Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine

Abstract

Objective To determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment. Background ADAM is a novel patient-administered system for intracutaneous drug administration. In a phase 1 pharmacokinetic study, zolmitriptan administered using ADAM had much faster absorption than oral administration with higher exposure in the first two hours. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2b/3 study evaluating ADAM zolmitriptan 1 mg, 1.9 mg, and 3.8 mg versus placebo. Co-primary endpoints were pain freedom and freedom from most bothersome other migraine-associated symptom 2 hours post-dose. Results Of patients treated with ADAM zolmitriptan 3.8 mg or placebo, 41.5% and 14.2%, respectively were pain-free 2 hours post-dose ( p = 0.0001) and 68.3% and 42.9% were free from their most bothersome other symptom ( p = 0.0009). Due to the fixed sequential testing methodology, formal statistical significance was not established for secondary endpoints. However, the proportion of patients who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post-dose was higher in the ADAM zolmitriptan 3.8 mg group compared with placebo, as were the percentages of patients who were pain-free, and who experienced pain relief up to 48 hours post-dose. Systemic adverse events were consistent with previous triptan trials, and included dizziness, paresthesia, muscle tightness, and nausea, all of which occurred in < 5% of patients in any group. Application site reactions were generally mild and resolved within 48 hours, although erythema and bruising persisted for longer periods in some patients. Conclusion ADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated. ClinicalTrials.gov NCT02745392.

Keywords: Adhesive Dermally Applied Microarray; Migraine; drug delivery; headache; intracutaneous; triptan; zolmitriptan.

Figures

Figure 1.

Primary endpoints. Proportion of patients who were (a) pain-free or (b) free of their most bothersome other symptom at 2 hours post-dose. Error bars: 95% confidence intervals.

Figure 2.

Time course of pain freedom and pain relief. Proportion of patients who were (a) pain-free or (b) had pain relief, in the first 24 hours following dosing. Nominal p values: *p < 0.05, **p < 0.01.

Figure 3.

Secondary endpoints. Proportion of patients who, at 2 hours post-dose, were (a) photophobia-free, (b) phonophobia-free, (c) nausea-free, or (d) took rescue medications within 2 hours post-dose. Error bars: 95% confidence intervals. *p values are nominal.

Figure 4.

Proportions of patients who had sustained pain freedom and relief. (a) percentage of patients who were free from headache pain for the entire period of 2–24 hours (left panel) or 2–48 hours (right panel). (b) Percentage of patients who had pain relief for the entire period of 2–24 hours (left panel) or 2–48 hours (right panel). *p values are nominal.