A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

Abstract

Background: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.

Methods: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.

Results: Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.

Conclusions: This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint.

Trial registration: SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 ).

Keywords: Efficacy endpoints; Functional disability; Lasmiditan; Migraine; Most bothersome symptom (MBS); Pain freedom; Pain relief.

Conflict of interest statement

RL: – Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. Receives research support from the NIH, from the Migraine Research Foundation and the National Headache Foundation. Serves on the editorial board of Neurology, senior advisor to Headache, and associate editor to Cephalalgia. Reviewed for the NIA and NINDS, holds stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from or conducted studies funded by the American Academy of Neurology, Abbvie/Allergan, American Headache Society, Amgen, Biohaven, Dr. Reddy’s, Electrocore, Eli Lilly and Company, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Teva, Trigemina, Vector, Vedanta. Receives royalties from Wolff’s Headache 7th and 8th Edition, Oxford Press University, 2009, Wiley and Informa.

ST: - Grants for research (no personal compensation): Allergan, Amgen, Dr. Reddy’s, ElectroCore, Eli Lilly, eNeura, Lundbeck, Neurolief, Novartis, Satsuma, Scion Neurostim, Teva, Zosano. Consultant and/or Advisory Boards (honoraria): Acorda, Aeon, Alexsa, Align Strategies, Allergan, Alphasights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, Charleston Labs, ClearView Helathcare Partners, CoolTech, CRG, Currax, Decision Resources, DeepBench, Eli Lilly, eNeura, Equinox, ExpertConnect, GLG, GSK, Guidepoint Global, Healthcare Consultancy Group, Health Science Communications, Impel, Lundbeck, M3 Global Research, Magellan Rx Management, Marcia Berenson Connected Research and Consulting, Medicxi, Navigant Consulting, Neurolief, Nordic BioTech, Novartis, Pulmatrix, Reckner Healthcare, Relevale, Revance, SAI MedPartners, Satsuma, Scion Neurostim, Slingshot Insights, Sorrento, Spherix Global Insights, Sudler and Hennessey, Synapse Medical Communications, System Analytic, Teva, Theranica, Thought Leader Select, Trinity Partners, Unity HA, XOC, Zosano. Salary: Dartmouth-Hitchcock Medical Center, American Headache Society, Thomas Jefferson University. CME honoraria: American Academy of Neurology, American Headache Society, Cleveland Clinic Foundation, Diamond Headache Clinic, Elsevier, Forefront Collaborative, Hamilton General Hospital, Ontario, Canada, Headache Cooperative of New England, Henry Ford Hospital, Detroit, Inova, Medical Learning Institute Peerview, Medical Education Speakers Network, Miller Medical Communications, North American Center for CME, Physicians’ Education Resource, Rockpointe, ScientiaCME, WebMD/Medscape.

SKB, JHK, RV, EMP, PMH and LSL, are full-time employees and minor stockholders of Eli Lilly and Company.

© 2021. The Author(s).

Figures

Fig. 1

Relative timing of freedom from most bothersome symptom (MBS) or functional disability and pain status. (a) Sequence of outcomes in patients that experienced MBS freedom and either pain freedom (N = 839) or mild pain (N = 388) at 2 h. (b) Sequence of outcomes in patients that experienced functional disability freedom and either pain freedom (N = 795) or mild pain (N = 116) at 2 h. Notes: Unsustained represented patients who experienced freedom from MBS or functional disability freedom and either freedom from pain or improvement to mild and then moved out of that group prior to 2 h post-dose. The denominator was the total population that achieved the MBS freedom or disability freedom at 2 h post-dose in either the pain free or mild pain groups