Efficacy, Safety, and Tolerability Study of Oral Ubrogepant in the Acute Treatment of Migraine

• Ubrogepant (Drug): 50 mg ubrogepant tablet(s) orally for the treatment of a qualifying migraine attack.
• Placebo-matching Ubrogepant (Drug): Placebo-matching ubrogepant tablet(s) orally for the treatment of a qualifying migraine attack.

Primary outcomes

• Percentage of Participants With Pain Freedom at 2 Hours After Initial Dose [Baseline (Predose) to 2 hours after initial dose]: Pain freedom was defined as a reduction in headache severity from moderate/severe at baseline to no pain at 2 hours after the initial dose. Participants were provided with an electronic diary (eDiary) to rate headache severity on a scale from no pain to severe pain. Number analyzed is the number of participants with non-missing postdose pain severity assessment at or before 2 hours after initial dose.
• Percentage of Participants With Absence of the Most Bothersome Migraine-Associated Symptom Identified at Baseline at 2-Hours After Initial Dose [Baseline (Predose) to 2 hours after initial dose]: The most bothersome migraine-associated symptom was the symptom (photophobia, phonophobia or nausea) present at pre-dose baseline identified by the participant to be 'most bothersome'. Participants were provided with an eDiary to record absence or presence of migraine-associated symptoms. Number analyzed is the number of participants with non-missing postdose most bothersome migraine-associated symptoms.

Secondary outcomes

• Percentage of Participants With Pain Relief at 2 Hours After the Initial Dose [Baseline (Predose) to 2 hours after initial dose]: Pain relief was defined as a reduction of a moderate/severe migraine headache to a mild headache or to no headache. Participants were provided with an eDiary to rate headache severity on a scale from no pain to severe pain. Number analyzed is the number of participants with non-missing pain severity assessment at or before 2 hours after initial dose.
• Percentage of Participants With Sustained Pain Relief From 2 to 24 Hours After Initial Dose [2 to 24 hours after initial dose]: Sustained pain relief was defined as a pain relief at 2 hours with no administration of either rescue medication or the second dose of study drug, and with no occurrence thereafter of a moderate/severe headache up to 24 hours after dosing with study drug. Participants were provided with an eDiary to rate headache severity on a scale from no pain to severe pain. Determinable cases: participants for whom sustained pain relief from 2 to 24 hours status can be determined based on the observed headache severity at scheduled time points, use of rescue medication or optional second dose between 2 and 24 hours, and the answer to the headache recurrence question at 24 hours. Number analyzed is the number of participants with determinable sustained pain relief from 2 to 24 hours after initial dose.
• Percentage of Participants With Sustained Pain Freedom From 2 to 24 Hours After Initial Dose [2 to 24 hours after initial dose]: Sustained pain freedom was defined as a pain freedom at 2 hours with no administration of either rescue medication or the second dose of study drug, and with no occurrence thereafter of a mild/moderate/severe headache up to 24 hours after dosing with study drug. Participants were provided with an eDiary to rate headache severity on a scale from no pain to severe pain. Determinable cases: participants for whom sustained pain relief from 2 to 24 hours status can be determined based on the observed headache severity at scheduled time points, use of rescue medication or optional second dose between 2 and 24 hours, and the answer to the headache recurrence question at 24 hours. Number analyzed is the number of participants with determinable sustained pain freedom from 2 to 24 hours after initial dose.
• Percentage of Participants With the Absence of Photophobia at 2 Hours After the Initial Dose [2 hours after initial dose]: Photophobia was defined as sensitivity to light, a migraine-associated symptom. Participants were provided with an eDiary to record absence or presence photophobia. Number analyzed is the number of participants with non-missing postdose photophobia assessment at or before 2 hours after initial dose.
• Percentage of Participants With the Absence of Phonophobia at 2 Hours After the Initial Dose [2 hours after initial dose]: Phonophobia was defined as sensitivity to sound, a migraine-associated symptom. Participants were provided with an eDiary to record absence or presence of phonophobia. Number analyzed is the number of participants with non-missing postdose phonophobia assessment at or before 2 hours after initial dose.
• Percentage of Participants With Absence of Nausea at 2 Hours After the Initial Dose [2 hours after initial dose]: Nausea was a migraine-associated symptom. Participants were provided with an eDiary to record absence or presence of nausea. Number analyzed is the number of participants with non-missing postdose nausea assessment at or before 2 hours after initial dose.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* At least a 1-year history of migraine with or without aura consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd edition, beta version
* Migraine onset before age 50
* History of migraines typically lasting between 4 and 72 hours if untreated or treated unsuccessfully and migraine episodes are separated by at least 48 hours of headache pain freedom
* History of 2 to 8 migraine attacks per month with moderate to severe headache pain in each of the previous 3 months.

Exclusion Criteria:

* Difficulty distinguishing migraine headache from other headaches
* Has taken medication for acute treatment of headache (including acetaminophen, nonsteroidal anti-inflammatory drugs \[NSAIDs\], triptans, ergotamine, opioids, or combination analgesics) on 10 or more days per month in the previous 3 months
* Has a history of migraine aura with diplopia or impairment of level of consciousness, hemiplegic migraine, or retinal migraine
* Has a current diagnosis of new persistent daily headache, trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy
* Required hospital treatment of a migraine attack 3 or more times in the previous 6 months
* Has a chronic non-headache pain condition requiring daily pain medication
* Has a history of malignancy in the prior 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
* Has a history of any prior gastrointestinal conditions (eg, diarrhea syndromes, inflammatory bowel disease) that may affect the absorption or metabolism of investigational product; participants with prior gastric bariatric interventions which have been reversed are not excluded
* Has a history of hepatitis within previous 6 months.

