Effect of Ubrogepant vs Placebo on Pain Among Patients With Acute Migraine Headaches | Headache | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of MigraineThe ACHIEVE II Randomized Clinical Trial

Educational Objective
To learn about the acute treatment of migraine.
1 Credit CME
Key Points

Question  Is ubrogepant, an oral calcitonin gene–related peptide receptor antagonist, effective in the acute treatment of migraine?

Findings  In this randomized clinical trial that included 1686 participants, rates of pain freedom at 2 hours were significantly greater with ubrogepant 50 mg (21.8%) or 25 mg (20.7%) than with placebo (14.3%). Rates of freedom from the most bothersome migraine-associated symptom at 2 hours were significantly greater with the 50-mg (38.9%) dose but not the 25-mg (34.1%) dose vs placebo (27.4%).

Meaning  Acute treatment of migraine with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with both the 50-mg and 25-mg doses, and freedom from the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose.

Abstract

Importance  Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist under investigation for acute treatment of migraine.

Objective  To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack.

Design, Setting, and Participants  Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month.

Interventions  Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity.

Main Outcomes and Measures  Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication.

Results  Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]).

Conclusions and Relevance  Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.

Trial Registration  ClinicalTrials.gov Identifier: NCT02867709

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Richard B. Lipton, MD, Montefiore Headache Center, Albert Einstein College of Medicine, 1225 Morris Park Ave, Van Etten Bldg, Room 3c12c, Bronx, NY 10461 (richard.lipton@einstein.yu.edu).

Accepted for Publication: September 23, 2019.

Correction: This article was corrected on April 7, 2020, to correct an imprecise statement in the Discussion section and fix a typographical error in Figure 2.

Author Contributions: Dr Lipton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lipton, Lu, Finnegan, Szegedi, Trugman.

Acquisition, analysis, or interpretation of data: Lipton, Dodick, Ailani, Lu, Finnegan, Szegedi, Trugman.

Drafting of the manuscript: Lipton, Ailani, Szegedi, Trugman.

Critical revision of the manuscript for important intellectual content: Lipton, Dodick, Ailani, Lu, Finnegan, Szegedi, Trugman.

Statistical analysis: Lu.

Administrative, technical, or material support: Finnegan, Trugman.

Supervision: Ailani, Szegedi, Trugman.

Conflict of Interest Disclosures: Dr Lipton reports that he serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache; has received research support from the National Institutes of Health (NIH); receives support from the Migraine Research Foundation and the National Headache Foundation; has reviewed for the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS); serves as consultant, advisory board member, or has received honoraria from Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Boston Scientific, Dr Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta; receives royalties from Wolff’s Headache and Informa; holds stock options in eNeura Therapeutics and Biohaven. Dr Dodick reports receiving personal fees from Amgen, Autonomic Technologies, Axsome, Aural Analytics, Allergan, Alder, Biohaven, Charleston Laboratories, Dr Reddy's Laboratories/Promius, Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), Theranica, Teva, Vedanta, WL Gore, Zosano, ZP Opco, Foresite Capital, Oppenheimer, Upjohn (Division of Pfizer), Pieris, Revance, Equinox, Salvia, and Amzak Health; has received CME fees or royalty payments from Healthlogix, Medicom, Medlogix, Mednet, Miller Medical, PeerView, WebMD/Medscape, Chameleon, Academy for Continued Healthcare Learning, Universal Meeting Management, Haymarket, Global Scientific Communications, UpToDate, Oxford University Press, Cambridge University Press, and Wolters Kluwer; has stock options for Aural Analytics, Healint, Theranica, Second Opinion/Mobile Health, Epien, GBS/Nocira, Matterhorn/Ontologics, and King-Devick Technologies; serves as a consultant without fee for Aural Analytics, Healint, Second Opinion/Mobile Health, and Epien; sits on the board of directors for Epien, Matterhorn/Ontologics, and King-Devick Technologies; has a patent (17189376.1-1466) for a botulinum toxin dosage regimen for chronic migraine prophylaxis, for which he receives no fee; receives research support from the American Migraine Foundation, Henry Jackson Foundation, Department of Defense, and Sperling Foundation; receives professional society fees or reimbursement for travel from the American Academy of Neurology, American Brain Foundation, American Headache Society, American Migraine Foundation, International Headache Society, and Canadian Headache Society; and has a use agreement through employer, Myndshft, Neuroassessment Systems. Dr Ailani reports that she serves as a consultant for, speaks on behalf of, or both for Allergan, Amgen, Alder, Avanir, Biohaven, Electrocore, Eli Lilly, Promius, Impel, Satsuma, Aptus, Miller Medical Communications, and Alpha sites and has served on clinical trials for Allergan, the American Migraine Foundation, and Theranica; and is an editor for Current Pain and Headache Reports. Drs Lu, Finnegan, Szegedi, and Trugman are full-time employees and stockholders of Allergan plc.

