Epigallocatechin Gallate in Progressive MS: A Randomized, Placebo-Controlled Trial

Rebekka Rust, Claudia Chien, Michael Scheel, Alexander U Brandt, Jan Dörr, Jens Wuerfel, Katharina Klumbies, Hanna Zimmermann, Mario Lorenz, Klaus-Dieter Wernecke, Judith Bellmann-Strobl, Friedemann Paul, Rebekka Rust, Claudia Chien, Michael Scheel, Alexander U Brandt, Jan Dörr, Jens Wuerfel, Katharina Klumbies, Hanna Zimmermann, Mario Lorenz, Klaus-Dieter Wernecke, Judith Bellmann-Strobl, Friedemann Paul

Abstract

Objective: To examine whether treatment with epigallocatechin gallate (EGCG) influences progression of brain atrophy, reduces clinical and further radiologic disease activity markers, and is safe in patients with progressive multiple sclerosis (PMS).

Methods: We enrolled 61 patients with primary or secondary PMS in a randomized double-blind, parallel-group, phase II trial on oral EGCG (up to 1,200 mg daily) or placebo for 36 months with an optional open-label EGCG treatment extension (OE) of 12-month duration. The primary end point was the rate of brain atrophy, quantified as brain parenchymal fraction (BPF). The secondary end points were radiologic and clinical disease parameters and safety assessments.

Results: In our cohort, 30 patients were randomized to EGCG treatment and 31 to placebo. Thirty-eight patients (19 from each group) completed the study. The primary endpoint was not met, as in 36 months the rate of decrease in BPF was 0.0092 ± 0.0152 in the treatment group and -0.0078 ± 0.0159 in placebo-treated patients. None of the secondary MRI and clinical end points revealed group differences. Adverse events of EGCG were mostly mild and occurred with a similar incidence in the placebo group. One patient in the EGCG group had to stop treatment due to elevated aminotransferases (>3.5 times above normal limit).

Conclusions: In a phase II trial including patients with multiple sclerosis (MS) with progressive disease course, we were unable to demonstrate a treatment effect of EGCG on the primary and secondary radiologic and clinical disease parameters while confirming on overall beneficial safety profile.

Clinicaltrialgov identifier: NCT00799890.

Classification of evidence: This phase II trial provides Class II evidence that for patients with PMS, EGCG was safe, well tolerated, and did not significantly reduce the rate of brain atrophy.

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

Figures

Figure 1. Consort Diagram
Figure 1. Consort Diagram
ITT = intention-to-treat population; OE = open-label extension; PAS = primary analysis set; PP = per-protocol population.
Figure 2. Multivariate Longitudinal Analysis of Brain…
Figure 2. Multivariate Longitudinal Analysis of Brain Atrophy Over 48 Months
(A) Primary outcome: brain parenchymal fraction; only a significant effect of time was observed (p < 0.001), no group difference (p = 0.520) and no interaction (p = 0.647). (B) Secondary outcome: percentage brain volume change; significant effect of time (p < 0.001), no group difference (p = 0 0.476), and no interaction (p = 0.807). Bars represent 25%–75% quartiles. EGCG = epigallocatechin-3-gallate; OE = open-label extension.
Figure 3. Multivariate Longitudinal Analysis of T2w…
Figure 3. Multivariate Longitudinal Analysis of T2w Lesions Over 48 Months
(A) Secondary outcome: median T2w lesion counts; a significant effect of time was observed (p < 0.001), no group difference (p = 0.582) and no interaction (p = 0.417). (B) Secondary outcome: median T2w lesion volume in mL; significant effect of time (p < 0.001), no group difference (p = 0.821), and no interaction (p = 0.324). Bars represent 25%–75% quartiles. EGCG = epigallocatechin gallate; OE = open-label extension.

