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Background: Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed., Methods: ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed., Findings: Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group., Interpretation: Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population., Funding: Allergan (now AbbVie)., Competing Interests: Declaration of interests JMT, KN, HG, RDAF, and GF are employees of AbbVie and may hold AbbVie stock. CT reports support from Abbvie and Novartis for investigator-initiated trials; consulting fees from Abbvie, Eli Lilly, Dompé, Teva, Lundbeck, Pfizer, and Medscape for participating in advisory boards; support from Abbvie, Eli Lilly, Dompé, Teva, Lundbeck, and Pfizer for attending meetings; and personal fees from Abbvie, Eli Lilly, Teva, Lundbeck, and Pfizer for lecturing at symposia. She is principal investigator of clinical trials sponsored by Abbvie, Eli Lilly, Lundbeck, Pfizer, and Teva. She has received research grants from the European Commission, the Italian Ministry of Health, and the Migraine Research Foundation. PP-R reports support for the present study from AbbVie and personal fees for consulting from AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, and Teva. She has received personal fees for speaking from AbbVie, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, and Teva, and has had grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigación Carlos III, International Headache Society, Novartis, and Teva. She has participated in an advisory board for Lilly Foundation Spain. ML-M reports support for the present study from AbbVie and reports personal fees for speaker panels from Amicus, Eli Lilly, Lundbeck, Teva, UPSA, and Zambon. He has received consulting fees from AbbVie, Eli Lilly, Grunenthal, Lundbeck, Medtronic, Novartis, Orion, Pfizer, Reckitt Benkiser, Sun Pharmaceutical, Teva, UPSA, and Zambon. He has received grants for institutional support from Eli Lilly, Lundbeck, Medtronic, Novartis, Pfizer, and Teva. SS has received consulting fees from Impel Neuropharma, and personal payment as a speaker for AbbVie, Amgen, BDSI, Biohaven, Eli Lilly, Impel Neuropharma, and Teva. She has participated in advisory boards for AbbVie, Amgen, BDSI, Biohaven, Eli Lilly, Impel Neuropharma, and Teva and serves as Board of Directors for the Southern Headache Society and Carolina Headache Foundation. TN reports support for the present study from AbbVie and has received personal payments for consulting fees and speaking fees from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St Jude Medical, Teva Pharmaceuticals, and UCB. He has received grants for institutional support from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St Jude Medical, Teva Pharmaceuticals, and UCB. He also has served on advisory boards or as a principal investigator in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Neurocrine, Novartis, Teva Pharmaceuticals, and UCB., (Copyright © 2024 Elsevier Ltd. All rights reserved.)