24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD.

BACKGROUND: Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 µg delivered using innovative co-suspension delivery technology) administered twice daily. METHODS: Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks' treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0-24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity. RESULTS: GFF MDI treatment significantly increased FEV1AUC0-24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0-12 and 12-24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12-24 compared to 0-12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (-0.84 [p<0.0001] and -1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (-0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings. CONCLUSIONS: GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI. TRIAL REGISTRATION: Pearl Therapeutics, Inc.; www.clinicaltrials.gov ; NCT02347072 and NCT02347085 . Registered 21 January 2015.

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD.

BACKGROUND: Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. METHODS: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 µg, FF MDI 9.6 µg, or placebo MDI (all twice daily), or tiotropium 18 µg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. RESULTS: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). CONCLUSIONS: We conclude that GFF MDI 18/9.6 µg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD.

BACKGROUND: This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination formulated using novel Co-Suspension™ Delivery Technology and delivered via a metered dose inhaler (GFF MDI). The study aimed to confirm the optimal dose of GP to formulate with FF 9.6 µg in the fixed-dose combination product, GFF MDI. METHODS: This multicenter, randomized, double-blind, chronic-dosing, balanced incomplete block, crossover study (NCT01587079) compared five doses of GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6 and 1.2/9.6 µg, twice daily [BID]) with its monocomponents FF MDI 9.6 µg and GP MDI 18 µg (both BID) and open-label tiotropium (18 µg once daily) as the active control. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 7. RESULTS: In total, 159 patients were randomized to treatment and 132 patients (52.2% male, mean age 62.8 years) were included in the intent-to-treat population. All doses of GFF MDI (except 1.2/9.6 µg) resulted in statistically significant improvements in FEV1 AUC0-12 versus monocomponents and open-label tiotropium. GFF MDI 18/9.6 µg consistently showing the greatest improvement over monocomponents and open-label tiotropium. Adverse events for each GFF MDI dose were similar versus GP MDI 18 µg, FF MDI 9.6 µg and open-label tiotropium. CONCLUSIONS: These findings further support selection of GP 18 µg as the optimal dose to combine with FF MDI 9.6 µg for advancement into Phase III clinical trials of GFF MDI.