A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study)

Abstract

Objective: To evaluate the efficacy and safety of AVP-825, a drug-device combination of low-dose sumatriptan powder (22 mg loaded dose) delivered intranasally through a targeted Breath Powered device vs an identical device containing lactose powder (placebo device) in the treatment of migraine headache.

Background: Early treatment of migraine headaches is associated with improved outcome, but medication absorption after oral delivery may be delayed in migraineurs because of reduced gastric motility. Sumatriptan powder administered with an innovative, closed-palate, Bi-Directional, Breath Powered intranasal delivery mechanism is efficiently absorbed across the nasal mucosa and produces fast absorption into the circulation. Results from a previously conducted placebo-controlled study of AVP-825 showed a high degree of headache relief with an early onset of action (eg, 74% AVP-825 vs 38% placebo device at 1 hour, P<.01).

Methods: In this double-blind, placebo-controlled, parallel-group study in adults with a history of migraine with or without aura, participants were randomized via computer-generated lists to AVP-825 or placebo device to treat a single migraine headache of moderate or severe intensity. The primary endpoint was headache relief (defined as reduction of headache pain intensity from severe or moderate migraine headache to mild or none) at 2 hours post-dose.

Results: Two hundred and thirty patients (116 AVP-825 and 114 placebo device) were randomized, of whom 223 (112 and 111, respectively) experienced a qualifying migraine headache (their next migraine headache that reached moderate or severe intensity). A significantly greater proportion of AVP-825 patients reported headache relief at 2 hours post-dose compared with those using the placebo device (68% vs 45%, P=.002, odds ratio 2.53, 95% confidence interval [1.45, 4.42]). Between-group differences in headache relief were evident as early as 15 minutes, reached statistical significance at 30 minutes post-dose (42% vs 27%, P=.03), and were sustained at 24 hours (44% vs 24%, P=.002) and 48 hours (34% vs 20%, P=.01). Thirty-four percent of patients treated with AVP-825 were pain-free at 2 hours compared with 17% using the placebo device (P=.008). More AVP-825 patients reported meaningful pain relief (patient interpretation) of migraine within 2 hours of treatment vs placebo device (70% vs 45%, P<.001), and fewer required rescue medication (37% vs 52%, P=.02). Total migraine freedom (patients with no headache, nausea, phonophobia, photophobia, or vomiting) reached significance following treatment with AVP-825 at 1 hour (19% vs 9%; P=.04). There were no serious adverse events (AEs), and no systemic AEs occurred in more than one patient. Chest pain or pressure was not reported, and only one patient taking AVP-825 reported mild paresthesia. No other triptan sensations were reported.

Conclusions: Targeted delivery of a low-dose of sumatriptan powder via a novel, closed-palate, Breath Powered, intranasal device (AVP-825) provided fast relief of moderate or severe migraine headache in adults that reached statistical significance over placebo by 30 minutes. The treatment was well tolerated with a low incidence of systemic AEs.

Trial registration: ClinicalTrials.gov NCT01462812.

Keywords: AVP-825; Bi-Directional nasal delivery; Breath Powered nasal delivery; intranasal delivery; migraine; sumatriptan powder.

Fig 1

Gamma camera image of deposition 2 minutes after delivery of a solution of ^99mTcO₄ in saline using a conventional liquid spray device (A) and ^99mTc-labeled lactose powder delivered using the Breath Powered device (B). The image of the nasal cavity is superimposed on the corresponding sagittal MRI section. The images were from the same subject after each method of administration.

Fig 2

Patient disposition. The Safety Analysis Dataset includes all patients who received at least one dose of the study drug. The Full Analysis Dataset includes all patients who received at least one dose of the study drug and recorded at least one post-treatment assessment of pain severity.

Fig 3

Patients with headache relief up to 120 minutes and sustained relief at 24 and 48 hours (FAS). ^*P < .05;^†P < .01;^‡P < .001. Headache relief  =  reduction from severe (grade 3) or moderate (grade 2) headache pain to mild (grade 1) headache pain or none (grade 0). Sustained relief at 24 or 48 hours was calculated for patients with headache relief at 120 minutes and required that patients had no recurrence of headache, or rescue medication usage during that timeframe.