Progression Rate of MSA Under EGCG Supplementation as Anti-Aggregation-Approach

NCT02008721 | Completed Phase 3 Results DMC

• 1 other identifier: PROMESA
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 12

Brief Summary

MSA is a rapidly progressive disorder with an average survival time of about 7 years after the first clinical manifestation. No potent symptomatic treatment is currently available. A disease-modifying therapy does not exist either. The growing understanding in recent years of the underlying pathological mechanisms of the disease allows the development of new treatment options that have a modifying effect on the disease progression. Therefore, treatments are urgently required that effect the central underlying pathological mechanism, which appears to be the intracellular aggregation of toxic oligomers of α-synuclein. EGCG, a polyphenol found in green tea, has shown to inhibit the formation of toxic α-synuclein oligomers in vitro and has shown to transform α-synuclein-oligomers in non-toxic oligomer species. There is also evidence for a neuroprotective effect in MPTP-mouse models of PD and is an antioxidant and iron chelator. There are currently 63 clinical studies (http://clinicaltrial.gov) in which EGCG was applied for various indications, such as Multiple Sclerosis, various forms of cancer and Huntington's disease. All of which have shown good tolerability and safety with the applied doses of EGCG of up to 1200 mg per day, demonstrating the safety of the drug under controlled clinical conditions (see 5.3.1 for hepatotoxicity in uncontrolled conditions). These data provide a solid rationale for testing in a clinical trial if supplementation of EGCG can interfere with the core disease mechanism in MSA and consequently retard the clinical progression of the MSA-related disability.

Conditions

Multiple System Atrophy

Keywords

Multiple System Atrophy; epigallocatechin gallate

Outcome Measures

Primary Outcomes (1)

• Change of Score in Motor Examination (ME) of the Unified MSA Rating Scale (UMSARS-ME) From V1 to V7.

  To assess the efficacy of EGCG vs. Placebo to reduce the progression in the motor examination (ME) of the Unified MSA Rating Scale (UMSARS-ME) from V1 to V7. The UMSARS-ME (Unified Multiple System Atrophy Rating Scale, Motor examination) assesses 14 operationalised signs of multiple system atrophy. 25 Scores for all 14 items range from 0 to 4, thus total scores range from 0 to 56. Higher scores mean a worse outcome.

  52 weeks

Secondary Outcomes (12)

• Possible Symptomatic Effects of EGCG vs. Placebo Measured by the Change in the UMSARS - ME in the Wash-out Phase (From V6-V7)

  4 weeks

• Change in the UMSARS Total Score From V1 to V7

  52 weeks

• Possible Symptomatic Effects of EGCG vs. Placebo Measured by the UMSARS Total Score From V6 to V7 (During the Washout Phase)

  4 weeks

• Percentage of Striatal Volume Loss in MRI (3D MP-RAGE MRI Volumetry, 3D FLAIR) From Baseline to V7 as Effect of Treatment (Epigallocatechin Gallate vs Placebo)

  baseline to 52 weeks

• Clinical Safety and Tolerability of EGCG Measured by Death Rates

  52 weeks

Study Arms (2)

EGCG as putative neuroprotective agent

ACTIVE COMPARATOR

Treatment with 800 mg - 1200 mg EGCG as putative neuroprotective agent

Drug: EGCG as putative neuroprotective agent

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

EGCG as putative neuroprotective agent DRUG

Treatment with 800 mg - 1200 mg EGCG as putative neuroprotective agent

Also known as: Sunphenon EGCg

EGCG as putative neuroprotective agent

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• "clinical possible" or "clinical probable" MSA (Gilman et al., Neurology, 2008 26;71:670-6)
• Hoehn \& Yahr stage I - III
• A stable regimen for at least 1 month prior to V1 and willingness / no fore-seeable need to change the regimen throughout the 52 week follow-up pe-riod for
• drugs acting against Parkinsonism (e.g. Levodopa, Dopamine-Agonists, Amantadine and MAO-B-Inhibitors)
• drugs acting against autonomic dysfunction (e.g. ephedrin, midodrin, fludrucortison, octreotide, desmopresin, oxybutinine)
• antidepressant and antidementive drugs.
• No regular consumption of EGCG, green tea, or more than two cups of black tea per day
• Capability and willingness to give written informed consent indicating that the subject has been informed of and understood all aspects pertinent to the study
• Capability and willingness to comply with the procedures of the study
• Contraception by adequate contraceptive methods (oral, injected or im-planted hormonal contraceptive methods, intrauterine pessar, sterilisation or real abstinence) in all female patients with childbearing potential
• Absence of liver disease documented by transaminases and bilirubin below 2-folds of the upper normal level.

