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

ObjectiveTo determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment.BackgroundADAM 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.MethodsThis 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.ResultsOf 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.ConclusionADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated.ClinicalTrials.govNCT02745392

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).…”

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

“…In this multicenter, randomized, double‐blind, placebo‐controlled, parallel group Phase 2b/3 study, patients treated with ADAM zolmitriptan 3.8 mg were significantly more likely to be pain‐free and/or MBS‐free at 2 hours post‐treatment than those receiving placebo 5. Approximately 80 patients per treatment group were sufficient to show a clear difference between an effective therapy and placebo.…”

“…Pain freedom is now recommended in place of pain relief as a primary efficacy endpoint, as it is considered more clinically meaningful. It is also the recommended primary endpoint for acute migraine treatment trials by the International Headache Society 5. The major associated symptoms of migraine—photophobia, phonophobia, and nausea—are important for assessing a therapy's effect on the migraine, but all symptoms are not always present.…”

“…The ZOTRIP trial is the only published pivotal trial to use prespecified usual MBS freedom as a co‐primary endpoint along with pain freedom at 2 hours 5. In this multicenter, randomized, double‐blind, placebo‐controlled, parallel group Phase 2b/3 study, patients treated with ADAM zolmitriptan 3.8 mg were significantly more likely to be pain‐free and/or MBS‐free at 2 hours post‐treatment than those receiving placebo 5.…”

“…Detailed methods and primary study results were previously reported 5. Eligible patients experienced 2‐8 migraine headaches (with or without aura) during a 28‐day run‐in period.…”