Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA.

Background: Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome.
Methods: This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020).
Findings: Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo.
Interpretation: Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome.
Funding: AbbVie.
Competing Interests: Declaration of interests DWD is a consultant for Amgen, Atria, CapiThera, Cerecin, Ceruvia Lifesciences, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer; receives honoraria from the American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group, Clinical Education Alliance, Teva, Amgen, Eli Lilly, Lundbeck, Pfizer, Vector Psychometric, Clinical Care Solutions, CME Outfitters, Curry Rockefeller, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin, Medlogix Communications, Medica Communications, MJH Life Sciences, Miller Medical Communications, WebMD Health, Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press; receives speaker fees from Teva, Amgen, Eli Lilly, Lundbeck, and Pfizer; is a board member for the American Brain Foundation, American Migraine Foundation, OneNeurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation, Panfila, Epien, Matterhorn, Ontologics, King-Devick Technologies, Precon Health, Axon Therapeutics, and Cephalgia; receives research support from the US Department of Defense, US National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, and US Patient-Centered Outcomes Research Institute; holds stock options in Ctrl M, Aural Analytics, ExSano, Palion, Man and Science, Healint, Theranica, Second Opinion, Mobile Health, Epien, Nocira, King-Devick Technologies, Precon Health, AYYA Biosciences, Axon Therapeutics, Cephalgia, and Atria Health; is a shareholder in Matterhorn and Ontologics; is an employee of Atria Health; holds patent 17189376.1-1466 (Onabotulinum toxin dosage regimen for chronic migraine prophylaxis); and has submitted a patent application for SynaQuell via Precon Health. PJG receives financial support for this study and personal fees from AbbVie; receives a grant from Celgene; receives personal fees from Aeon Biopharma, Amgen, BioDelivery Sciences International, CoolTech, Dr Reddy's, Eli Lilly, Epalex, Impel NeuroPharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, ShiraTronics, Teva Pharmaceuticals, Tremeau, Gerson Lehrman, Guidepoint, SAI Med Partners, and Vector Metric; receives fees for educational materials from CME Outfitters, Omnia Education, and WebMD; receives fees for publishing and for medicolegal advice for headache from Massachusetts Medical Society and Oxford University Press; and holds a patent for Magnetic stimulation for headache, licensed to eNeura. TJS is on the board of directors for the American Headache Society and the American Migraine Foundation; receives research support from Amgen, Henry Jackson Foundation, Mayo Clinic, US National Institutes of Health, US Patient-Centered Outcomes Research Institute, SPARK Neuro, and US Department of Defense; is a consultant or advisory board member for AbbVie, Allergan, Axsome, Collegium, Eli Lilly, Linpharma, Lundbeck, Satsuma, and Theranica; holds stock options in Aural Analytics and Nocira; and receives royalties from UpToDate. RBL receives financial support for this study from AbbVie; receives research support, paid to his institution, from the US National Institutes of Health, the S&L Marx Foundation, the Czap Foundation, the National Headache Foundation, and the US Food and Drug Administration; is a consultant or advisory board member for and receives honoraria or research support from AbbVie, Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr Reddy's, Promius, electroCore, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Alder, Merck Sharp & Dohme, Pernix, Pfizer, Teva, Vector, and Vedanta Research; and holds stock options in Biohaven and Manistee. CL and JMT are employees of AbbVie and hold AbbVie stock. KL, SYY, LS, and MF are former employees of AbbVie and hold AbbVie stock.
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