Schmidt, Peter

Objective To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications. Background ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention‐to‐treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients’ usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post‐dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications. Methods The ZOTRIP trial was a multicenter, randomized, double‐blind, placebo‐controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran–Mantel–Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo. Results In patients with nausea, 2‐hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group ( P = .005) (odds ratio = 5.11, 95% CI: 1.96–13.30), and 2‐hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo ( P = .009) (odds ratio = 2.86, 95% CI: 1.28–6.43). For those with severe pain, corresponding pain‐free values were 26% (10/39) and 15% (5/33) ( P = .249) (odds ratio = 2.14, 95% CI: 0.60–7.62), and MBS‐free values were 64% (25/39) and 42% (14/33) ( P = .038) (odds ratio = 2.86, 95% CI: 1.05–7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain‐free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively ( P = .006) (odds ratio = 4.29, 95% CI: 1.50–12.31), and 72% (26/36) vs 39% (17/44) were MBS‐free, respectively ( P = .003) (odds ratio = 4.40, 95% CI: 1.61–12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively ( P = .017) (odds ratio = 4.33, 95% CI: 1.24–15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group ( P = .014) (odds ratio = 3.37, 95% CI: 1.27–8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction. Conclusion Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2‐hour headache freedom and 2‐hour MBS freedom) compared with those who received placebo.

Objective To 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. Background Adhesive 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. Methods We 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. Results Of 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. Conclusion In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co‐primary endpoints.