Abstract and Introduction
Objective.— To evaluate the efficacy and tolerability of MAP0004 compared with placebo for a single migraine in adult migraineurs: The FREEDOM-301 Study.
Background.— Acute treatment of migraine remains a clinical challenge despite the availability of triptans and other agents. Injectable dihydroergotamine, although effective, is considered invasive and inconvenient, and intranasal dihydroergotamine is associated with inconsistent systemic dosage delivery. MAP0004 is an orally inhaled formulation of dihydroergotamine delivered to the systemic circulation. In a phase 2 study, MAP0004 provided significant early onset of pain relief (10 minutes, P < .05) and sustained pain relief for up to 48 hours with a favorable adverse event profile.
Methods.— A phase 3, randomized, double-blind, placebo-controlled, parallel-group, single-attack, outpatient study of MAP0004, an inhaled dihydroergotamine was conducted at 102 sites in 903 adults with a history of episodic migraine. Patients were randomized (1:1) to receive MAP0004 (0.63 mg emitted dose; 1.0 mg nominal dose) or placebo, administered after onset of a migraine headache with moderate to severe pain. The co-primary endpoints were patient-assessed pain relief and absence of photophobia, phonophobia, and nausea at 2 hours after treatment.
Results.— A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced a qualifying migraine. MAP0004 was superior to placebo in all 4 co-primary endpoints: pain relief (58.7% vs 34.5%, P < .0001), phonophobia free (52.9% vs 33.8%, P < .0001), photophobia free (46.6% vs 27.2%, P < .0001), and nausea free (67.1% vs 58.7%, P = .0210). Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 than with placebo (28.4% vs 10.1%, P < .0001). MAP0004 was well tolerated; no drug-related serious adverse events occurred.
Conclusions.— In this study, MAP0004 was effective and well tolerated for the acute treatment of migraine with or without aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with migraine compared with placebo.
Migraine is common, with US prevalence ~6% in men and ~18% in women. It is also debilitating, resulting in 112 million bedridden days and $13 billion in annual costs to employers. Underdiagnosis, undertreatment, and inadequate relief with treatment are frequently reported despite the availability of 7 different triptans and other options used for acute treatment of migraine.
Patient dissatisfaction with available therapies for the acute treatment of migraine is high. In a questionnaire administered in 3 headache centers to 183 patients with migraine diagnosed according to the 2nd edition of the International Classification of Headache Disorders (2004), 96.4% of whom took triptans alone or in combination as usual care, slow onset of action (37%), inadequate pain relief (42%), recurrence/worsening of pain (50%), inability to quickly function normally after taking medication (48%), and undesirable adverse event (AE) profiles (38%) were reasons cited for dissatisfaction. In light of these issues, 79% of these patients expressed a willingness to try a new medication to treat their migraine headaches. Undesirable AEs associated with triptans, collectively known as "triptan sensations," which may include tingling, paresthesias, chest pain or pressure, flushing, dizziness, and sensations of warmth involving the head, neck, chest, and extremities, may be of concern to patients that experience them.
Dihydroergotamine (DHE) has been used effectively for the acute treatment of migraine since the 1940s. Migraine treatment guidelines recommend DHE for severe migraines, refractory migraines, and recurrent headaches, and repetitive IV DHE has been reported to relieve symptoms in 90% of those with refractory headache, including chronic daily headache with and without medication overuse, short-duration headache, and cluster headache. IV DHE is associated with nausea, frequently necessitating pre-administration of antiemetic therapy. The invasiveness and inconvenience of injectable DHE and inconsistent systemic dosage delivery resulting from intranasal DHE administration have limited its use for the acute treatment of migraine.
MAP0004 (LEVADEX™, MAP Pharmaceuticals, Mountain View, CA, USA) is a novel formulation of DHE delivered by oral inhalation through the lungs to the systemic circulation using the TEMPO® inhaler (MAP Pharmaceuticals), designed to offer consistent, convenient, and noninvasive dosing. The inhaled route of administration may overcome limitations of current oral therapies in migraineurs experiencing gastric stasis, nausea, and vomiting, as well as providing more consistent drug delivery than intranasal administration. In a phase 2 study, MAP0004 provided a statistically significant early onset of pain relief (10 minutes) and meaningful sustained pain relief (SPR) for up to 48 hours with a favorable AE profile, including absence of nausea and relative lack of triptan sensation-type AEs. Pharmacokinetic studies with MAP0004 have shown that Cmax is reached in ~10 minutes, with a Cmax at least an order of magnitude lower than with IV DHE but with a similar area under the curve, which may account for the observed decrease in concentration-dependent AEs with MAP0004 compared with IV DHE.
The primary objective of this phase 3, double-blind, multicenter FREEDOM-301 study was to evaluate the efficacy and tolerability of orally inhaled MAP0004 compared with placebo for the acute treatment of a single migraine with or without aura. The 0.63 mg emitted dose (1.0 mg nominal dose or 0.5 mg systemic equivalent) was selected based on prior dose finding studies. The nominal dose is the dose metered out by the canister and delivered from the valve of the device; the emitted dose is that which comes out of the inhaler and is received by the patient. Efficacy assessments focused on migraine symptoms at the 2-hour time point after treatment, as is standard in migraine studies evaluating acute pharmacotherapies.