References

    1. Fazekas F. Where to go next with neuroprotection in multiple sclerosis? Lancet Neurol 2010;9:647–648.
    1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis N Engl J Med 2018;378:169–180.
    1. Fiol MP, Ysrraelit MC, Gaitán MI, Correale J. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 2016;140:527–546.
    1. Montalban X, Hauser SL, Kappos L, et al. . Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209–220.
    1. Kappos L, Bar-Or A, Cree BAC, et al. . Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018;391:1263–1273.
    1. Chen JE, Glover GH. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2016;25:289–313.
    1. Pervin M, Unno K, Takagaki A, Isemura M, Nakamura Y. Function of green tea catechins in the brain: epigallocatechin gallate and its metabolites. Int J Mol Sci 2019;20:1–12.
    1. Wang J, Ren Z, Xu Y, Xiao S, Meydani SN, Wu D. Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets. Am J Pathol 2012;180:221–234.
    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. Aktas O, Prozorovski T, Smorodchenko A, et al. . Green tea epigallocatechin-3-gallate mediates T cellular NF- B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol J Immunol 2004:173:5794-5800.
    1. Mähler A, Steiniger J, Bock M, et al. . Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial. Am J Clin Nutr 2015;101:487–495.
    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. Dekant W, Fujii K, Shibata E, Morita O, Shimotoyodome A. Safety assessment of green tea based beverages and dried green tea extracts as nutritional supplements. Toxicol Lett 2017;277:104–108.
    1. Polman CH, Reingold SC, Edan G, et al. . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria.” Ann Neurol 2005;58:840–846.
    1. Kurtzke JF. On the origin of EDSS. Mult Scler Relat Disord 2015;4:95–103.
    1. Cohen JA, Reingold SC, Polman CH, Wolinsky JS. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol 2012;11:467–476.
    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. Krupp LB, Larocca NG, Muir Nash J, Steinberg AD. The fatigue severity scale: application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–1123.
    1. Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994;18:S79–S83.
    1. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–571.
    1. Smith SM, Zhang Y, Jenkinson M, et al. . Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002;17:479–489.
    1. Yushkevich PA, Piven J, Hazlett HC, et al. . User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage 2006;31:1116–1128.
    1. Kalkers NF, Ameziane N, Bot JCJ, Minneboo A, Polman CH, Barkhof F. Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype. Arch Neurol 2002;59:1572–1576.
    1. Friede T, Kieser M. Sample size recalculation in internal pilot study designs: a review. Biom J 2006;48:537–555.
    1. Brunner E, Domhof S, Langer F. Nonparametric Analysis of Longitudinal Data in Factorial Experiments. J. Wiley; 2002. Available at: .
    1. Bathke A, Brunner E. A nonparametric alternative to analysis of covariance. In: Akritas MG, Politis DN, eds. Recent Advances and Trends in Nonparametric Statistics. Amsterdam, the Netherlands: Elsevier BV; 2003:109–120.
    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. Bellmann-Strobl J, Paul F, Wuerfel J, et al. . Epigallocatechin-gallate in relapsing-remitting MS: a randomized, double-blind, placebo-controlled trial. Neurol Neuroimmunol Neuroinflamm 2021;8:e981. doi: 10.1212/NXI.0000000000000981.
    1. Altmann DR, Jasperse B, Barkhof F, et al. . Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis. Neurology 2009;72:595–601..
    1. Chataway J, De Angelis F, Connick P, et al. . Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020;19:214–225.
    1. Lublin F, Miller DH, Freedman MS, et al. . Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:1075–1084.
    1. Kapoor R, Furby J, Hayton T, et al. . Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010;9:681–688.
    1. Kapoor R, Ho PR, Campbell N, et al. . Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol 2018;17:405–415.
    1. Chataway J, Schuerer N, Alsanousi A, et al. . Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014;383:2213–2221.
    1. Chakrawarti L, Agrawal R, Dang S, Gupta S, Gabrani R. Therapeutic effects of EGCG: a patent review. Expert Opin Ther Pat 2016;26:907–916.
    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 Vitam Nutr Res 2004;74:269–278.
    1. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet 2017;389:1357–1366.
    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. 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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