MAP0004, Orally Inhaled DHE

A Randomized, Controlled Study in the Acute Treatment of Migraine

Sheena K. Aurora, MD; Stephen D. Silberstein, MD; Shashidhar H. Kori, MD; Stewart J. Tepper, MD; ScottW. Borland, MS; Min Wang, PhD; DavidW. Dodick, MD

Disclosures

Headache. 2011;51(4):507-517. 

In This Article

Methods

Patients

The study population included 903 male and female migraineurs, 18–65 years of age, with a history of episodic migraine with or without aura according to International Classification of Headache Disorders-2 criteria.[11] Eligible patients must have been diagnosed with migraine for a minimum of 1 year prior to the study and, in the 6 months prior to the screening visit, suffered from an average of 2–8 headaches/month. Patients on migraine prophylaxis and those with a prior history of triptan treatment were eligible for study inclusion. Eligible patients were required to complete a spirometry evaluation, with forced expiratory volume at 1 second (FEV1) ≥50% predicted and FEV1/forced vital capacity ratio ≥70% predicted. Eligible patients must also have had a normal or clinically insignificant electrocardiogram.

Patients with a known allergy or hypersensitivity to DHE or who were users of any concomitant excluded medication were ineligible. Participation in another MAP0004 trial, any other clinical trial in the past 30 days, or a history of hemiplegic or basilar migraine were causes for exlusion. Patients with ≥2 coronary artery disease risk factors, history of coronary artery disease, coronary vasospasm, aortic aneurysm, peripheral vascular disease or other ischemic diseases, or a history of stroke, transient ischemic attacks, or seizures were also excluded. Patients with a history of severe uncontrolled asthma, bronchospasm with inhaled medications, or chronic pulmonary disease other than asthma were excluded; however, patients with controlled asthma were eligible to participate in the trial and were also eligible to participate in the long-term open-label safety portion of the trial.

Standard Protocol Approvals, Registrations, and Patient Consents

The FREEDOM-301 study was conducted in accordance with Good Clinical Practices, International Conference on Harmonisation guidelines, applicable regulatory requirements, and ethical principles of the Declaration of Helsinki of 1975 (as revised in 2000). An appropriate Institutional Review Board approved the study protocol at each clinical site. Written informed consent was obtained from each potential patient prior to any protocol-related activities in accordance with Good Clinical Practices, the Code of Federal Regulations, and the Health Insurance Portability and Accountability Act of 1996. The first patient was enrolled in July 2008, and the last patient completed study assessments in March 2009 at 123 centers in the USA. All study personnel, patients, monitors, and the sponsor remained blinded to treatment assignment until after the database was locked at completion of the double-blind period. The study was registered at ClinicalTrials.gov (NCT00623636).

Procedures

This study was a phase 3, double-blind, multicenter comparison of MAP0004 0.6 mg emitted dose (1.0 mg nominal dose or 0.5 mg systemic equivalent) and placebo in the acute treatment of a single migraine. The double-blind portion of the study reported here consisted of 3 clinic visits. During visit 1, patients underwent baseline evaluations, were trained on use of the inhaler and electronic diary (e-diary), and completed the Headache Impact Test questionnaire.[20] At visit 2, patients were required to have reported at least 2 but not more than 8 migraines and to have had ≥20 headache-free days on their e-diary during the previous 28-day run-in period. Patients had to continue to satisfy all eligibility criteria to be randomized.

Eligible patients were randomly assigned in a 1:1 ratio without stratification to receive either MAP0004 or placebo. Randomization was centralized and performed by an automated interactive voice recognition system. Randomized patients were instructed to use study drug to treat a single qualifying migraine, defined by the Headache Classification Committee of the International Headache Society (2nd edition)[11] as a migraine with moderate or severe pain (patient assessed) that was either unilateral, throbbing (pulsating), or worsened with activity and occurred in the presence of either nausea, vomiting, or both phonophobia and photophobia. No triptan or ergot administration was allowed within the 24 hours prior to migraine onset. The e-diary directed patients to treat if the migraine was qualifying. The active inhaler contained DHE mesylate suspended in a mixture of hydrofluoroalkane propellants, while the placebo inhaler contained only the hydrofluoroalkane mixture. Patients returned for visit 3 for follow-up evaluations after treatment, and eligible patients were given the option to continue in a long-term open-label safety period if required baseline evaluations were completed.

