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. 2024 Sep 16;81(11):1140-1149.
doi: 10.1001/jamaneurol.2024.3043. Online ahead of print.

Efficacy and Safety of Erenumab for Nonopioid Medication Overuse Headache in Chronic Migraine: A Phase 4, Randomized, Placebo-Controlled Trial

Stewart J Tepper  1 , David W Dodick  2   3 , Michel Lanteri-Minet  4   5 , David Dolezil  6 , Raquel Gil-Gouveia  7   8 , Christian Lucas  9 , Karolina Piasecka-Stryczynska  10 , Gyöngyi Szabó  11 , Daniel D Mikol  12 , Mahan Chehrenama  12 , Denise E Chou  12 , Yiping Yang  12 , Gabriel Paiva da Silva Lima  12
Affiliations

Efficacy and Safety of Erenumab for Nonopioid Medication Overuse Headache in Chronic Migraine: A Phase 4, Randomized, Placebo-Controlled Trial

Stewart J Tepper et al. JAMA Neurol. .

Abstract

Importance: Patients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.

Objective: To assess erenumab efficacy and safety in patients with nonopioid CM-MOH.

Design, settings, and participants: This randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort).

Interventions: Erenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks.

Main outcomes and measures: The primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs.

Results: The primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P < .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was -9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, -2.7; 95% CI, -3.9 to -1.6; P < .001) and -7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, -1.2; 95% CI, -2.4 to -0.1; P = .03), vs -6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common.

Conclusions and relevance: In this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months.

