Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study

Yuanyuan Li, Chunyi Wang, Ningdi Luo, Fangzheng Chen, Liche Zhou, Mengyue Niu, Wenyan Kang, Jun Liu, Yuanyuan Li, Chunyi Wang, Ningdi Luo, Fangzheng Chen, Liche Zhou, Mengyue Niu, Wenyan Kang, Jun Liu

Abstract

Background: As the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson's disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population.

Methods: The EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40-75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020.

Discussion: This is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence.

Trial registration: Clinicaltrials.gov, identifier: NCT04534023.

Keywords: efficacy and safety; idebenone; randomized controlled trial; rapid eye movement sleep behavior disorder (RBD); α-synucleinopathies.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer YZ declared a shared parent affiliation with the authors to the handling editor at the time of review.

Copyright © 2022 Li, Wang, Luo, Chen, Zhou, Niu, Kang and Liu.

Figures

Figure 1
Figure 1
Flowchart of study design.

References

    1. Dauvilliers Y, Schenck CH, Postuma RB, Iranzo A, Luppi PH, Plazzi G, et al. . Sleep behaviour disorder. Nat Rev Dis Primers. (2018) 4:19. 10.1038/s41572-018-0016-5
    1. Hogl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration - an update. Nat Rev Neurol. (2018) 14:40–55. 10.1038/nrneurol.2017.157
    1. Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. Neuropathology and molecular diagnosis of synucleinopathies. Mol Neurodegener. (2021) 16:83. 10.1186/s13024-021-00501-z
    1. Galbiati A, Verga L, Giora E, Zucconi M, Ferini-Strambi L. The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies. Sleep Med Rev. (2019) 43:37–46. 10.1016/j.smrv.2018.09.008
    1. Miglis MG, Adler CH, Antelmi E, Arnaldi D, Baldelli L, Boeve BF, et al. . Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder. Lancet Neurol. (2021) 20:671–84. 10.1016/S1474-4422(21)00176-9
    1. McKenna D, Peever J. Degeneration of rapid eye movement sleep circuitry underlies rapid eye movement sleep behavior disorder. Mov Disord. (2017) 32:636–44. 10.1002/mds.27003
    1. Peever J, Luppi PH, Montplaisir J. Breakdown in REM sleep circuitry underlies REM sleep behavior disorder. Trends Neurosci. (2014) 37:279–88. 10.1016/j.tins.2014.02.009
    1. St Louis B., Boeve BF. REM sleep behavior disorder in Parkinson's disease and other synucleinopathies. Mov Disord. (2017) 32:645–58. 10.1002/mds.27018
    1. Tekriwal A, Kern DS, Tsai J, Ince NF, Wu J, Thompson JA, et al. . Sleep behaviour disorder: prodromal and mechanistic insights for Parkinson's disease. J Neurol Neurosurg Psychiatry. (2017) 88:445–51. 10.1136/jnnp-2016-314471
    1. Iranzo A, Santamaria J, Tolosa E. The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases. Sleep Med Rev. (2009) 13:385–401. 10.1016/j.smrv.2008.11.003
    1. Howell MJ, Schenck CH. Rapid eye movement sleep behavior disorder and neurodegenerative disease. JAMA Neurol. (2015) 72:707–12. 10.1001/jamaneurol.2014.4563
    1. Postuma RB, Iranzo A, Hu M, Hogl B, Boeve BF, Manni R, et al. . Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. (2019) 142:744–59. 10.1093/brain/awz030
    1. Zhang H, Iranzo A, Hogl B, Arnulf I, Ferini-Strambi L, Manni R, et al. . Risk factors for phenoconversion in rapid eye movement sleep behavior disorder. Ann Neurol. (2022) 91:404–16. 10.1002/ana.26298
    1. Iranzo A, Santamaria J, Tolosa E. Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions. Lancet Neurol. (2016) 15:405–19. 10.1016/S1474-4422(16)00057-0
    1. Diagnosis C. Future directions. Mayo Clin Proc. (2017) 92:1723–36. 10.1016/j.mayocp.2017.09.007
    1. Ferri R, Rundo F, Silvani A, Zucconi M, Bruni O, Ferini-Strambi L, Plazzi G, Manconi M. REM Sleep EEG instability in REM sleep behavior disorder and clonazepam effects. Sleep. (2017) 40:zsx080. 10.1093/sleep/zsx080
    1. McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Med. (2015) 16:19–26. 10.1016/j.sleep.2014.09.011
    1. Gilat M, Coeytaux Jackson A, Marshall NS, Hammond D, Mullins AE, Hall JM, et al. . Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: a randomised controlled trial. Mov Disord. (2020) 35:344–9. 10.1002/mds.27886
    1. Malpartida AB, Williamson M, Narendra DP, Wade-Martins R, Ryan BJ. Mitochondrial dysfunction and mitophagy in parkinson's disease: from mechanism to therapy. Trends Biochem Sci. (2021) 46:329–43. 10.1016/j.tibs.2020.11.007
    1. Gueven N, Ravishankar P, Eri R, Rybalka E. Idebenone: when an antioxidant is not an antioxidant. Redox Biol. (2021) 38:101812. 10.1016/j.redox.2020.101812
    1. Yan J, Sun W, Shen M, Zhang Y, Jiang M, Liu A, et al. . Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice. Cell Death Discov. (2022) 8:28. 10.1038/s41420-022-00826-8