Funding/Support: This trial was sponsored by Allergan plc, Dublin, Ireland. Medical writing and editorial support were provided by Lela Creutz, PhD, and Lisa Feder, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, New Jersey, and Amy Kuang, PhD, of Allergan plc and funded by Allergan plc.

Role of the Funder/Sponsor: The design and conduct of the study, as well as collection, management, analysis, and interpretation of the data, were undertaken by the sponsor in collaboration with the academic authors. Preparation, review, and approval of the manuscript were done by all authors, and by a professional medical writer and editor employed by the sponsor. All authors approved the final manuscript for submission. The sponsor did not have the right to veto publication or to control the decision regarding to which journal the paper was submitted.

Disclaimer: The opinions expressed in this article are those of the authors.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the participants and investigators who participated in this study. We acknowledge Hassan Lakkis, PhD, for his contributions to the statistical analyses of the results of this study. Hassan Lakkis was an employee of Allergan plc at the time these analyses were conducted. His current affiliation is unknown.

References
1.
GBD 2015 Neurological Disorders Collaborator Group.  Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.   Lancet Neurol. 2017;16(11):877-897. doi:10.1016/S1474-4422(17)30299-5 PubMedGoogle ScholarCrossref
2.
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators.  Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.   Lancet. 2017;390(10100):1211-1259. doi:10.1016/S0140-6736(17)32154-2 PubMedGoogle ScholarCrossref
3.
Headache Classification Committee of the International Headache Society.  Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition.   Cephalalgia. 2018;38(1):1-211. doi:10.1177/0333102417738202PubMedGoogle ScholarCrossref
4.
Lipton  RB , Bigal  ME , Diamond  M , Freitag  F , Reed  ML , Stewart  WF ; AMPP Advisory Group.  Migraine prevalence, disease burden, and the need for preventive therapy.   Neurology. 2007;68(5):343-349. doi:10.1212/01.wnl.0000252808.97649.21 PubMedGoogle ScholarCrossref
5.
Buse  DC , Murray  S , Dumas  PK ,  et al.  Life with migraine, effect on relationships, career and finances, and overall health and well-being: results of the Chronic Migraine Epidemiology and Outcomes (CAMEO) study  [abstract MTIS2008-009].  Cephalalgia. 2018;38(1)(suppl):9-10.Google Scholar
6.
Buse  DC , Silberstein  SD , Manack  AN , Papapetropoulos  S , Lipton  RB .  Psychiatric comorbidities of episodic and chronic migraine.   J Neurol. 2013;260(8):1960-1969. doi:10.1007/s00415-012-6725-x PubMedGoogle ScholarCrossref
7.
American Headache Society.  The American Headache Society position statement on integrating new migraine treatments into clinical practice.   Headache. 2019;59(1):1-18.PubMedGoogle Scholar
8.
Lipton  RB , Buse  DC , Serrano  D , Holland  S , Reed  ML .  Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study.   Headache. 2013;53(8):1300-1311. doi:10.1111/head.12154 PubMedGoogle ScholarCrossref
9.
Bigal  M , Rapoport  A , Aurora  S , Sheftell  F , Tepper  S , Dahlof  C .  Satisfaction with current migraine therapy: experience from 3 centers in US and Sweden.   Headache. 2007;47(4):475-479. doi:10.1111/j.1526-4610.2007.00752.x PubMedGoogle ScholarCrossref
10.
Thorlund  K , Sun-Edelstein  C , Druyts  E ,  et al.  Risk of medication overuse headache across classes of treatments for acute migraine.   J Headache Pain. 2016;17(1):107. doi:10.1186/s10194-016-0696-8 PubMedGoogle ScholarCrossref
