Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial

Judith Bellmann-Strobl, Friedemann Paul, Jens Wuerfel, Jan Dörr, Carmen Infante-Duarte, Elmira Heidrich, Benedict Körtgen, Alexander Brandt, Caspar Pfüller, Helena Radbruch, Rebekka Rust, Volker Siffrin, Orhan Aktas, Christoph Heesen, Jürgen Faiss, Frank Hoffmann, Mario Lorenz, Benno Zimmermann, Sergiu Groppa, Klaus-Dieter Wernecke, Frauke Zipp, Judith Bellmann-Strobl, Friedemann Paul, Jens Wuerfel, Jan Dörr, Carmen Infante-Duarte, Elmira Heidrich, Benedict Körtgen, Alexander Brandt, Caspar Pfüller, Helena Radbruch, Rebekka Rust, Volker Siffrin, Orhan Aktas, Christoph Heesen, Jürgen Faiss, Frank Hoffmann, Mario Lorenz, Benno Zimmermann, Sergiu Groppa, Klaus-Dieter Wernecke, Frauke Zipp

Abstract

Objective: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments.

Results: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups.

Conclusion: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients.

Classification of evidence: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI.

Trial registration information: Clinical trial registration number: NCT00525668.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Trial Flowchart
Figure 1. Trial Flowchart
ITT = intention to treat; PP = per protocol.
Figure 2. T2w and T1w Hypointense Lesion…
Figure 2. T2w and T1w Hypointense Lesion Volumes
Mean change over time of volume (A) T2w lesion load (B) T1w hypointense lesion. EGCG = epigallocatechin-3-gallate.

References

    1. Zipp F, Gold R, Wiendl H. Identification of inflammatory neuronal injury and prevention of neuronal damage in multiple sclerosis: hope for novel therapies? JAMA Neurol 2013;70:1569–1574.
    1. Frischer JM, Bramow S, Dal-Bianco A, et al. . The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009;132:1175–1189.
    1. Dörr J, Paul F. The transition from first-line to second-line therapy in multiple sclerosis. Curr Treat Options Neurol 2015;17:25.
    1. Wingerchuk DM, Weinshenker BG. Disease modifying therapies for relapsing multiple sclerosis. BMJ 2016;354:i3518.
    1. Fazekas F. Where to go next with neuroprotection in multiple sclerosis? Lancet Neurol 2010;9:647–648.
    1. Morinobu A, Biao W, Tanaka S, et al. . (-)-Epigallocatechin-3-gallate suppresses osteoclast differentiation and ameliorates experimental arthritis in mice. Arthritis Rheum 2008;58:2012–2018.
    1. Noratiqah S, Naina-Mohamed I, Zulfarina M, Qodriyah H. Natural polyphenols in the treatment of Alzheimer's disease. Curr Drug Targets 2017;18:1.
    1. Ashihara H, Deng WW, Mullen W, Crozier A. Distribution and biosynthesis of flavan-3-ols in Camellia sinensis seedlings and expression of genes encoding biosynthetic enzymes. Phytochemistry 2010;71:559–566.
    1. Aktas O, Prozorovski T, Smorodchenko A, et al. . Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004;173:5794–5800.
    1. Sun Q, Zheng Y, Zhang X, et al. . Novel immunoregulatory properties of EGCG on reducing inflammation in EAE. Front Biosci (Landmark Ed) 2013;18:332–342.
    1. Herges K, Millward JM, Hentschel N, Infante-Duarte C, Aktas O, Zipp F. Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin-3-gallate in neuroinflammation. PLoS One 2011;6:e25456.
    1. McDonald WI, Compston A, Edan G, et al. . Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444.
    1. Zhao G, Koopmans R, Li D, Bedell L, Paty DW. Effect of interferon beta-1b in MS: assessment of annual accumulation of PD/T2 activity of MRI. Neurology 2000;54:200–206.
    1. Friede T, Kieser M. Sample size recalculation for binary data in internal pilot study designs. Pharm Stat 2004;3:269–279.
    1. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the type I error rate. Stat Med 2003;22:3571–3581.
    1. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment. Mult Scler J 1999;5:244–250.
    1. Lorenz M, Paul F, Moobed M, et al. . The activity of catechol-O-methyltransferase (COMT) is not impaired by high doses of epigallocatechin-3-gallate (EGCG) in vivo. Eur J Pharmacol 2014;740:645–651.
    1. Brunner E, Domhof S, Langer F. Nonparametric Analysis of Longitudinal Data in Factorial Experiments. J. Wiley; 2002. Available at: . Accessed February 12, 2018.
    1. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol 2003;2:117–127.
    1. Pisters KM, Newman RA, Coldman B, et al. . Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 2001;19:1830–1838.
    1. Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 2006;66:1234–1240.
    1. Unno T, Kondo K, Itakura H, Takeo T. Analysis of (-)-epigallocatechin gallate in human serum obtained after ingesting green tea. Biosci Biotechnol Biochem 1996;60:2066–2068.
    1. Lee MJ, Wang ZY, Li H, et al. . Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol Biomarkers Prev 1995;4:393–399.
    1. Ullmann U, Haller J, Decourt JD, Girault J, Spitzer V, Weber P. Plasma-kinetic characteristics of purified and isolated green tea catechin epigallocatechin gallate (EGCG) after 10 days repeated dosing in healthy volunteers. Int J vitamin Nutr Res 2004;74:269–278.
    1. Mähler A, Mandel S, Lorenz M, et al. . Epigallocatechin-3-gallate: a useful, effective and safe clinical approach for targeted prevention and individualised treatment of neurological diseases? EPMA J 2013;4:5.
    1. Chakrawarti L, Agrawal R, Dang S, Gupta S, Gabrani R. Therapeutic effects of EGCG: a patent review. Expert Opin Ther Patents 2016;26:907–916.
    1. Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006;144:68–71.
    1. Lovera J, Ramos A, Devier D, et al. . Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies. J Neurol Sci 2015;358:46–52.
    1. O'Connor P, Wolinsky JS, Confavreux C, et al. . Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293–1303.
    1. Fox RJ, Miller DH, Phillips JT, et al. . Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087–1097.
    1. Confavreux C, O'Connor P, Comi G, et al. . Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:247–256.
    1. Gold R, Kappos L, Arnold DL, et al. . Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098–1107.
    1. Singh NA, Mandal AKA, Khan ZA. Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutr J 2016;15:60.
    1. Levin J, Maaß S, Schuberth M, et al. . Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2019;18:724–735.
    1. Dehay B, Bourdenx M, Gorry P, et al. . Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol 2015;14:855–866.
    1. Rust R, Chien C, Scheel Met al. . Epigallocatechin- gallate in progressive multiple sclerosis: a randomized, placebo-controlled trial. Neurol Neuroimmunol Neuroinflamm 2021;8:e964.
    1. de la Torre R, de Sola S, Hernandez G, et al. . Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:801–810.
    1. de la Torre R, de Sola S, Farré M, et al. . A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome. Clin Nutr 2020;39:378–387.

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