Objective: Evaluate efficacy of a second dose of ubrogepant for the acute treatment of migraine. Background: Ubrogepant is an oral CGRP receptor antagonist in development for the acute treatment of migraine. Two doses of acute treatment separated over time is sometimes needed for migraine management. Design/Methods: ACHIEVE-I (NCT02828020) and ACHIEVE-II (NCT02867709) were single-attack, Phase 3 trials. Adults with a history of migraine, with/without aura were randomized 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25mg or 50mg, ACHIEVE-II). An optional second dose was allowed starting 2 hours post-initial dose if pain was still moderate. Participants initially randomized to ubrogepant were re-randomized to placebo or ubrogepant; those initially randomized to placebo received placebo for the second dose. Data for ubrogepant-50mg and placebo were pooled for this analysis. Treatment comparisons were based on those who took the same initial dose. Results: Participants’ (n=3358 randomized) mean age was 41 years; the majority were female and white. Of those who took an optional second dose of study medication (n=1144), a significantly higher proportion achieved 2-hour pain freedom with an optional second dose of ubrogepant-50mg (n=53/156, 34% pooled; OR: 2.20 [95%CI: 1.26, 3.85], p=0.0057) versus ubrogepant-50mg/placebo (n=25/131, 19% pooled). Of those who achieved 2-hour pain relief post-initial dose, a significantly higher proportion achieved pain freedom post-optional second dose of ubrogepant-50mg (n=41/75, 55% pooled; OR: 2.64 [95%CI: 1.27, 5.49] p=0.0091) versus ubrogepant-50mg/placebo (n=19/57, 33% pooled). Higher response rates were also observed following an optional second dose of ubrogepant-25mg and -100mg; however, differences were not significant. The proportion of participants reporting adverse events after 2 doses of ubrogepant was similar across treatment groups (8%–15%) and comparable to placebo/placebo (12%). Conclusions: Ubrogepant is the first and only treatment to demonstrate statistically higher rates of pain freedom at second dose compared to placebo. No safety concerns were identified following 2 doses of ubrogepant. Disclosure: Dr. Ailani has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amgen, Allergan, Eli Lilly and Company, Biohaven, Lundbeck, Theranica, Impel, Satsuma, Zosano, Revance,and Teva. Dr. Ailani has received personal compensation in an editorial capacity for Current Pain and Headache. Dr. Ailani has received research support from Allergan, Biohaven, Zosano, Eli Likky and Company.Dr. Blumenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for consulting and promotional activities from: Allergan, Alder, Amgen, Teva, Lilly, Biohaven, Theranica, Supernus, Novartis.. Dr. Blumenfeld holds stock and/or stock options in Alder, sold. Dr. Blumenfeld has received research support from Not personally, many research projects funded by Pharma were done with The Neurology Center, who also employs me..Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan, Teva, Eagalet, Amgen, Promius, AAN, Depomed. Dr. Klein has received royalty, license fees, or contractual rights payments from AppsbyDocs, LLC. Dr. Klein has received research support from Eli Lilly, Allergan. Dr. Finnegan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of Allergan plc. Dr. Finnegan holds stock and/or stock options as a full-time employee and stockholder of Allergan plc. which sponsored research in which Dr. Finnegan was involved as an investigator. Dr. Finnegan holds stock and/or stock options as a full-time employee and stockholder of Allergan plc.. Dr. Finnegan has received research support from Allergan plc.. Dr. Severt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lawrence Severt, MD, PhD, is a full-time employee and stockholder of Allergan plc.. Dr. Severt holds stock and/or stock options in Lawrence Severt, MD, PhD, is a full-time employee and stockholder of Allergan plc. which sponsored research in which Dr. Severt was involved as an investigator. Dr. Severt holds stock and/or stock options in Lawrence Severt, MD, PhD, is a full-time employee and stockholder of Allergan plc.. Dr. Severt has received research support from Lawrence Severt, MD, PhD, is a full-time employee and stockholder of Allergan plc.. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allergan plc.. Dr. Liu holds stock and/or stock options in ChengCheng Liu is a full-time employee and stockholder of Allergan plc. which sponsored research in which Dr. Liu was involved as an investigator. Dr. Liu has received research support from ChengCheng Liu is a full-time employee and stockholder of Allergan plc.. Dr. Trugman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Joel M. Trugman, MD, is a full-time employee and stockholder of Allergan plc.. Dr. Trugman holds stock and/or stock options in Joel M. Trugman, MD, is a full-time employee and stockholder of Allergan plc. which sponsored research in which Dr. Trugman was involved as an investigator. Dr. Trugman holds stock and/or stock options in Joel M. Trugman, MD, is a full-time employee and stockholder of Allergan plc.. Dr. Trugman has received research support from Joel M. Trugman, MD, is a full-time employee and stockholder of Allergan plc..