You may not qualify if:

• Hoehn \& Yahr stage \> III (loss of postural reflexes, no independent walking possible, inability to stand unassisted, wheelchair-bound).
• Neurodegenerative diseases other than MSA
• Severe liver disease with elevation of transaminases and bilirubin above 2-folds of the upper normal level or regular intake of hepatotoxic drugs
• Known hypersensitivity to EGCG or to drugs with similar chemical structure
• Participation in another clinical trial involving administration of an investigational medicinal product within 1 month prior to V1
• A physical or psychiatric condition, which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
• Persistent abuse of medication, drugs or alcohol
• Consumption of \> 500 ml grapefruit juice per day (leading to inhibition of cytochrome P-450 isoenzyme 3A4, which may be involved in degradation of EGCG).
• Current or planned pregnancy or breast feeding in females
• Females of childbearing potential, who are not using medically reliable methods of contraception for the entire study duration (such as oral, inject-able, or implantable contraceptives, or intrauterine contraceptive devices).
• Intake of COMT-inhibitors (e.g. Entacapone, Tolcapone)
• Current or planned therapy with Bortezomib and/ or history of plasmocytoma.
• Anemia at Screening (Hb \< 10g/dl)
• Other severe medical conditions upon discretion of the LKP

Sponsors & Collaborators

• Dr. Johannes Levin: lead
• German Center for Neurodegenerative Diseases (DZNE): collaborator
• Deutsche Parkinson Vereinigung: collaborator
• German Foundation for Neurology: collaborator
• ParkinsonFonds Deutschland gGmbH: collaborator

Study Sites (12)

Neurology Department, Ludwig-Maximilians University

München, Bavaria, 81377, Germany

Location

Department of Neurology, Klinikum rechts der Isar, Technische Universität München

München, Bavaria, 81675, Germany

Location

Kliniken Beelitz GmbH, Neurologisches Fachkrankenhaus für Bewegungsstörungen

Beelitz-Heilstätten, 14547, Germany

Location

Charité - Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

Technische Universität Dresden

Dresden, 01062, Germany

Location

Heinrich-Heine-Universität, Neurologische Klinik

Düsseldorf, 40225, Germany

Location

Paracelsus-Elena-Klinik Kassel

Kassel, 34128, Germany

Location

Universität Leipzig

Leipzig, 04103, Germany

Location

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Lübeck, 23562, Germany

Location

Philipps Universität Marburg

Marburg, 35043, Germany

Location

Eberhard Karls Universität Tübingen

Tübingen, 72076, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Related Publications (19)

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  PMID: 18725592 BACKGROUND

• Wenning GK, Tison F, Seppi K, Sampaio C, Diem A, Yekhlef F, Ghorayeb I, Ory F, Galitzky M, Scaravilli T, Bozi M, Colosimo C, Gilman S, Shults CW, Quinn NP, Rascol O, Poewe W; Multiple System Atrophy Study Group. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord. 2004 Dec;19(12):1391-402. doi: 10.1002/mds.20255.

  PMID: 15452868 BACKGROUND

• Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N, Trenkwalder C, Sixel-Doring F, Herting B, Kamm C, Gasser T, Sawires M, Geser F, Kollensperger M, Seppi K, Kloss M, Krause M, Daniels C, Deuschl G, Bottger S, Naumann M, Lipp A, Gruber D, Kupsch A, Du Y, Turkheimer F, Brooks DJ, Klockgether T, Poewe W, Wenning G, Schade-Brittinger C, Oertel WH, Eggert K. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord. 2010 Jan 15;25(1):97-107. doi: 10.1002/mds.22732.

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• Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S. Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem. 2001 Sep;78(5):1073-82. doi: 10.1046/j.1471-4159.2001.00490.x.

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• Levin J, Maass S, Schuberth M, Giese A, Oertel WH, Poewe W, Trenkwalder C, Wenning GK, Mansmann U, Sudmeyer M, Eggert K, Mollenhauer B, Lipp A, Lohle M, Classen J, Munchau A, Kassubek J, Gandor F, Berg D, Egert-Schwender S, Eberhardt C, Paul F, Botzel K, Ertl-Wagner B, Huppertz HJ, Ricard I, Hoglinger GU; PROMESA Study Group. Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2019 Aug;18(8):724-735. doi: 10.1016/S1474-4422(19)30141-3. Epub 2019 Jul 2.

  PMID: 31278067 DERIVED

Related Links

• Fox trial finder of the Michael J Fox foundation

MeSH Terms

Conditions

Multiple System Atrophy

Interventions

epigallocatechin gallate

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Limitations and Caveats

The PROMESA trial had several limitations. The trial was powered to detect a 50% reduction in disease progression, not to detect smaller changes. Furthermore, the assummed dropout rate was 20% while the observed drop out rate was approximately 27%. Furthermore, center size was heterogeneous, only four of the 12 centres recruited ten or more patients.

Results Point of Contact

• Title: Prof. Dr. Johannes Levin
• Organization: Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany

johannes.levin@med.uni-munechen.de

Study Officials

• Johannes Levin, MD

  Ludwig Maximilians University, Department of Neurology

  PRINCIPAL INVESTIGATOR

• Günter Höglinger, MD

  Deutsches Zentrum für Neurodegenerative Erkrankungen e.V.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor delegated person

Study Record Dates

• First Submitted: December 8, 2013
• First Posted: December 11, 2013
• Study Start: January 1, 2014
• Primary Completion: September 1, 2016
• Study Completion: December 1, 2016
• Last Updated: March 12, 2024
• Results First Posted: March 12, 2024

Record last verified: 2023-08

Locations

DE (12)