Abstract
Introduction
Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed.
Methods
Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.
Results
A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.
Conclusion
In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.
Trial Registration
NCT03670810.
Plain Language Summary
Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT1F receptor) with a proven efficacy and safety in phase 2 and 3 studies. Owing to some differences in clinical practice between China and western countries, there is need to get additional evidence on safety of lasmiditan in the Chinese population to support its usage in clinical practice.
This post hoc analysis was conducted to present the detailed safety profile of lasmiditan in the Chinese population using data from the CENTURION study. Approximately half of the analyzed population was not covered in the published primary cohort.
The results show that in the Chinese population of the study, most of the treatment-emergent adverse events (TEAEs) were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort with no new safety concerns observed in the Chinese population. The overall safety profile of lasmiditan in the Chinese population was generally consistent with the primary cohort. The results provide additional evidence and emphasize that lasmiditan may be considered as a useful acute treatment option with acceptable safety profile for patients with migraine in China.
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References
Burch RC, Buse DC, Lipton RB. Migraine: epidemiology, burden, and comorbidity. Neurol Clin. 2019;37:631–49.
Yao C, Wang Y, Wang L, et al. Burden of headache disorders in China, 1990–2017: findings from the Global Burden of Disease Study 2017. J Headache Pain. 2019;20:102.
Luo N, Qi W, Zhuang C, et al. A satisfaction survey of current medicines used for migraine therapy in China: is Chinese patent medicine effective compared with Western medicine for the acute treatment of migraine? Pain Med. 2014;15:320–8.
Zhao H, Zhang L, Ford J, et al. Treatment patterns and real-world outcomes among patients with episodic migraine in China: results from the Chinese Adelphi Disease Specific Programme. ISPOR Annual Meeting 2021, PND64. https://www.ispor.org/conferences-education/conferences/past-conferences/ispor-2021/program/posters. Accessed 30 Mar 2022.
Ong JJY, De Felice M. Migraine treatment: current acute medications and their potential mechanisms of action [published correction appears in Neurotherapeutics. 2018 Jan 8]. Neurotherapeutics. 2018;15:274–90.
MAXALT (rizatriptan benzoate) tablets, for oral use highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020864s011s016s017s018s019,020865s012s016s018s020s021lbl.pdf. Accessed 10 Mar 2022.
Tfelt-Hansen P, Saxena PR, Dahlöf C, et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain. 2000;123(Pt 1):9–18.
DURLAZA (aspirin) Extended-Release Capsules, for oral use highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/200671s000lbl.pdf. Accessed 3 Feb 2022.
FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory. Accessed 16 Feb 2022.
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;53:1300–11.
Mafi JN, Edwards ST, Pedersen NP, Davis RB, McCarthy EP, Landon BE. Trends in the ambulatory management of headache: analysis of NAMCS and NHAMCS data 1999–2010. J Gen Intern Med. 2015;30:548–55.
Yu S, Zhang Y, Yao Y, Cao H. Migraine treatment and healthcare costs: retrospective analysis of the China Health Insurance Research Association (CHIRA) database. J Headache Pain. 2020;21:53.
Clemow DB, Johnson KW, Hochstetler HM, et al. Lasmiditan mechanism of action—review of a selective 5-HT1F agonist. J Headache Pain. 2020;21:71.
REYVOW (lasmiditan) tablets, for oral use. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211280s000lbl.pdf Accessed 3 Nov 2021.
Färkkilä M, Diener HC, Géraud G, et al. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol. 2012;11:405–13.
Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142:1894–904.
Krege JH, Rizzoli PB, Liffick E, et al. Safety findings from phase 3 lasmiditan studies for acute treatment of migraine: results from SAMURAI and SPARTAN [published correction appears in Cephalalgia. 2021; 41:1035. Cephalalgia. 2019;39:957–66.
Ashina M, Reuter U, Smith T, et al. Randomized, controlled trial of lasmiditan over four migraine attacks: findings from the CENTURION study. Cephalalgia. 2021;41:294–304.