During the double-blind phase, patients recorded time of onset of their qualifying migraine, severity of migraine symptoms, rescue medication use, and presence or absence of allodynia and other migraine attributes at baseline, upon administration of study drug, and at several time points up to 48 hours after treatment in the e-diary. Pain, nausea, photophobia, and phonophobia were assessed using a 4-point scale for severity (0-no symptoms, 1-mild symptoms, 2-moderate symptoms, 3-severe symptoms). All AEs reported by patients during treatment were recorded, and incidences of serious, severe, and treatment-related AEs were tabulated.

Outcome Measures

This study tested the hypothesis that MAP0004 would be superior to placebo for all 4 co-primary endpoints at the 2-hour time point. These endpoints, derived from US Food and Drug Administration requirements for regulatory approval, included the proportion of patients who achieved pain relief and those who were photophobia-free, phonophobia-free, and nausea-free at 2 hours posttreatment with no rescue medication use prior to the 2-hour time point. Four secondary endpoints were also analyzed: proportion of patients with SPR from 2–24 hours; time to pain relief during the 2-hour period; proportion of patients with pain relief at 4 hours; and proportion of patients with pain relief at 10 minutes. SPR from 2–24 hours was defined as the proportion of patients reporting pain relief at 2 hours which was subsequently maintained from 2–24 hours with no rescue medication use. Time to pain relief was defined as the time when pain relief (mild or no pain) was first observed and maintained through 2 hours with no rescue medication use at or prior to this time point. Pain relief at 4 hours and at 10 minutes was defined similarly to the 2-hour pain relief endpoint.

Other prespecified endpoints for analysis included time to pain freedom in the 2-hour period posttreatment; proportion of patients pain-free at 2 hours; proportion of patients with SPR from 2–48 hours posttreatment; and proportion of patients who were sustained pain-free (SPF) from 2–24 hours and 2–48 hours posttreatment, with no rescue medication use at or prior to the identified time point. Time to pain freedom, pain freedom at 2 hours, and SPF were defined similarly to the time to pain relief, pain relief, and SPR endpoints, respectively, but with a requirement of no pain.

Statistical Analysis

Sample size was determined using a 2-group continuity corrected chi-square test with a 2-sided, 5% type I error rate based on the following assumptions: rates of pain relief of 60% vs 40%, freedom from nausea of 71.5% vs 60%, freedom from photophobia of 55% vs 40%, and freedom from phonophobia of 55% vs 40% for MAP0004 vs placebo. Assuming a 10% dropout rate at treatment period end, approximately 850 patients were to be randomized to obtain 766 treated patients to provide an overall 86% power for a 2-sided test with 5% type I error rate.

The intent to treat (ITT) population was defined as all randomized patients and was primarily used to describe patient disposition. The predetermined modified ITT population, defined as all randomized patients who reported a qualifying migraine, received at least 1 dose of study drug, and reported a posttreatment efficacy evaluation for ≥1 time point at or before the 2-hour time point, was used for the primary analysis of efficacy. The safety population consisted of all patients who received 1 dose of study drug and had ≥1 posttreatment safety evaluation.

Each co-primary and secondary endpoint was tested for treatment effect by comparing MAP0004 and placebo-treated patients. A gate-keeping strategy was employed to control for the family-wise error rate of 0.05. If all 4 co-primary endpoints reached statistical significance, the first identified secondary endpoint (proportion of patients with SPR 2–24 hours) was tested for significance. Sequential significance testing of other secondary endpoints proceeded only if the preceding endpoint reached significance, otherwise no further testing was performed. Time to pain relief and freedom were analyzed using a log-rank test and Kaplan-Meier survival analysis techniques. All other prespecified and post hoc endpoints were analyzed using the Cochran-Mantel-Haenszel test, controlling for each respective baseline score, but not adjusted for multiplicity. All endpoints were analyzed at a 2-sided, 5% significance level.

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