BackgroundLong-acting muscarinic antagonist/long-acting β2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI).MethodsThis was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD (NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety.ResultsGFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV1 AUC0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated.ConclusionsGFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD.Trial registrationClinicalTrials.gov NCT01085045. Registered 9 March 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0491-8) contains supplementary material, which is available to authorized users.
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.
Rationale:In developing an alternative formulation of formoterol fumarate (FF), systemic exposure from the new product must be similar to an approved formulation and maintain a similar pharmacodynamic (PD) response. In order to evaluate dose-response, and assure assay sensitivity, doses higher than the approved product should be administered to demonstrate superior PD response relative to the approved dose. Pearl has previously demonstrated bioequivalence between FF-MDI and Foradil® Aerolizer® (Foradil). Pearl conducted a single dose crossover study to compare FF-MDI to Foradil at the approved and higher doses. Methods: In a randomized, double-blind, six period, crossover study conducted in patients with moderate to severe COPD that were reversible to albuterol, 3 doses of FF-MDI (7.2, 9.6 and 19.2µg) were compared to placebo MDI, and Foradil (12 and 24 µg). Pharmacokinetic (PK) and PD assessments were conducted for 12 hours following each dose. The primary efficacy endpoint was FEV AUC relative to pre-dose 1 0-12 baseline at the start of each treatment day. Secondary endpoints included Peak FEV , morning trough FEV and safety assessments. Full 1 1 PK profiles were obtained throughout the 12â€'hour observation period. An ANOVA was used in the analyses of the ln-transformed PK parameters AUC , and C . The resulting mean estimates (Geometric Least-Squares Means, Geometric LSM) for each treatment were 0-12 max computed. Results: Fifty patients were randomized. All doses of FF-MDI and Foradil were superior to placebo for the primary endpoint (P<0.0001 for all comparisons). FF-MDI 7.2 µg and FF-MDI 9.6 µg were non-inferior to Foradil 12 µg. Foradil 24 µg was superior to Foradil 12 µg (mean difference = 52 mL) and FF-MDI 19.2 µg was superior to FF-MDI 9.6 µg (mean difference = 42 mL), demonstrating assay sensitivity across both formulations. Bioequivalence between FF-MDI 9.6 µg and Foradil 12 µg was demonstrated by the ratio of Geometric LSMs and 90% CI for AUC (0.98, 0.90-1.07, respectively), and for Cmax (0.96, 0.87-1.07, respectively). Similar PK results were observed for the 0-12 comparison between FF-MDI 19.2 µg and Foradil 24 µg. All products were safe and well tolerated with no substantial differences across formulations. Conclusion: This is the second study in which Pearl Therapeutics' formulation of FF-MDI 9.6 µg demonstrated bioequivalence and comparable efficacy and safety to Foradil® Aerolizer® 12 µg. In this study, assay sensitivity was achieved with comparable findings across the two higher doses.
Migraine is prevalent during pregnancy. Antimigraine medications such as dihydroergotamine (DHE) and triptans have been associated with adverse pregnancy outcomes in individual studies but lack of consensus remains. We compared the risk of prematurity, low birth weight (LBW), major congenital malformations (MCM), and spontaneous abortions (SA) associated with gestational use of DHE or triptans. Three cohort and one nested-case–control analyses were conducted within the Quebec Pregnancy Cohort to assess the risk of prematurity, LBW, MCM, and SA. Exposure was defined dichotomously as use of DHE or triptan during pregnancy. Generalized estimation equations were built to quantify the associations, adjusting for potential confounders. 233,900 eligible pregnancies were included in the analyses on prematurity, LBW, and MCM; 29,104 cases of SA were identified. Seventy-eight subjects (0.03%) were exposed to DHE and 526 (0.22%) to triptans. Adjusting for potential confounders, DHE and triptans were associated with increased risks of prematurity, LBW, MCM, and SA but not all estimates were statistically significant. DHE was associated with the risk of prematurity (aRR: 4.12, 95% CI 1.21–13.99); triptans were associated with the risk of SA (aOR: 1.63, 95% CI 1.34–1.98). After considering maternal migraine, all antimigraine specific medications increased the risk of some adverse pregnancy outcomes, but estimates were unstable.
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