Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies

Fernando J Martinez, Brian J Lipworth, Klaus F Rabe, David J Collier, Gary T Ferguson, Sanjay Sethi, Gregory J Feldman, Gerald O'Brien, Martin Jenkins, Colin Reisner, Fernando J Martinez, Brian J Lipworth, Klaus F Rabe, David J Collier, Gary T Ferguson, Sanjay Sethi, Gregory J Feldman, Gerald O'Brien, Martin Jenkins, Colin Reisner

Abstract

Background: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.

Methods: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.

Results: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.

Conclusions: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.

Trial registration: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).

Keywords: Chronic obstructive pulmonary disease; Clinically important deterioration; Exacerbations; Fixed-dose combination; Formoterol fumarate dihydrate; GFF MDI; Glycopyrronium; LAMA/LABA; Metered dose inhaler; Symptomatic.

Conflict of interest statement

FJM reports grants from AstraZeneca during the conduct of the study; personal fees and non-financial support from American College of Chest Physicians, AstraZeneca, Boehringer Ingelheim, Chiesi, Concert, Continuing Education, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl – a member of the AstraZeneca Group, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Roche, Sunovion, and Theravance; non-financial support from ProterixBio; personal fees from American Thoracic Society, Columbia University, Haymarket Communications, Integritas, inThought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, and Western Connecticut Health Network; and grants from National Institutes of Health, outside of the submitted work.

BJL is one of several co-investigators on an AstraZeneca-sponsored grant received by the University of Dundee to support genomic studies in COPD and an investigator-initiated grant from AstraZeneca. He has also received speaker fees and consulting fees from AstraZeneca; payment for consulting and speaking from Boehringer Ingelheim and Chiesi; grant support from Boehringer Ingelheim, Chiesi, Mylan, and Janssen; advisory board and speaker fees from Teva; and consulting fees from Cipla, Dr. Reddys, Genentech, Glenmark, Lupin, Novartis, Sandoz, and Sanofi.

KFR reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Pharmaceuticals, InterMune, Novartis, Sanofi, and Teva; and grants from Ministry of Education and Science, Germany, outside of the submitted work.

DJC is supported in part by the National Institute for Health Research (NIHR) Barts Biomedical Research Center and received a grant from Pearl – a member of the AstraZeneca group for normal recruitment of patients.

GTF reports grants, personal fees, and non-financial support from AstraZeneca during the conduct of the study; grants, personal fees, and non-financial support from AstraZeneca, Boehringer Ingelheim, Novartis, Pearl – a member of the AstraZeneca Group, and Sunovion; grants and personal fees from Theravance; and personal fees from Circassia, GlaxoSmithKline, Innoviva, Mylan, and Verona, outside of the submitted work.

SS reports grant support from AstraZeneca, GlaxoSmithKline, and Sanofi; and other support from Aradigm, AstraZeneca, Boehringer Ingelheim, Circassia, Gilead, GlaxoSmithKline, Nabriva Therapeutics, Novavax, Paratek, Pulmonx, Sunovion, and Theravance Biopharma.

GJF reports no conflict of interest in this work.

MJ and CR are employees of AstraZeneca and hold stock and/or stock options in the company. GO is a former employee of AstraZeneca and holds stock and/or stock options in the company.

Figures

Fig. 1
Fig. 1
PINNACLE-1, -2, and -4 study design. PINNACLE-1 also included an open-label tiotropium arm (not shown). FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; MDI, metered dose inhaler
Fig. 2
Fig. 2
Patient disposition (pooled PINNACLE population). Patients were excluded from the pooled population if they did not receive any study treatment or if they had overlapping treatment exposure from enrollment in more than one PINNACLE study (further details are provided in the Methods). FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler.
Fig. 3
Fig. 3
Lung function endpoints at week 24. Change from baseline in morning pre-dose trough FEV1 (a) and peak change from baseline in FEV1 within 2 h post-dose (b) (ITT population of the individual and pooled studies). Data are least squares mean treatment differences (95% confidence intervals) shown in mL. p < 0.0001 for all comparisons except for trough FEV1 in PINNACLE-2, GFF MDI versus GP MDI (p = 0.0003) and FF MDI (p = 0.0002). Data for PINNACLE-1, -2, and -4 studies have been published previously [7, 9]. FEV1, forced expiratory volume in 1 s; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler
Fig. 4
Fig. 4
Lung function endpoints over time. Change from baseline in morning pre-dose trough FEV1 (a) and peak change from baseline in FEV1 within 2 h post-dose (b) (pooled ITT population). Data are least squares mean ± standard error. FEV1, forced expiratory volume in 1 s; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; LSM, least squares mean; MDI, metered dose inhaler
Fig. 5
Fig. 5
Time to first moderate or severe COPD exacerbation in the pooled ITT population (a), exacerbation history population (b), and CAT ≥15 population (c). The exacerbation history population includes patients with ≥1 moderate or severe exacerbations in the previous year. CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler.
Fig. 6
Fig. 6
Time to first moderate or severe COPD exacerbation (a), time to treatment failure (b), and time to first CID (c) in the pooled ITT, exacerbation history, and CAT ≥15 populations. Data are hazard ratios (95% confidence intervals). *p < 0.05; **p < 0.01; ***p < 0.001; †p < 0.0001. The exacerbation history population includes patients with ≥1 moderate or severe exacerbations in the previous year. CAT, COPD assessment test; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; Exac., exacerbation; FF, formoterol fumarate; GFF, glycopyrrolate/formoterol fumarate; GP, glycopyrrolate; ITT, intent-to-treat; MDI, metered dose inhaler.

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