Participant flow

Outcome results

• Percentage of Participants With Pain Freedom at 2 Hours After Initial Dose (Primary), Number, percentage of participants: Placebo 11.8; Ubrogepant 50 mg 19.2; Ubrogepant 100 mg 21.2 (p 0.0023)
• Percentage of Participants With Absence of the Most Bothersome Migraine-Associated Symptom Identified at Baseline at 2-Hours After Initial Dose (Primary), Number, percentage of participants: Placebo 27.8; Ubrogepant 50 mg 38.6; Ubrogepant 100 mg 37.7 (p 0.0023)
• Percentage of Participants With Pain Relief at 2 Hours After the Initial Dose (Secondary), Number, percentage of participants: Placebo 49.1; Ubrogepant 50 mg 60.7; Ubrogepant 100 mg 61.4 (p 0.0023)
• Percentage of Participants With Sustained Pain Relief From 2 to 24 Hours After Initial Dose (Secondary), Number, percentage of participants: Placebo 20.8; Ubrogepant 50 mg 36.3; Ubrogepant 100 mg 38.0 (p 0.0023)
• Percentage of Participants With Sustained Pain Freedom From 2 to 24 Hours After Initial Dose (Secondary), Number, percentage of participants: Placebo 8.6; Ubrogepant 50 mg 12.7; Ubrogepant 100 mg 15.4 (p 0.0577)
• Percentage of Participants With the Absence of Photophobia at 2 Hours After the Initial Dose (Secondary), Number, percentage of participants: Placebo 31.4; Ubrogepant 50 mg 40.7; Ubrogepant 100 mg 45.8 (p 0.0577)
• Percentage of Participants With the Absence of Phonophobia at 2 Hours After the Initial Dose (Secondary), Number, percentage of participants: Placebo 47.1; Ubrogepant 50 mg 57.9; Ubrogepant 100 mg 54.5 (p 0.0577)
• Percentage of Participants With Absence of Nausea at 2 Hours After the Initial Dose (Secondary), Number, percentage of participants: Placebo 62.3; Ubrogepant 50 mg 70.2; Ubrogepant 100 mg 69.2 (p 0.0962)

Adverse events

Time frame: From first dose through 30 days after the last dose of study drug (approximately 30 days)

Serious adverse events by term

• Results publication: Goadsby PJ, Jurgens TP, Brand-Schieber E, Nagy K, Liu Y, Boinpally R, Stodtmann S, Trugman JM. Efficacy of ubrogepant and atogepant in males and females with migraine: A secondary analysis of randomized clinical trials. Cephalalgia. 2025 Feb;45(2):3331024251320610. doi: 10.1177/03331024251320610. PMID 39982105
• Results publication: Johnston KM, Powell L, Popoff E, Harris L, Croop R, Coric V, L'Italien G. Rimegepant, Ubrogepant, and Lasmiditan in the Acute Treatment of Migraine Examining the Benefit-Risk Profile Using Number Needed to Treat/Harm. Clin J Pain. 2022 Nov 1;38(11):680-685. doi: 10.1097/AJP.0000000000001072. PMID 36125279
• Results publication: Lipton RB, Singh RBH, Revicki DA, Zhao S, Shewale AR, Lateiner JE, Dodick DW. Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials. J Headache Pain. 2022 Apr 25;23(1):50. doi: 10.1186/s10194-022-01419-7. PMID 35468729
• Results publication: Blumenfeld AM, Knievel K, Manack Adams A, Severt L, Butler M, Lai H, Dodick DW. Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase 3 Trials. Adv Ther. 2022 Jan;39(1):692-705. doi: 10.1007/s12325-021-01923-3. Epub 2021 Dec 7. PMID 34874514
• Results publication: Hutchinson S, Silberstein SD, Blumenfeld AM, Lipton RB, Lu K, Yu SY, Severt L. Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II. Cephalalgia. 2021 Aug;41(9):979-990. doi: 10.1177/03331024211000311. Epub 2021 Apr 19. PMID 33874756
• Results publication: Hutchinson S, Dodick DW, Treppendahl C, Bennett NL, Yu SY, Guo H, Trugman JM. Ubrogepant for the Acute Treatment of Migraine: Pooled Efficacy, Safety, and Tolerability From the ACHIEVE I and ACHIEVE II Phase 3 Randomized Trials. Neurol Ther. 2021 Jun;10(1):235-249. doi: 10.1007/s40120-021-00234-7. Epub 2021 Feb 20. PMID 33608814
• Results publication: Goadsby PJ, Blumenfeld AM, Lipton RB, Dodick DW, Kalidas K, M Adams A, Jakate A, Liu C, Szegedi A, Trugman JM. Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications. Cephalalgia. 2021 Apr;41(5):546-560. doi: 10.1177/0333102420970523. Epub 2020 Nov 26. PMID 33241721
• Results publication: Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, Szegedi A. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019 Dec 5;381(23):2230-2241. doi: 10.1056/NEJMoa1813049. PMID 31800988

• Study Protocol (PDF, 2017-05-19)
• Statistical Analysis Plan (PDF, 2018-01-22)

• Adele Thorpe, Study director, Allergan