Tassorelli C, Bragg S, Krege J, et al. Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine. J Headache Pain. 2021;22:132.
Lipton RB, Marcus SC, Shewale AR, Dodick DW, Viswanathan HN, Doshi JA. Acute treatment patterns in patients with migraine newly initiating a triptan. Cephalalgia. 2020;40:437–47.
Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S49–73 (Erratum in Circulation. 2014;129:S74–5).
Tepper SK, Krege J, Lombard L, et al. Characterization of dizziness after lasmiditan: findings from the SAMURAI and SPARTAN acute migraine treatment randomized trials. Headache. 2019;59:1052–62.
Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol. 2002;59:1084–8.
Bigal ME, Kurth T, Hu H, et al. Migraine and cardiovascular disease: possible mechanisms of interaction. Neurology. 2009;72:1864–71.
Dodick DW, Shewale AS, Lipton RB, et al. Migraine patients with cardiovascular disease and contraindications: an analysis of real-world claims data. J Prim Care Community Health. 2020;11:2150132720963680.
Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin, 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358:1668–75.
Nilsson T, Longmore J, Shaw D, et al. Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol. 1999;128:1133–40.
Neeb L, Meents J, Reuter U. 5-HT1F receptor agonists: a new treatment option for migraine attacks? Neurotherapeutics. 2010;7:176–82.
Rubio-Beltrán E, Labastida-Ramírez A, Villalon CM, et al. Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol Ther. 2018;186:88–97.
Depomed Inc. CAMBIA (diclofenac potassium), for oral solution. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022165lbl.pdf. Accessed 3 Nov 2021.
Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol. 2016;4:131–42.
Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100:747–58.
Acknowledgements
The authors would like to thank the study participants for their consent and participation in the study.
Funding
This study, and the journal’s Rapid Service fee for the publication were funded and supported by Eli Lilly and Company.
Medical Writing, Editorial, and Other Assistance
The authors would like to thank Yan Cheng, Chenxi Qian, and Quan Hu from Eli Lilly and Company for their valuable review of this article. The authors would like to thank Nan Yao from Eli Lilly and Company for project management, medical writing, and editorial assistance. The authors would like to thank Deepika Kajarekar, from Syneos Health for medical writing support. The funding for this support was provided by Eli Lilly and Company.
Author Contributions
Shengyuan Yu was involved in study design. Shengyuan Yu, Jiying Zhou, Guogang Luo, Yuming Xu, Xiaosu Yang, Xiaoping Pan, Zhao Dong, Shiying Zhong, and Hui Liu were involved in collection and interpretation of data. Shiying Zhong, Hui Liu, Jiying Zhou, Fei Ji drafted the manuscript, and all authors reviewed the manuscript. Fei Ji performed the statistical analyses. All authors read and approved the final manuscript.
Disclosures
Shiying Zhong, Hui Liu, and Fei Ji are full-time employees at Eli Lily and Company. Shengyuan Yu serves as associate editor of the Journal of Headache and Pain and as a member of the International Headache Society. Jiying Zhou, Guogang Luo, Yuming Xu, Xiaosu Yang, Xiaoping Pan, Zhao Dong, and Shengyuan Yu report financial relationships with Eli Lilly and Company for clinical research fee.
Compliance with Ethics Guidelines
The study received approval from the relevant ethics committees from all study sites, and patients provided written informed consent for study participation. The study was conducted in accordance with the Declaration of Helsinki.
Data Availability
The datasets generated during and/or analyzed during the current study are available on reasonable request from the corresponding author.
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Zhou, J., Luo, G., Xu, Y. et al. Safety Findings in Lasmiditan as a Novel Acute Treatment of Migraine in Chinese Patients: A Post Hoc Analysis of the Randomized Controlled Phase 3 CENTURION Trial. Adv Ther 39, 5229–5243 (2022). https://doi.org/10.1007/s12325-022-02291-2
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DOI: https://doi.org/10.1007/s12325-022-02291-2