Trial document




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  DRKS00005610

Trial Description

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Title

Double blind, randomised, prospective placebo controlled parallel group phase III study to investigate the Effect of EGCG supplementation on disease progression of patients with Multiple System Atrophy (MSA)

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Trial Acronym

PROMESA

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URL of the Trial

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Brief Summary in Lay Language

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Brief Summary in Scientific Language

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.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00005610
  •   2014/01/03
  •   2013/12/08
  •   yes
  •   Approved
  •   5851/13, Ethik-Kommission der Fakultät für Medizin der Technischen Universität München
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Secondary IDs

  •   2012-000928-18 
  •   NCT02008721  (clinicaltrials.gov)
  •   ORPHA425659  (www.orpha.net)
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Health Condition or Problem studied

  •   G90.3 -  Multi-system degeneration
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Interventions/Observational Groups

  •   Epigallocatechin gallate (Sunphenon EGCg), 1200 mgs/day p.o. (tablet), 48 weeks
  •   placebo
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, caregiver, assessor
  •   Placebo
  •   Treatment
  •   Parallel
  •   III
  •   N/A
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Primary Outcome

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 (52 weeks), (80% power, 5% P-level, 50% effect size, i.e. an expected mean yearly UMSARS-ME increase of 3.9 under verum treatment compared to 7.8 ± 6.8 (mean ± standard deviation) under Placebo-treatment.

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Secondary Outcome

Clinical safety and tolerability of EGCG (physical and neurological examination, laboratory parameters, adverse events, vital signs, drop-out rates, survival rates and survival time) during the EGCg administration phase (verum group) of 48 weeks.
To assess the efficacy of EGCG vs. Placebo to reduce the disease progression from V1 to V7 (52 weeks) the following parameters are of interest:
- UMSARS total score
- clinical global impression (CGI)
- global and regional cerebral atrophy (3D MP-RAGE MRI volumetry, 3D FLAIR).
- global and regional cerebral iron deposition in pons and striatum (T2* MRI).
To assess any effect of EGCG vs. Placebo on the evolution of the above mentioned parameters during the wash-out phase (from V6 to V7; 4 weeks) to explore possible symptomatic effects.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2014/04/23
  •   86
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

Subjects can be included if they meet the following criteria:
1.„clinical possible“ or „clinical probable“ MSA (Gilman et al., Neurology, 2008 26;71:670-6)
2.Hoehn & Yahr stage I – III
3.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
a.drugs acting against Parkinsonism (e.g. Levodopa, Dopamine-Agonists, Amantadine and MAO-B-Inhibitors)
b.drugs acting against autonomic dysfunction (e.g. ephedrin, midodrin, fludrucortison, octreotide, desmopresin, oxybutinine)
c.antidepressant and antidementive drugs.
4.No regular consumption of EGCG, green tea, or more than two cups of black tea per day
5.Capability and willingness to give written informed consent indicating that the subject has been informed of and understood all aspects pertinent to the study
6.Capability and willingness to comply with the procedures of the study
7.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
8.Absence of liver disease documented by transaminases and bilirubin below 2-folds of the upper normal level.

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Exclusion Criteria

Subjects will not be included if any of the following criteria applies:
1.Hoehn & Yahr stage > III (loss of postural reflexes, no independent walking possible, inability to stand unassisted, wheelchair-bound).
2.Neurodegenerative diseases other than MSA
3.Severe liver disease with elevation of transaminases and bilirubin above 2-folds of the upper normal level or regular intake of hepatotoxic drugs
4.Known hypersensitivity to EGCG or to drugs with similar chemical structure
5.Participation in another clinical trial involving administration of an investiga-tional medicinal product within 1 month prior to V1
6.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
7.Persistent abuse of medication, drugs or alcohol
8.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).
9.Current or planned pregnancy or breast feeding in females
10.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).
11.Intake of COMT-inhibitors (e.g. Entacapone, Tolcapone)
12.Current or planned therapy with Bortezomib and/ or history of plasmocyto-ma.
13.Anemia at Screening (Hb < 10g/dl)
14.Other severe medical conditions upon discretion of the LKP

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Addresses

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    • Klinikum der Universität München, Campus Großhadern
    • Marchioninistraße 15
    • 81377  München
    • Germany
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    • Klinikum rechts der Isar der TU München
    • Ismaninger Str. 22
    • 81675  München
    • Germany
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    • Klinikum der Universität München, Campus Großhadern
    • Mr.  Dr. med.  Johannes  Levin 
    • Marchioninistraße 15
    • 81377  München
    • Germany
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    • Klinikum der Universität München, Campus Großhadern
    • Mr.  Priv.-Doz. Dr. med.  Johannes  Levin 
    • Marchioninistraße 15
    • 81377  München
    • Germany
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Sources of Monetary or Material Support

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    • Internationale Parkinson Fonds (Deutschland) gGmbH, Dom Aquaree
    • Karl-Liebknecht-Strasse 5
    • 10178  Berlin
    • Germany
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    • Bischof Dr. Karl Golser Stiftung
    • 39100  Bozen
    • Italy
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    • DSN - Deutsche Stiftung Neurologie
    • Leopoldstr. 153
    • 80804  München
    • Germany
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    • Deutsche Parkinson Vereinigung e.V. -Bundesverband-
    • Moselstraße 31
    • 41464  Neuss
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2016/09/16
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Trial Publications, Results and other Documents

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