified a dose-related response to glycopyrronium when alternative definitions of baseline FEV 1 (using postbronchodilator FEV 1 and taking the mean of prebronchodilator FEV 1 from visits 3 and 4) were used in the analysis.…”

“…75 Furthermore, if neuronal plasticity is considered to be a treatable trait, it may be warranted to consider triple therapy earlier than currently recommended by the GINA report; however, this therapeutic approach must be confirmed in appropriately statistically powered clinical trials. 76 In clinical trials in patients with inadequately controlled asthma with ICS plus LABA (see Table E4 in this article's Online Repository at www.jacionline.org), 42,[46][47][48] the addition of a LAMA resulted in a significant improvement in peak FEV 1 42 and trough FEV 1 , 42,47 ACQ-7 score, 42 and in-clinic trough PEF rate, 47 increased the time to first severe exacerbation, 42 and provided modest sustained bronchodilation. 42 A post hoc analysis of 2 of these studies 42 showed that compared with placebo the efficacy of add-on TioR to ICS plus LABA is independent of baseline characteristics, including age, sex, body mass index, disease duration, age at asthma onset, smoking status, allergic status, and FEV 1 reversibility.…”

“…A total of 25 studies were included for assessing the efficacy and safety of LAMAs as an add-on therapy to ICS and LABA, and 22 were included on the basis of the number of patients and quality of studies. Among these studies, there were 3 systematic reviews [34][35][36] ; 11 double-blind, phase III, randomized controlled trials (n 5 114-620 in the LAMA arm) [37][38][39][40][41][42][43][44][45][46][47] ; 6 phase II/ III randomized controlled trials (n 5 94-240 in the LAMA arm) [48][49][50][51][52][53] ; 1 open-label, parallel-group, pragmatic, randomized controlled trial (n 5 532 in the LAMA arm) 54 ; and 1 real-world retrospective cohort study (n 5 2619 in the LAMA arm) 55 (Table I). For a complete summary of studies reviewed in the preparation of this article, please see this article's Online Repository at www.jacionline.org.…”

“…A post hoc analysis identified a dose-related response to glycopyrronium when alternative definitions of baseline FEV 1 (using postbronchodilator FEV 1 and taking the mean of prebronchodilator FEV 1 from visits 3 and 4) were used in the analysis. 48 According to a systematic review, add-on tiotropium may also reduce the need for rescue OCS in patients with severe asthma who are inadequately controlled with ICS plus LABA. 37 A realworld evidence study in the United Kingdom that enrolled 2042 adult patients with asthma who were prescribed tiotropium from 2001 to 2013 revealed that tiotropium was prescribed by primary care physicians mostly as an add-on therapy in older patients (62% of the study population was aged >60 years) with poorly controlled asthma despite good treatment adherence to ICS with or without LABA, particularly in those who were current or former smokers (>50% of the study population).…”