The bronchodilator effects of extrafine glycopyrronium added to combination treatment with beclometasone dipropionate plus formoterol in COPD: A randomised crossover study (the TRIDENT study).
This multicentre, double-blind, randomised, placebo-controlled, crossover study aimed to determine the dose-response of the long-acting muscarinic antagonist (LAMA) glycopyrronium bromide (GB) when added to beclometasone dipropionate plus formoterol fumarate (BDP/FF) in patients with COPD. Patients received extrafine GB 12.5, 25 or 50 μg twice daily (BID) or placebo for 7 days via pressurised metered dose inhaler (pMDI), and extrafine BDP/FF via pMDI throughout the study. The primary objective was to demonstrate superiority of GB plus BDP/FF versus BDP/FF in terms of FEV1 area under the curve from 0 to 12 h (AUC0-12h) on Day 7. Secondary endpoints included: FEV1 AUC0-12h on Day 1; peak FEV1 and FVC on Days 1 and 7; and trough (12 h post-dose) FEV1, FVC and inspiratory capacity (IC) on Days 1 and 7. Of 178 patients randomised (mean age 62.7 years, post-bronchodilator FEV1 48.9%), 172 (96.6%) completed. Mean FEV1 AUC0-12h on Day 7 was significantly higher (p < 0.001) for all GB doses plus BDP/FF compared to BDP/FF alone, with the difference for the 25 and 50 μg BID doses being clinically relevant (i.e., ≥100 mL). The results for the other spirometry endpoints were consistent with the primary endpoint. Adverse events were reported in 7.4, 5.7 and 8.0% of patients receiving GB 12.5, 25 and 50 μg BID, respectively, versus 11.0% of patients receiving BDP/FF alone. This study confirms the value of adding GB to BDP/FF to improve lung function in COPD patients. The dose of extrafine GB 25 μg BID was associated with the best efficacy/safety profile.



ClinicalTrials.gov.



NCT01476813.
University of Manchester, Medicines Evaluation Unit, Manchester, UK. Electronic address: dsingh@meu.org.uk.
Dave
D
Singh
Pulmonology Department, Gelnhausen, Germany.
Winfried
W
Schröder-Babo
Global Clinical Development, Chiesi S.A., Paris, France.
Géraldine
G
Cohuet
Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy.
Annamaria
A
Muraro
Global Clinical Development, Chiesi S.A., Paris, France.
Françoise
F
Bonnet-Gonod
Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy.
Stefano
S
Petruzzelli
Pneumologicum, Practice for Internal Medicine and Pneumology, Hannover, Germany.
Martin
M
Hoffmann
Respiratory System Diagnostics and Bronchoscopy Department of Medical University in Bialystok, Poland and Private Practice Internal Medicine and Allergology, Bialystok, Poland.
Zenon
Z
Siergiejko
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000368:Aged; D001507:Beclomethasone / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate / Q000008:administration & dosage / Q000494:pharmacology*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011237:Predictive Value of Tests; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004338:Drug Combinations; D005938:Glucocorticoids; D018727:Muscarinic Antagonists; D001507:Beclomethasone; D006024:Glycopyrrolate; D000068759:Formoterol Fumarate
Bronchodilators; COPD; Extrafine; Triple therapy