Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post‐Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial

Abstract

ObjectiveTo better understand the utility of using pain freedom and most bothersome headache‐associated symptom (MBS) freedom as co‐primary endpoints in clinical trials of acute migraine interventions.BackgroundAdhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co‐primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain‐free and MBS‐free at 2 hours post‐dose, was significantly higher than for placebo.MethodsWe undertook a post‐hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co‐primary endpoints of pain relief, nausea, photophobia, and phonophobia.ResultsOf the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two‐hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two‐hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.ConclusionIn this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co‐primary endpoints.

Most Bothersome Symptom in Persons With Migraine: Results From the Migraine in America Symptoms and Treatment (MAST) Study

“…Initial models included all covariates, but the following variables were eliminated from the final model estimates because they did not significantly contribute to predicting the presence of the selected MBS: MIDAS, MHD frequency, medication overuse, MSSS, PROMIS Pain Interference, TPI, PHQ-2 anxiety, and PHQ-2 depression. b Monthly headache days over the past 90 days, divided by 3. c Responses to 12 ASC questions scored as 0 (never or rarely), 1 (less than half the time), and 2 (half the time or more), and summed (range 0-24), categories: none (0-2), mild (3)(4)(5), moderate (6)(7)(8), and severe (9 or more). The nausea MBS model found that men were less likely than women to designate nausea as their MBS (OR .77, 95% CI .66, .89).…”

Review of Acute Treatment of Migraine Trial Results With the New FDA Endpoints: Design Implications for Future Trials

“…Trials differed in size and design, with several trials investigating multiple drug doses. Notably, in trials investigating ubrogepant and sumatriptan injection, MBS was identified at the time of treatment, whereas in the trial investigating ADAM zolmitriptan, patients prespecified their usual MBS on the first day of the run‐in period and were required to have that symptom at the time of the treated migraine . For the remaining trials, insufficient information has been published thus far to ascertain when MBS was specified.…”

“…Correlation between 2‐hour MBS freedom and 2‐hour pain freedom is unknown and may be inconstant. Notably however, in the recently completed ZOTRIP trial, only 1 patient (<1%) achieved pain freedom without achieving MBS freedom …”

“…The newly recommended co‐primary endpoints (2‐hour pain freedom and 2‐hour MBS‐freedom) for clinical trials of acute migraine treatments are intended to better address the symptoms considered most important to patients. One additional potential advantage to the use of the new endpoints is that sample sizes might be reduced, leading to faster and more cost‐effective clinical trials . With the emerging data on placebo responses and effect sizes observed in trials using the newly revised endpoints, we can now begin to determine whether this is the case.…”

“…Conversely, election immediately prior to dosing ensures that the selected MBS specifically reflects the treated migraine attack but may not reflect the participant’s historical MBS. Both approaches have merits and have been discussed elsewhere …”