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Is ubrogepant, an oral calcitonin gene–related peptide receptor antagonist, effective in the acute treatment of migraine?
In this randomized clinical trial that included 1686 participants, rates of pain freedom at 2 hours were significantly greater with ubrogepant 50 mg (21.8%) or 25 mg (20.7%) than with placebo (14.3%). Rates of freedom from the most bothersome migraine-associated symptom at 2 hours were significantly greater with the 50-mg (38.9%) dose but not the 25-mg (34.1%) dose vs placebo (27.4%).
Acute treatment of migraine with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with both the 50-mg and 25-mg doses, and freedom from the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose.
Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist under investigation for acute treatment of migraine.
To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack.
Design, Setting, and Participants
Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month.
Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity.
Main Outcomes and Measures
Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication.
Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]).
Conclusions and Relevance
Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.
ClinicalTrials.gov Identifier: NCT02867709
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Corresponding Author: Richard B. Lipton, MD, Montefiore Headache Center, Albert Einstein College of Medicine, 1225 Morris Park Ave, Van Etten Bldg, Room 3c12c, Bronx, NY 10461 (firstname.lastname@example.org).
Accepted for Publication: September 23, 2019.
Correction: This article was corrected on April 7, 2020, to correct an imprecise statement in the Discussion section and fix a typographical error in Figure 2.
Author Contributions: Dr Lipton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lipton, Lu, Finnegan, Szegedi, Trugman.
Acquisition, analysis, or interpretation of data: Lipton, Dodick, Ailani, Lu, Finnegan, Szegedi, Trugman.
Drafting of the manuscript: Lipton, Ailani, Szegedi, Trugman.
Critical revision of the manuscript for important intellectual content: Lipton, Dodick, Ailani, Lu, Finnegan, Szegedi, Trugman.
Statistical analysis: Lu.
Administrative, technical, or material support: Finnegan, Trugman.
Supervision: Ailani, Szegedi, Trugman.
Conflict of Interest Disclosures: Dr Lipton reports that he serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache; has received research support from the National Institutes of Health (NIH); receives support from the Migraine Research Foundation and the National Headache Foundation; has reviewed for the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS); serves as consultant, advisory board member, or has received honoraria from Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Boston Scientific, Dr Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta; receives royalties from Wolff’s Headache and Informa; holds stock options in eNeura Therapeutics and Biohaven. Dr Dodick reports receiving personal fees from Amgen, Autonomic Technologies, Axsome, Aural Analytics, Allergan, Alder, Biohaven, Charleston Laboratories, Dr Reddy's Laboratories/Promius, Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), Theranica, Teva, Vedanta, WL Gore, Zosano, ZP Opco, Foresite Capital, Oppenheimer, Upjohn (Division of Pfizer), Pieris, Revance, Equinox, Salvia, and Amzak Health; has received CME fees or royalty payments from Healthlogix, Medicom, Medlogix, Mednet, Miller Medical, PeerView, WebMD/Medscape, Chameleon, Academy for Continued Healthcare Learning, Universal Meeting Management, Haymarket, Global Scientific Communications, UpToDate, Oxford University Press, Cambridge University Press, and Wolters Kluwer; has stock options for Aural Analytics, Healint, Theranica, Second Opinion/Mobile Health, Epien, GBS/Nocira, Matterhorn/Ontologics, and King-Devick Technologies; serves as a consultant without fee for Aural Analytics, Healint, Second Opinion/Mobile Health, and Epien; sits on the board of directors for Epien, Matterhorn/Ontologics, and King-Devick Technologies; has a patent (17189376.1-1466) for a botulinum toxin dosage regimen for chronic migraine prophylaxis, for which he receives no fee; receives research support from the American Migraine Foundation, Henry Jackson Foundation, Department of Defense, and Sperling Foundation; receives professional society fees or reimbursement for travel from the American Academy of Neurology, American Brain Foundation, American Headache Society, American Migraine Foundation, International Headache Society, and Canadian Headache Society; and has a use agreement through employer, Myndshft, Neuroassessment Systems. Dr Ailani reports that she serves as a consultant for, speaks on behalf of, or both for Allergan, Amgen, Alder, Avanir, Biohaven, Electrocore, Eli Lilly, Promius, Impel, Satsuma, Aptus, Miller Medical Communications, and Alpha sites and has served on clinical trials for Allergan, the American Migraine Foundation, and Theranica; and is an editor for Current Pain and Headache Reports. Drs Lu, Finnegan, Szegedi, and Trugman are full-time employees and stockholders of Allergan plc.
Funding/Support: This trial was sponsored by Allergan plc, Dublin, Ireland. Medical writing and editorial support were provided by Lela Creutz, PhD, and Lisa Feder, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, New Jersey, and Amy Kuang, PhD, of Allergan plc and funded by Allergan plc.
Role of the Funder/Sponsor: The design and conduct of the study, as well as collection, management, analysis, and interpretation of the data, were undertaken by the sponsor in collaboration with the academic authors. Preparation, review, and approval of the manuscript were done by all authors, and by a professional medical writer and editor employed by the sponsor. All authors approved the final manuscript for submission. The sponsor did not have the right to veto publication or to control the decision regarding to which journal the paper was submitted.
Disclaimer: The opinions expressed in this article are those of the authors.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the participants and investigators who participated in this study. We acknowledge Hassan Lakkis, PhD, for his contributions to the statistical analyses of the results of this study. Hassan Lakkis was an employee of Allergan plc at the time these analyses were conducted. His current affiliation is unknown.
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