PROMESA: A randomised, double-blind, placebo-controlled trial to evaluate the progression rate of MSA under EGCG supplementation as anti-aggregation-approach

Objective: To evaluate the safety and tolerability of epigallocatechin gallate (EGCG) in high doses and its efficacy to slow down disease progression in patients with Multiple System Atrophy (MSA). Background: Due to rapid disease progression and lack of effective symptomatic treatments, there is a high and unmet need for a disease modifying therapy for MSA. Intracellular α‐synuclein (αSyn) aggregates in neuronal and glial cells are believed to be the key pathological mechanism underlying the disease. Inhibition of αSyn aggregation appears as a rational approach to develop a disease‐modifying treatment. EGCG is an orally bioavailable small molecule that inhibits αSyn aggregation in cell free in vitro assays and blocks formation of toxic αSyn aggregates in cell culture1. Methods: A phase 2/3 double‐blind, parallel group, clinical trial was conducted at 12 centers. Participants met clinical consensus criteria for MSA and were able to walk independently. EGCG (800‐1200 mg daily) or placebo (randomized 1:1) was administered orally for 48 weeks, followed by a four‐week wash‐out phase. The primary endpoint was the change in the Unified MSA Rating Scale Motor Examination (UMSARS‐ME) from baseline up to 52 weeks2. Secondary read out parameters included changes in automated MRIvolumetry. Results: 127 participants were screened, 92 were randomized, and 67 (72.8%) completed the treatment. We observed significantly more hepatic adverse events in the EGCG group and two serious adverse events related to gastrointestinal toxicity, which led to the exclusion of the participants. There were no statistically significant group differences in the UMSARS‐ME at baseline and at the end of the trial EGCG (mean 5.7 [95% confidence interval (CI) 3.7, 7.6]) and placebo groups (mean 6.6 [95% CI 4.7, 8.5]). However, we observed a significantly reduced striatal volume loss in EGCGvs. placebo‐treated MSA patients by blinded automated MRIvolumetry. Conclusions: Individual cases of hepatotoxicity in the EGCG group show that the limit of maximal tolerable doses was reached. Treatment with EGCG in high doses over 48 weeks in our cohort did not slow disease progression of MSA. The reduced regional brain atrophy on MRI suggests that treatment approaches with more effective antiaggregational compounds may indeed be considered for future disease modifying trials in MSA.