Trial registration: ClinicalTrials.gov Identifier: NCT03971071.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tepper reported personal fees from Amgen during the conduct of the study; and research funding from Abbvie, Aeon, Amgen, Annovis, Axsome, Cassava, Cognition, Eli Lilly, Inhibikase, Ipsen, Lundbeck, Merz, Neurolief, Pfizer, PrecisionMed, Revance, Scilex, Suven, and UCB; consultant and/or advisory board honoraria from Abbvie, Aeon, Alphasights, Amgen, Aruene/eNeura, Atheneum, Axsome Therapeutics, Becker Pharmaceutical , ClearView Healthcare Partners, ClickTherapeutics, CoolTech, CRG Medical Services, Decision Resources, Defined Health, Decision Resources Group, Eli Lilly, ExpertConnect, FCB Health, Fenix, Gilmartin Capital, Gerson Lehrman Group, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, Initiator Pharma, InteractiveForums, IQVIA, Keyquest, Ki Health Partners, Krog and Partners, Lundbeck, M3 Global Research, Magellan Health, Magnolia Innovation, Miravo Healthcare, MJH Holdings, Neurofront Therapeutics, Neurolief, Nocira, Novartis, P Value Communications, Pain Insights, Palion Medical, Perfood, Pfizer, Pulmatrix, Putnam Associates, Rehaler, SAI MedPartners, Satsuma, Scilex, Slingshot Insights, Spherix Global Insights, Strategy, Synapse Medical Communication, System Analytic, Taylor and Francis, Tegus, Teva, Theranica, Third Bridge, Tonix, Trinity Partners, Unity HA, Vial, and XOC Technologies; salary from Dartmouth-Hitchcock Medical Center, Thomas Jefferson University, and Ki Health Partners; speakers fees from AbbVie, Eli Lilly, Pfizer, Scilex, and Teva; and Continuing Medical Education honoraria from the American Academy of Neurology, the American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, HMP Global, Medical Education Speakers Network, Medical Learning Institute Peerview, Migraine Association of Ireland, Miller Medical Education, the 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. Dr Dodick reported personal fees from Amgen during the conduct of the study; personal fees from the American Academy of Neurology, Headache Cooperative of the Pacific, Headache Cooperative of New England, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company, Teva, Amgen Japan, Eli Lilly Canada, Lundbeck, Amgen, Atria, CapiThera, Cerecin, Ceruvia Lifesciences, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, Escient, GlaxoSmithKline, Halion, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer outside the submitted work; in addition, Dr Dodick had a patent for Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (17189376.1-1466) (nonroyalty bearing) issued and has a patent application submitted for Synaquell (Precon Health) pending; and reported a full disclosure statement (5 years) and consulting fees from Amgen, Atria, CapiThera, Cerecin, Ceruvia Lifesciences, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, Escient, GlaxoSmithKline, Halion, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, and Pfizer; honoraria from the American Academy of Neurology, Headache Cooperative of the Pacific, Headache Cooperative of New England, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company, Teva, Amgen Japan, Eli Lilly Canada, Lundbeck, Pfizer, Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin, Medlogix Communications, Medica Communications, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, and Cambridge University Press; nonprofit board membership from the American Brain Foundation, the American Migraine Foundation, ONE Neurology, Precon Health Foundation, Global Patient Advocacy Coalition, Atria Health Collaborative, Atria Academy of Science and Medicine, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation/Panfila, and CSF Leak Foundation; research support from the US Department of Defense, the National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, the American Migraine Foundation, Henry Jackson Foundation, and Patient Centered Outcomes Research Institute; stock options/shareholder/patents/board of directors from Ctrl M, Aural analytics, Axon Therapeutics, ExSano, Palion, Keimon Medical, Man and Science, Healint, Theranica, Second Opinion/Mobile Health, Epien, Nocira, Matterhorn, Ontologics, King-Devick Technologies, Precon Health, ScotiaLyfe, EigenLyfe, AYYA Biosciences, Axon Therapeutics, Cephalgia Group, and Atria Health; a patent for Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (nonroyalty bearing) (17189376.1-1466) and a patent application submitted for Synaquell (Precon Health). Dr Lanteri-Minet reported taking part in a study with Amgen during the conduct of the study and personal fees from Abbvie, Eli Lilly, Grunenthal, Lundbeck, Medtronic, Orion Pharma, Per Food, Orion Pharma, Pfizer, Reckitt Benckiser, Salvia Bio Electronics, Sanofi Aventis, Teva, and University of Professional Studies outside the submitted work. Dr Dolezil reported participating in clinical trials with Allergan/AbbVie, Amgen, and Novartis and personal fees from Lundbeck, Teva, Eli Lilly, and Organon outside the submitted work. Dr Gouveia reported being a principal investigator for an Amgen clinical trial during the conduct of the study, personal fees from AbbVie Pfizer, Teva, Organon, Lilly, Novartis, and grants from Novartis outside the submitted work. Dr Lucas reported personal fees from Abbvie, Amgen, Lilly, Lundbeck, Pfizer, Orion, Teva, and Reckitt during the conduct of the study. Dr Mikol reported personal fees and employment from Amgen during the conduct of the study and employment from NervGen outside the submitted work. Dr Chou reported prior employment and stock ownership from Amgen during the conduct of the study and current employment and stock ownership with Pfizer outside the submitted work. Dr Yang reported current employment and stock ownership with Amgen. Dr Paiva da Silva Lima reported being a fulltime employee and holding stocks/stock options of Amgen. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
DBTP indicates double-blind treatment period.
Figure 2.
Figure 2.. Absence of Medication Overuse Headache (MOH) at Month 6
Absence of MOH at month 6 was the primary end point of the study and was defined by mean monthly acute headache medication days (AHMD) less than 10 days over months 4, 5, and 6 or mean monthly headache days less than 14 days over months 4,5, and 6 of the double-blind treatment period where AHMD include any electronic diary day in which an acute headache medication intake is reported. Common odds ratio (OR) and P value are obtained from a Cochran-Mantel-Haenszel test, stratified by the stratification factor of concomitant oral migraine preventive treatment initiated before screening and taken during baseline (yes or no).
Figure 3.
Figure 3.. Change From Baseline in Mean Monthly Acute Headache Medication Days (AHMD) and Sustained Medication Overuse Headache (MOH) Remission During the Double-Blind Treatment Period (DBTP)
A, Change from baseline in mean monthly AHMD over months 4, 5, and 6 of the DBTP. Adjusted analysis uses a generalized linear mixed model that includes treatment, visit, treatment-by-visit interaction, the stratification factor of concomitant oral migraine preventive treatment initiated before screening and taken during baseline (yes or no), and baseline value as covariates and assumes a first-order auto regression covariance structure. Adjusted analysis results were obtained using contrasts. Nominal P value is presented without multiplicity adjustment. B, Sustained MOH remission during DBTP, as defined by absence of MOH at months 3 and 6 of the DBTP, and the absence of MOH is achieved when mean monthly AHMD less than 10 days or mean MHD less than 14 days over the respective 3-month period. Common odds ratio (OR) and P value are obtained from a Cochran-Mantel-Haenszel test, stratified by the stratification factor of concomitant oral migraine preventive treatment initiated before screening and taken during baseline (yes or no). LMS indicates least squares mean; LS, least squares.
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