Research Submissions Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered V R Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan Stephen Silberstein, MD; Paul K. Winner, DO; Peter J. McAllister, MD; Stewart J. Tepper, MD; Rashmi Halker, MD; Ramy A. Mahmoud, MD, MPH; Joao Siffert, MD * Objective.—To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA V R Xsail V R (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults. Background.—AVP-825 is a delivery system that uses a patient’s own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa condu- cive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan pow- der administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for effi- cacy, safety, and tolerability endpoints. Design/Methods.—COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sus- tained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occur- ring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs). From the Jefferson Headache Center, Philadelphia, PA, USA (S. Silberstein); Palm Beach Headache Center/Premiere Research Institute at Palm Beach Neurology, West Palm Beach, FL, USA (P.K. Winner); New England Institute for Neurol- ogy and Headache, Stamford, CT, USA (P.J. McAllister); Geisel School of Medicine at Dartmouth, Hanover, NH, USA (S.J. Tepper); Mayo Clinic Phoenix, Scottsdale, AZ, USA (R. Halker); OptiNose US Inc., Yardley, PA, USA (R.A. Mahmoud); Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA (J. Siffert). Address all correspondence to S. Silberstein, Jefferson Headache Center, Philadelphia, PA, USA, email: stephen.silberstein@ jefferson.edu Accepted for publication March 23, 2017. 1 ISSN 0017-8748 Headache doi: 10.1111/head.13105 V C 2017 American Headache Society Published by Wiley Periodicals, Inc.