    1. Yan A, Liu Z, Song L, Wang X, Zhang Y, Wu N, et al. . Idebenone alleviates neuroinflammation and modulates microglial polarization in LPS-stimulated BV2 Cells and MPTP-induced Parkinson's disease mice. Front Cell Neurosci. (2018) 12:529. 10.3389/fncel.2018.00529
    1. Avci B, Gunaydin C, Guvenc T, Yavuz CK, Kuruca N, Bilge SS. Idebenone ameliorates rotenone-induced Parkinson's disease in rats through decreasing lipid peroxidation. Neurochem Res. (2021) 46:513–22. 10.1007/s11064-020-03186-w
    1. Tai KK, Pham L, Truong DD. Idebenone induces apoptotic cell death in the human dopaminergic neuroblastoma SHSY-5Y cells. Neurotox Res. (2011) 20:321–8. 10.1007/s12640-011-9245-z
    1. He PK, Gao YY Lyu FJ, Chen JN, Zhang YH, Nie K, et al. . Idebenone-activating autophagic degradation of alpha-synuclein via Inhibition of AKT-mTOR pathway in a SH-SY5Y-A53T model of Parkinson's disease: a network pharmacological approach. Evid Based Complement Alternat Med. (2021) 2021:8548380. 10.1155/2021/8548380
    1. American Academy of Sleep Medicine . International Classification of Sleep Disorders. 3rd ed. American Academy of Sleep Medicine, Darien, IL; (2014).
    1. Weyer G, Babej-Dölle RM, Hadler D, Hofmann S, Herrmann WM. A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease. Neuropsychobiology. (1997) 36:73–82. 10.1159/000119366
    1. Bergamasco B, Villardita C, Coppi R. Effects of idebenone in elderly subjects with cognitive decline. Results of a multicentre clinical trial. Arch Gerontol Geriatr. (1992) 15:279–86. 10.1016/0167-4943(92)90063-a
    1. Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, Folstein MF, Brandt J, Ross CA, Folstein SE. A controlled trial of idebenone in Huntington's disease. Mov Disord. (1996) 11:549–54. 10.1002/mds.870110510
    1. Liu J, Wang LN. Mitochondrial enhancement for neurodegenerative movement disorders: a systematic review of trials involving creatine, coenzyme Q10, idebenone and mitoquinone. CNS Drugs. (2014) 28:63–8. 10.1007/s40263-013-0124-4
    1. Li Y, Yang Y, Zhao A, Luo N, Niu M, Kang W, et al. . Parkinson's disease peripheral immune biomarker profile: a multicentre, cross-sectional and longitudinal study. J Neuroinflammation. (2022) 19:116. 10.1186/s12974-022-02481-3
    1. Li Y, Hao S, Zhang H, Mao W, Xue J, Zhang Y, et al. . Hypomethylation of SNCA in idiopathic REM sleep behavior disorder associated with phenoconversion. Mov Disord. (2021) 36:955–62. 10.1002/mds.28421
    1. Zhao A, Li Y, Niu M, Li G, Luo N, Zhou L, et al. . Hypomethylation in rapid eye movement sleep behavior disorder is a potential biomarker for Parkinson's disease. J Parkinsons Dis. (2020) 10:1023–31. 10.3233/JPD-201912
    1. Zhou L, Li G, Zhang Y, Zhang M, Chen Z, Zhang L, et al. . Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder. Brain. (2021) 144:1488–97. 10.1093/brain/awab039
    1. Li G, Chen Z, Zhou L, Zhao A, Niu M, Li Y, et al. . Altered structure and functional connectivity of the central autonomic network in idiopathic rapid eye movement sleep behaviour disorder. J Sleep Res. (2021) 30:e13136. 10.1111/jsr.13136
    1. Li G, Chen Z, Zhou L, Yao M, Luo N, Kang W, et al. . Abnormal intrinsic brain activity of the putamen is correlated with dopamine deficiency in idiopathic rapid eye movement sleep behavior disorder. Sleep Med. (2020) 75:73–80. 10.1016/j.sleep.2019.09.015
    1. Gueven N, Woolley K, Smith J. Border between natural product and drug: comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biol. (2015) 4:289–95. 10.1016/j.redox.2015.01.009
    1. Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, et al. . A controlled trial of idebenone in Huntington's disease. Mov Disord. (1996) 11:549–54.
    1. Huang Y, Ma M, Zhu X, Li M, Guo M, Liu P, et al. . Effectiveness of idebenone nanorod formulations in the treatment of Alzheimer's disease. J Control Release. (2021) 336:169–80. 10.1016/j.jconrel.2021.06.024
    1. Gutzmann H, Kühl KP, Hadler D, Rapp MA. Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry. (2002) 35:12–8. 10.1055/s-2002-19833
    1. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. (2007) 6:878–86. 10.1016/S1474-4422(07)70220-X
    1. Buyse GM, Voit T, Schara U, Straathof CSM, D'Angelo MG, Bernert G, et al. . Efficacy of idebenone on respiratory function in patients with duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet. (2015) 385:1748–57. 10.1016/S0140-6736(15)60025-3
    1. Lee HJ, Park JH, Hoe HS. Idebenone regulates abeta and LPS-induced neurogliosis and cognitive function through inhibition of NLRP3 inflammasome/IL-1beta axis activation. Front Immunol. (2022) 13:749336. 10.3389/fimmu.2022.749336

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner