Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial

Abstract

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT02867709.

Conflict of interest statement

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.

Figures

Figure 1.. Flow Through the ACHIEVE II Randomized Trial of Ubrogepant vs Placebo for Treating Patients With Migraine Headaches

aOne participant was a protocol deviation as a duplicate subject and 2 participants were protocol deviations because staff were unable to collect adequate blood work due to small veins or vein collapse. bOne participant discontinued before randomization due to a serious adverse event of renal vein thrombosis. cThe primary analysis set used for efficacy analyses included all randomized participants who received at least 1 dose of the study medication, recorded baseline migraine headache severity, and reported at least 1 postdose migraine headache severity rating or migraine-associated symptom outcome at or before 2 hours after the initial dose. dAnother 2 participants who took the study medication but had missing or partial data for the dosing date were excluded from the safety population.

Figure 2.. Kaplan-Meier Plots of Time to Headache Pain Freedom After Initial Dose

A, The percentage of participants who were censored between 0 and 8 hours was 32% for the 25-mg dose, 28% for the 50-mg dose, and 45% for placebo. C, The percentage of participants who were censored between 0 and 8 hours was 59% for the 25-mg dose, 54% for the 50-mg dose, and 71% for placebo. B and D, Plots including and excluding data collected 24 and 48 hours after use of an optional second dose of the study medication.