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Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis—a systematic review and meta-analysis

  • Linting Luo
  • Zhibin SongEmail author
  • Xiaoqiang Li
  • Huiwang
  • Yaqing Zeng
  • Qinwang
  • Meiqi
  • Jianli He
Review Article
  • 100 Downloads

Abstract

Background

Based on the results of randomized, double-blind, placebo-controlled trials, the benefit and safety of edaravone in the treatment of amyotrophic lateral sclerosis remain controversial. We performed a meta-analysis to evaluate the efficacy and safety of edaravone in the treatment of this disease.

Methods

We searched PubMed, the Cochrane Library, and Embase from the inception of electronic data to April 2018. We included randomized, double-blind, placebo-controlled trials reporting amyotrophic lateral sclerosis patients receiving 60-mg intravenous edaravone or intravenous saline placebo for 24 weeks. The primary efficacy evaluation was changed in Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to after the trial. Measure of safety was the frequency of investigated adverse events and serious adverse events. Data synthesis and analysis and evaluation of risk of bias were performed using RevMan 5.3 software. Heterogeneity among studies was evaluated with the I2 statistic.

Results

A total of 367 patients were analyzed across three randomized controlled trials (183 patients receiving intravenous edaravone; 184 receiving placebo). A difference in ALSFRS-R score between groups at 24 weeks was found (mean difference [MD] = 1.63, 95% confidence interval [CI] 0.26–3.00, P = .02). No differences in the frequency of adverse events (odds ratio [OR] = 1.22, 95% CI 0.68–2.19, P = .50) or serious adverse events (OR = 0.71, 95% CI 0.43–1.19, P = .20) were found.

Conclusion

Intravenous edaravone is efficacious in amyotrophic lateral sclerosis patients, with no severe adverse effects. Additional reliable randomized controlled trials with larger sample sizes will further assess the efficacy and safety of edaravone in amyotrophic lateral sclerosis.

Clinical trial registration

The systematic review and meta-analysis was registered in the international prospective register of systematic reviews. (PROSPERO registration number: CRD42018096191; http://www.crd.york.ac.uk/PROSPERO.)

Keywords

Amyotrophic lateral sclerosis Edaravone ALSFRS-R score 

Abbreviations

ALS

Amyotrophic lateral sclerosis

ALSFRS-R

Amyotrophic lateral sclerosis functional rating scale

RevMan

Review manager

RCTs

Randomized controlled trials

MD

Mean difference

CI

Confidence interval

OR

Odds ratio

Supplementary material

10072_2018_3653_MOESM1_ESM.doc (58 kb)
ESM 1 (DOC 58 kb)
10072_2018_3653_MOESM2_ESM.docx (14 kb)
ESM 2 (DOCX 13 kb)
10072_2018_3653_MOESM3_ESM.doc (51 kb)
ESM 3 (DOC 51 kb)

