Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine., Methods and Analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo ( n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population., Ethics and Dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results., Competing Interests: RJ has given lectures for Pfizer, Berlin-Chemie, Norspan, Merck, Autonomic Technologies, Teva, Allergan/AbbVie, Lundbeck, and Novartis and she is or has been a principal investigator on clinical trials sponsored by Eli Lilly, Lundbeck, and Autonomic Technologies. HS has received personal fees from Novartis, Lilly, Allergan/AbbVie, Teva, and Lundbeck and research support from Novartis, has served on advisory boards for Teva and Lundbeck, and is affiliated with BMJ Open as a reviewer. CT has received funding for participation in Advisory Boards or for scientific presentations from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and Teva and is or has been a principal investigator in clinical trials sponsored by Allergan, Eli Lilly, Lundbeck, Novartis, and Teva. GT is a board member for the Dutch Headache Society and the CGRP Education and Research Forum and is an advisory member for the Dutch Headache Alliance; she has received personal fees from Consultancy: Novartis, Teva, Allergan, Lilly, and Lundbeck, received research support from the Dutch Brain Foundation, Dutch Heart Foundation, Dutch Research Council, IRRF, and Dioraphte (all to institution), has a pending patent for an eDiary collaboration with Interactive Studios, is involved with the clinical trial WHATstudy on the effect of hormonal treatment in migraine, is a National Primary Investigator in the ALLEVIATE and CHRONICLE studies by Lundbeck, and is also a presenter for satellite symposia/webinars with Springer Media (Mednet)/Ashfield MedComms. LC has received grants from the Danish Health Authority. AM is a current employee of Lundbeck. OØ was previously an employee of Lundbeck and is now employed by Biogen. RL has been a consultant, advisory board member, and/or has received honoraria from Lundbeck Seattle BioPharmaceuticals, Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven Pharmaceuticals, BioVision, Boston Scientific, Dr. Reddy's Laboratories, electroCore Medical, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva Pharmaceuticals, Trigemina, Vector, and Vedanta, received compensation from eNeura and Biohaven Pharmaceuticals, has stock or stock options in Biohaven Pharmaceuticals and Manistee, and has received research support from Amgen, Migraine Research Foundation, and National Headache Foundation. ST reports grants for research (no personal compensation) from Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, and Zosano, is a consultant and/or on advisory boards (honoraria) for Aeon, Allergan/AbbVie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, Click Therapeutics, Collegium, CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, InteractiveForums, Keyquest, Krog and Partners, Lundbeck, M3 Global Research, Magnolia Innovation, MJH Holdings, Neurofront Therapeutics, Neurolief, Novartis, P Value Communications, Pain Insights Inc, Palion Medical, Pulmatrix, Putnam Associates, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Strategy Inc, System Analytic, Taylor and Francis, Teva, Theranica, Tremeau, Unity HA, XOC, and Zosano, and reports salary from Dartmouth-Hitchcock Medical Center and Thomas Jefferson University, and CME honoraria from the American Academy of Neurology, American Headache Society, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, Peerview, Medical Education Speakers Network, Migraine Association of Ireland, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Vindico Medical Education, and WebMD/Medscape. AB has served on advisory boards for Allergan, AbbVie, Aeon, Alder, Amgen, Axsome, Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, Theranica, and Zosano; has received funding for speaking from Allergan, AbbVie, Amgen, Biohaven, Lundbeck, Lilly, and Teva; has served as a consultant for Allergan, AbbVie, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica, received grant support from Allergan and Amgen, and has been a contributing author for Allergan, AbbVie, Amgen, Novartis, Teva, Lilly, and Biohaven. CL has participated on an advisory board and received payment for lectures arranged by AbbVie Pharma AS, Lundbeck, Novartis AS, and Roche AS, Norway and he has received research sponsorship from AbbVie Pharma, and is a regular reviewer with BMJ., (Copyright © 2023 Jensen, Schytz, Tassorelli, Terwindt, Carlsen, Mittoux, Østerberg, Lipton, Tepper, Blumenfeld and Lundqvist.)