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Background: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine., Methods: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137)., Findings: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%])., Interpretation: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant., Funding: Allergan (now AbbVie)., Competing Interests: Declaration of interests PPR reports support for the present study from AbbVie, personal fees from AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, and Teva, and grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigación Carlos III, International Headache Society, Novartis, and Teva. JA reports support for the present study from AbbVie, personal fees from AbbVie, Aeon, Amgen, Axsome, Biohaven, BioDelivery Sciences International, Eli Lilly, GlaxoSmithKline, Impel, Linpharma, Lundbeck, Miravio, Neso, Neurolief, Satsuma, Teva, and Theranica, clinical trial support from AbbVie, Biohaven, Eli Lilly, Satsuma, and Zosano, and stock options from CtrlM. She has provided editorial services to Current Pain and Headache Reports, Medscape, NeurologyLive, and SELF magazine. MA reports support for the present study from AbbVie, personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals, and grants paid to his institution from the Lundbeck Foundation, Novartis, and Novo Nordisk Foundation. PJG reports support for the present study and personal fees during the conduct of the study from AbbVie, a grant from Celgene, and personal fees from Aeon Biopharma, Amgen, BioDelivery Sciences International, CoolTech LLC, Dr Reddy's Laboratories, Eli Lilly and Company, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, Shiratronics, Teva Pharmaceuticals, and Tremeau, personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric, fees for educational materials from CME Outfitters and WebMD, and fees for publishing from Massachusetts Medical Society and Oxford University Press and for medicolegal advice in headache. He has a patent for magnetic stimulation for headache, which is licensed to eNeura without fee. RBL reports support for the present study from AbbVie, research support paid to his institution for the present study from the National Institutes of Health/National Institute on Aging (2PO1 AG003949, Einstein Aging Study), the S&L Marx Foundation, the Czap Foundation, the National Headache Foundation, the Migraine Research Foundation, and the US Food and Drug Administration, and personal fees from AbbVie/Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr. Reddy's Laboratories (Promius), electroCore, Eli Lilly, eNeura, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Teva, Vector, and Vedanta Research. He holds stock or options in Biohaven and Manistee. UR reports support for the present study paid to his institution from AbbVie, grants from BMBF (German Ministry for Research) and Novartis, and personal and institutional fees from AbbVie, Allergan, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, StreaMedUp, and Teva. HG, BS, RB, RDAF, EM, and JMT are employees of AbbVie and may hold AbbVie stock. KL, RM, SYY, LS, and MF are former employees of AbbVie and may hold AbbVie stock., (Copyright © 2023 Elsevier Ltd. All rights reserved.)