Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine

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.

Ubrogepant, an Acute Treatment for Migraine, Improved Patient‐Reported Functional Disability and Satisfaction in 2 Single‐Attack Phase 3 Randomized Trials, ACHIEVE I and II

“…Trial Design and Participants.-The designs of ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (NCT02867709; funded by Allergan plc), including complete inclusion and exclusion criteria, have been published elsewhere. 23,24 Both trials were multicenter, randomized, double-blind, placebo-controlled, parallel-group, single-attack phase 3 trials conducted in the United States (ACHIEVE I: 89 sites; ACHIEVE II: 99 sites). Eligible participants were 18-75 years of age, had a history of migraine with or without aura for at least 1 year consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd edition (beta version) criteria, 25 and must have experienced 2-8 migraine attacks with moderate to severe headache pain in each of the 3 months before screening.…”

“…23,24 Assessments.-The co-primary and secondary efficacy outcomes of ACHIEVE I and II have been published. 23,24 This article reports the results of prespecified efficacy analyses of additional PRO measures for each treatment group from each trial -namely, the Functional Disability Scale (FDS), participant satisfaction with study medication, and Patient Global Impression of Change (PGIC) scale. The results of a post hoc analysis of pooled data for a comparison of the pooled ubrogepant 50 mg group vs the pooled placebo group are also presented.…”

“…Statistical Analysis.-Each trial had a target sample size of 550 randomized participants per treatment group to provide at least 85% power to detect treatment differences between each ubrogepant dose and placebo for the co-primary efficacy outcomes. 23,24 The modified intention-to-treat (mITT) population included all randomized participants who received at least 1 dose of study medication, recorded baseline migraine headache severity, and reported at least 1 post dose migraine headache severity rating or migraine-associated symptom outcome at or before 2 hours after the initial dose. The proportion of participants in the mITT population reporting "no disability, able to function normally" on the FDS before dosing and at 1, 2, 4, and 8 hours after initial dose was analyzed using a logistic regression model, with categorical terms for treatment group, historical triptan response (triptan responder, triptan insufficient responder, or triptan naive), use of medication for migraine prevention (yes/no), and baseline headache severity (moderate or severe), with baseline functional disability score included as a covariate.…”

“…1). 24 The mITT population from ACHIEVE I included 456 participants in the placebo group, 423 in the ubrogepant 50 mg group, and 448 in the ubrogepant 100 mg group. In ACHIEVE II, the mITT population included 456 participants in the placebo group, 435 in the ubrogepant 25 mg group, and 464 in the ubrogepant 50 mg group.…”

“…These benefits were achieved with good tolerability; the incidence of treatment-emergent adverse events was similar in the ubrogepant and placebo groups. 23,24 Given the extensive burden and disability associated with migraine, patient-reported outcome (PRO) measures of functional disability and satisfaction are important for understanding the holistic treatment effect of an acute treatment. We hypothesized that treatment with ubrogepant is superior to placebo on improvement of functional disability and satisfaction with study treatment.…”