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.)
Similar content being viewed by others
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
References
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377(9769):942–955
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):1051–1067
Taylor JP, Brown RJ, Cleveland DW, Decoding ALS (2016) From genes to mechanism. Nature 539(7628):197–206
Katyal N, Govindarajan R (2017) Shortcomings in the current amyotrophic lateral sclerosis trials and potential solutions for improvement. Front Neurol 8:521
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):310–323
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 9:68
Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev (3):CD1447
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):20–38
Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205–214
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 2017:2525967
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):1621–1629
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):329–348
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):177–183
Geffard M, Mangas A, Bedat D, Covenas R (2018) GEMALS : A promising therapy for amyotrophic lateral sclerosis. Exp Ther Med 15(4):3203–3210
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):448–455
Tanaka M (2002) Pharmacological and clinical profile of the free radical scavenger edaravone as a neuroprotective agent. Nihon Yakurigaku Zasshi 119(5):301–308
Fujisawa A, Yamamoto Y (2016) Edaravone, a potent free radical scavenger, reacts with peroxynitrite to produce predominantly 4-NO-edaravone. Redox Rep 21(3):98–103
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 1382:321–325
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):247–251
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):104–112
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):505–512
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):610–617
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):40–48
Lundh A, Gotzsche PC (2008) Recommendations by Cochrane review groups for assessment of the risk of bias in studies. BMC Med Res Methodol 8:22
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 51.0. Available at: http://handbook.cochrane.org/.2011
(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):141–147
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):1427–1433
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):346–355
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):13–21
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):1758–1765
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 65:509–527
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Luo, L., Song, Z., Li, X. et al. Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis—a systematic review and meta-analysis. Neurol Sci 40, 235–241 (2019). https://doi.org/10.1007/s10072-018-3653-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-018-3653-2