References

  1. 1.
    Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377(9769):942–955CrossRefGoogle Scholar
  2. 2.
    Barber SC, Mead RJ, Shaw PJ (2006) Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta 1762(11–12):1051–1067CrossRefGoogle Scholar
  3. 3.
    Taylor JP, Brown RJ, Cleveland DW, Decoding ALS (2016) From genes to mechanism. Nature 539(7628):197–206CrossRefGoogle Scholar
  4. 4.
    Katyal N, Govindarajan R (2017) Shortcomings in the current amyotrophic lateral sclerosis trials and potential solutions for improvement. Front Neurol 8:521CrossRefGoogle Scholar
  5. 5.
    Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG (2009) Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 10(5–6):310–323CrossRefGoogle Scholar
  6. 6.
    Petrov D, Mansfield C, Moussy A, Hermine O (2017) ALS Clinical trials review: 20 years of failure. Are we any closer to registering a new treatment? Front Aging Neurosci 9:68CrossRefGoogle Scholar
  7. 7.
    Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev (3):CD1447Google Scholar
  8. 8.
    Watanabe K, Tanaka M, Yuki S, Hirai M, Yamamoto Y (2018) How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr 62(1):20–38CrossRefGoogle Scholar
  9. 9.
    Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205–214CrossRefGoogle Scholar
  10. 10.
    Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L (2017) Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxidative Med Cell Longev 2017:2525967Google Scholar
  11. 11.
    Duan W, Li X, Shi J, Guo Y, Li Z, Li C (2010) Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell. Neuroscience 169(4):1621–1629CrossRefGoogle Scholar
  12. 12.
    Zuo L, Zhou T, Pannell BK, Ziegler AC, Best TM (2015) Biological and physiological role of reactive oxygen species--the good, the bad and the ugly. Acta Physiol (Oxford) 214(3):329–348CrossRefGoogle Scholar
  13. 13.
    Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC, Mahata J, Kilty M, Bednarz K, Bell D, Gordon PH, Hornig M, Mehrazin M, Naini A, Flint BM, Factor-Litvak P (2008) Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler 9(3):177–183CrossRefGoogle Scholar
  14. 14.
    Geffard M, Mangas A, Bedat D, Covenas R (2018) GEMALS : A promising therapy for amyotrophic lateral sclerosis. Exp Ther Med 15(4):3203–3210PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S, Ito H, Nakano S, Kusaka H (2008) Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol 213(2):448–455CrossRefGoogle Scholar
  16. 16.
    Tanaka M (2002) Pharmacological and clinical profile of the free radical scavenger edaravone as a neuroprotective agent. Nihon Yakurigaku Zasshi 119(5):301–308CrossRefGoogle Scholar
  17. 17.
    Fujisawa A, Yamamoto Y (2016) Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone. Redox Rep 21(3):98–103CrossRefGoogle Scholar
  18. 18.
    Aoki M, Warita H, Mizuno H, Suzuki N, Yuki S, Itoyama Y (2011) Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. Brain Res 1382:321–325CrossRefGoogle Scholar
  19. 19.
    Yoshino H, Kimura A (2009) Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study). Amyotroph Lateral Scler 7(4):247–251CrossRefGoogle Scholar
  20. 20.
    Nagase M, Yamamoto Y, Miyazaki Y, Yoshino H (2016) Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration. Redox Rep 21(3):104–112PubMedGoogle Scholar
  21. 21.
    Abe K, Aoki M, Tsuji S, et al. (2017) Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trials. Lancet Neurol 16(7):505–512Google Scholar
  22. 22.
    Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H (2014) Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 15(7–8):610–617CrossRefGoogle Scholar
  23. 23.
    Abe K, Itoyama Y, Tsuji S, et al. (2017) Exploratory double-blind, Parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: grade 3, requiring assistance for eating, excretion or ambulation). Amyotroph Lateral Scler Frontotemporal Degener 18(sup1):40–48Google Scholar
  24. 24.
    Lundh A, Gotzsche PC (2008) Recommendations by Cochrane review groups for assessment of the risk of bias in studies. BMC Med Res Methodol 8:22CrossRefGoogle Scholar
  25. 25.
    Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 51.0. Available at: http://handbook.cochrane.org/.2011
  26. 26.
    (1996) The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. The ALS CNTF treatment study (ACTS) phase I-II study group. Arch Neurol 53(2):141–147Google Scholar
  27. 27.
    Kasarskis E, Shefner J, Miller R (1999) A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF study group (phase III). Neurology 52(7):1427–1433Google Scholar
  28. 28.
    Ohashi Y, Tashiro K, Itoyama Y, Nakano I, Sobue G, Nakamura S, Sumino S, Yanagisawa N (2001) Study of functional rating scale for amyotrophic lateral sclerosis: revised ALSFRS (ALSFRS-R) Japanese version. No To Shinkei 53(4):346–355PubMedGoogle Scholar
  29. 29.
    Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (phase III). J Neurol Sci 169(1–2):13–21CrossRefGoogle Scholar
  30. 30.
    Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH (2004) Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 62(10):1758–1765CrossRefGoogle Scholar
  31. 31.
    D’Amico E, Factor-Litvak P, Santella RM, Mitsumoto H (2013) Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 65:509–527CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Linting Luo
    • 1
  • Zhibin Song
    • 1
    Email author
  • Xiaoqiang Li
    • 1
  • Huiwang
    • 1
  • Yaqing Zeng
    • 1
  • Qinwang
    • 1
  • Meiqi
    • 1
  • Jianli He
    • 1
  1. 1.Department of Neurology, Affiliated Xiaolan HospitalSouthern Medical UniversityZhongshanChina

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