11.
Bigal  ME , Serrano  D , Buse  D , Scher  A , Stewart  WF , Lipton  RB .  Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study.   Headache. 2008;48(8):1157-1168. doi:10.1111/j.1526-4610.2008.01217.x PubMedGoogle ScholarCrossref
12.
Ho  TW , Edvinsson  L , Goadsby  PJ .  CGRP and its receptors provide new insights into migraine pathophysiology.   Nat Rev Neurol. 2010;6(10):573-582. doi:10.1038/nrneurol.2010.127 PubMedGoogle ScholarCrossref
13.
Lipton  RB , Croop  R , Stock  EG ,  et al.  Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine.   N Engl J Med. 2019;381(2):142-149. doi:10.1056/NEJMoa1811090 PubMedGoogle ScholarCrossref
14.
Croop  R , Goadsby  PJ , Stock  DA ,  et al.  Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.   Lancet. 2019;394(10200):737-745. doi:10.1016/S0140-6736(19)31606-X PubMedGoogle ScholarCrossref
15.
Voss  T , Lipton  RB , Dodick  DW ,  et al.  A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine.   Cephalalgia. 2016;36(9):887-898. doi:10.1177/0333102416653233 PubMedGoogle ScholarCrossref
16.
Headache Classification Committee of the International Headache Society (IHS).  The International Classification of Headache Disorders, 3rd edition (beta version) .  Cephalalgia. 2013;33(9):629-808. doi:10.1177/0333102413485658PubMedGoogle ScholarCrossref
17.
Cady  RK , McAllister  PJ , Spierings  EL ,  et al.  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).   Headache. 2015;55(1):88-100. doi:10.1111/head.12472 PubMedGoogle ScholarCrossref
18.
Temple  R .  Hy’s law: predicting serious hepatotoxicity.   Pharmacoepidemiol Drug Saf. 2006;15(4):241-243. doi:10.1002/pds.1211 PubMedGoogle ScholarCrossref
19.
US Food & Drug Administration [web page]. Drug-induced liver injury: premarketing clinical evaluation. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation. Issued 2009. Accessed February 6, 2019.
20.
Connor  KM , Shapiro  RE , Diener  HC ,  et al.  Randomized, controlled trial of telcagepant for the acute treatment of migraine.   Neurology. 2009;73(12):970-977. doi:10.1212/WNL.0b013e3181b87942 PubMedGoogle ScholarCrossref
21.
Ho  TW , Ferrari  MD , Dodick  DW ,  et al.  Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial.   Lancet. 2008;372(9656):2115-2123. doi:10.1016/S0140-6736(08)61626-8 PubMedGoogle ScholarCrossref
22.
Ho  TW , Mannix  LK , Fan  X ,  et al; MK-0974 Protocol 004 study group.  Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine.   Neurology. 2008;70(16):1304-1312. doi:10.1212/01.WNL.0000286940.29755.61 PubMedGoogle ScholarCrossref
23.
Bretz  F , Maurer  W , Brannath  W , Posch  M .  A graphical approach to sequentially rejective multiple test procedures.   Stat Med. 2009;28(4):586-604. doi:10.1002/sim.3495 PubMedGoogle ScholarCrossref
24.
Hewitt  DJ , Aurora  SK , Dodick  DW ,  et al.  Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine.   Cephalalgia. 2011;31(6):712-722. doi:10.1177/0333102411398399 PubMedGoogle ScholarCrossref
25.
Marmura  MJ , Silberstein  SD , Schwedt  TJ .  The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies.   Headache. 2015;55(1):3-20. doi:10.1111/head.12499 PubMedGoogle ScholarCrossref
26.
Lipton  RB , Reed  ML , Kurth  T , Fanning  KM , Buse  DC .  Framingham-based cardiovascular risk estimates among people with episodic migraine in the US population: results from the American Migraine Prevalence and Prevention (AMPP) Study.   Headache. 2017;57(10):1507-1521. doi:10.1111/head.13179 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close