A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Tolerability, and Safety of Celecoxib Oral Solution (ELYXYB) in Acute Treatment of Episodic Migraine with or without Aura

Abstract

Background: Safe, effective, oral therapies are needed for acute treatment of migraine. This clinical trial assessed the efficacy, tolerability, and safety of celecoxib oral solution (ELYXYB) in a single migraine attack associated with moderate-to-severe pain.

Methods: This was a phase III, randomized (1:1), double-blind, placebo-controlled trial, conducted at 41 US centers from December 2016 to October 2017. Adults with episodic migraine (with or without aura) for ≥1 year were treated with a single 4.8 mL dose of 120-mg celecoxib oral solution or placebo. Co-primary endpoints were the proportion of patients who were pain-free and free from the most bothersome migraine symptom (MBS) at 2 hours post-dose. The MBS was identified at screening from among nausea, photophobia, or phonophobia.

Results: Six hundred thirty-one patients were randomized (celecoxib oral solution, n=316; placebo, n=315; mean age 41 years, range 18-75; 84.3% female). One study site met prespecified outlier criteria (defined as a treatment effect estimate that was at least twice as large as all other sites) and was excluded from efficacy analyses. This site had a mean 2-hour pain freedom placebo response rate of 75% vs a combined mean of 23.5% for all other sites. In subsequent analysis, 2-hour post-dose pain freedom response rates were significantly higher in the celecoxib oral solution group vs placebo (32.8%, [27.2%, 38.8%]) vs 23.5%, [18.5%, 29.2%]; P=0.020). For 2-hour post-dose MBS freedom, response rates were significantly higher in the celecoxib oral solution group vs placebo (58.1% [51.4%, 64.5%] vs 43.9% [37.2%, 50.7%]; P=0.003). A total of 10.7% (31/289) of patients treated with celecoxib oral solution and 9.9% (28/283) of placebo-treated patients reported a treatment-emergent adverse event (TEAE). Study drug-related TEAEs were reported by 7.3% (21/289) and 7.4% (21/283) of celecoxib oral solution and placebo patients, respectively; the most common were nausea (celecoxib oral solution: 1.4% [4/289] vs placebo: 1.8% [5/283]) and dysgeusia (celecoxib oral solution: 1.7% [5/289] vs placebo: 1.1% [3/283]). No serious TEAEs, deaths, or drug-related TEAEs leading to withdrawal were reported.

Conclusion: Celecoxib oral solution is a safe, effective COX-2-selective nonsteroidal anti-inflammatory drug for the treatment of acute migraine. In this analysis, celecoxib oral solution was significantly more effective than placebo and was also associated with a low rate of gastric TEAEs. Celecoxib oral solution may provide a convenient, alternate option to currently available treatments.

Trial registration: ClinicalTrials.gov Identifier: NCT03009019; registered January 4, 2017; retrospectively registered, https://ichgcp.net/clinical-trials-registry/NCT03009019.

Keywords: clinical trial; cyclooxygenase 2 inhibitors; migraine disorders; non-steroidal anti-inflammatory agents; phase III.

Conflict of interest statement

RBL has received research support from the NIH. He also receives support from the FDA, Migraine Research Foundation and the National Headache Foundation. He serves on the editorial board of Neurology, senior advisor to Headache, and associate editor to Cephalalgia. He has reviewed for the NIA and NINDS, holds stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from American Academy of Neurology, Allergan, American Headache Society, AEON Biopharma, Amgen, Avanir, Biohaven, Biovision, Boston Scientific, CVS Health, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Invex, Lundbeck (Alder), Merck, Novartis, Pernix, Pfizer, Satsuma, Sun Pharma, Supernus, S&L Marx Foundation, Teva, Trigemina, Vector, Vedanta. He receives royalties from Oxford University Press (Wolff’s Headache 7th and 8th Edition), Wiley, and Informa. He reports stock options from CtrlM Health. SM is an employee of Dr. Reddy’s Laboratories and owns stock in the company. SJT received grants for research (no personal compensation) from Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, and Zosano; served as a consultant and/or on advisory boards (honoraria) for Aeon, Allergan/AbbVie, Alphasights, Amgen, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting ClearView Healthcare Partners, CoolTech, CRG, Currax, DRG, Eli Lilly, ExpertConnect, FCB Health, GLG, Guidepoint Global, Health Science Communications, HMP Communications, Impel, InteractiveForums, Krog and Partners, Lundbeck, M3 Global Research, MJH Holdings, Neurolief, Novartis, Palion Medical, Pulmatrix, SAI MedPartners, Satsuma, Spherix Global Insights, Strategy Inc, System Analytic, Taylor and Francis, Teva, Theranica, Unity HA, XOC, and Zosano; received salary from Dartmouth-Hitchcock Medical Center, American Headache Society, Thomas Jefferson University; and received CMR honoraria from American Academy of Neurology, American Headache Society, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, Peerview, Medical Education Speakers Network, Migraine Association of Ireland, North American Center for CME, The Ohio State University, Physicians’ Education Resource, PlatformQ Education, Primed, Texas Neurological Society, WebMD/Medscape, and Annenberg Center for Health Sciences. CI was a paid consultant of Dr. Reddy’s Laboratories. DS was a paid consultant of Dr. Reddy’s Laboratories. The authors report no other conflicts of interest related to this work.

© 2021 Lipton et al.

Figures

Figure 1

Participant disposition.

Figure 2

Freedom from nausea, photophobia, and phonophobia at prespecified timepoints post-dose using LOCF, FAS†. †Analysis excludes outlier site. *Denotes statistical significance.

Figure 3

Proportion of patients with headache pain relief by post-dose timepoint using LOCF, FAS†. †Analysis excludes outlier site.