The Association Between the Occurrence of Common Treatment-Emergent Adverse Events and Efficacy Outcomes After Lasmiditan Treatment of a Single Migraine Attack: Secondary Analyses from Four Pooled Randomized Clinical Trials

Abstract

Background: In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).

Objective: To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment.

Methods: Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities.

Results: At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE.

Conclusions: Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC.

Gov registration: SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810.

Conflict of interest statement

RBL receives research support from the NIH, FDA, as well as the National Headache Foundation and the Marx Foundation. He also receives research support from Allergan/Abbvie, Amgen, Eli Lilly, and Electrocore. He receives personal fees as a consultant or advisor from Allergan/Abbvie, Amgen, Biohaven Holdings, Dr. Reddy's, GlaxoSmithKline, Grifols, Impel NeuroPharma, Eli Lilly, Lundbeck, Merck, Novartis, and Teva Pharmaceuticals. He holds stock or options in Biohaven Holdings, CtrlM Health and Manistee. EGD, PMH, JHK, MK, AMH, and YD are employees and minor stockholders of Eli Lilly and Company.

© 2022. Eli Lilly and Company.

Figures

Fig. 1

(a). The percentage of participants in each pain group experiencing the indicated CTEAE within 48 h. Participants who achieve pain freedom or improve to mild pain were more likely to experience CNS-CTEAEs. *p < 0.05, **p < 0.01, ***p < 0.001 versus M/S. The only treatment by subgroup interaction p values < 0.1 were ≥ 1 CTEAE (0.021) and dizziness (0.033). (b) The incidence of CTEAEs is similar in those who do and do not achieve disability freedom. *p < 0.05, **p < 0.01, ***p < 0.001 Yes versus No disability freedom. The only treatment by subgroup interaction p value < 0.1 was for nausea (0.087). (c) The incidence of CNS-CTEAEs is similar in those who experienced improved PGIC (rating of “much better” or “very much better” vs. those who did not (all other ratings)). * p < 0.05, ** p < 0.01, *** p < 0.001 Yes versus No PGIC. No treatment by subgroup interaction p-values <0.1 were identified. CNS central nervous system, CTEAE common treatment-emergent adverse event, IMP improved to mild pain, L lasmiditan, M/S severe/moderate pain, PBO placebo, PF pain-free, PGIC patient global impression of change, TEAE treatment-emergent adverse event

Fig. 2

The percentage of participants experiencing efficacy in those that did or did not experience the given CTEAE. A higher percentage of participants experiencing ≥ 1 CTEAE, dizziness, somnolence, or paresthesia achieved pain freedom than those who did not (a) No consistent differences were observed for disability freedom (b) between those with and those without a CNS-CTEAE. The percentage of participants with PGIC was greater with a CNS-CTEAE versus no CNS-CTEAE (c). *p < 0.05, **p < 0.01, ***p < 0.001 Yes versus No CTEAE. The only treatment by subgroup interaction p values < 0.1 were dizziness and pain freedom (0.061), and nausea and disability freedom (0.047). CNS central nervous system, CTEAE common treatment-emergent adverse event, L lasmiditan, PBO placebo, PGIC patient global impression of change

Fig. 3

The percentage of participants experiencing efficacy in those that experienced the given CTEAE before or after 2 h. Generally, a higher percentage of participants whose CTEAE started at or before 2 h became pain-free compared to those whose CTEAE started after 2 h (a). There were no clinically meaningful differences in disability freedom (b) or PGIC (c) in those with a CTEAE onset at or before 2 h versus after 2 h. *p < 0.05, **p < 0.01, ***p < 0.001 ≤ 2 h versus > 2 h. The only treatment by subgroup interaction p values < 0.1 were ≤ 1 CTEAE and pain freedom (0.075), ≤ 1 CTEAE and disability freedom (0.056), and dizziness and disability freedom (0.089). CTEAE common treatment-emergent adverse event, h hour, L lasmiditan, PBO placebo, PGIC patient global impression of change

Fig. 4

Data visualization demonstrating the timing of common treatment-emergent adverse event (CTEAE) onset relative to head pain intensity. In this representative image, only dizziness and pain freedom occurring with lasmiditan 200 mg is shown. An interactive version of this figure is available as OSM where pain freedom/relief and CTEAE's/dose combinations may be selected. Nested donuts: nested donut chart representing the distribution of participants who did (including onset information) and did not (including pain level at 2 h) experience the specified CTEAE. “Other” includes participants that took a second dose or rescue medication before or at 2 h. Rainbow: Time course of head pain intensity and CTEAE onset for individual participants’ panel who experienced the indicated CTEAE at or before 2 h. Missing headache intensity was imputed using the last non-missing observation. Sorting options (i.e sorting by CTEAE onset) are available in Interactive Fig. 4. All sorts use imputed pain values regardless of whether imputed value box is checked or not. Horizontal bar charts: Summary of the proportion of participants by timing of CTEAE onset relative to the time each patient first achieved pain freedom or first achieved meaningful pain relief (PR-Interactive Fig. 4 only) within 2 h. All values obtained on a continuous time scale