Abstract
Background: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. Methods: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed. Findings: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference −0·94 [SE 1·41; 95% CI −3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. Interpretation: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. Funding: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.
| Original language | English |
|---|---|
| Journal | The Lancet Neurology |
| Volume | 18 |
| Issue number | 8 |
| Pages (from-to) | 724-735 |
| Number of pages | 12 |
| ISSN | 1474-4422 |
| DOIs | |
| Publication status | Published - 01.08.2019 |
Funding
In this randomised, double-blind, placebo-controlled trial, there was no evidence that epigallocatechin gallate modified disease progression in patients with multiple system atrophy as measured by the change in motor examination scores on UMSARS at 12 months. Epigallocatechin gallate was safe but was associated with more frequent increases in aminotransferase concentrations than was placebo, and serious liver toxicity occurred in two patients (a known side-effect of the compound 20 ). In an exploratory MRI sub-study, there was weak evidence to show that patients in the epigallocatechin gallate group had less striatal atrophy and lower motor examination scores on the UMSARS at 52 weeks than those in the placebo group. Basic science data provide a solid rationale for the use of small molecules to prevent α-synuclein aggregation and modify disease in multiple system atrophy. 6,7,33,34 Epigallocatechin gallate is an orally bioavailable polyphenol 21 that almost completely blocks pathological α-synuclein aggregation in in-vitro cellular and cell-free experiments and is approved for use in human beings. 8–10,12,14,35 In vivo, monkeys with parkinsonism that were given epigallocatechin gallate showed a reduction in disease progression of approximately 50% compared with those given placebo as measured by a validated parkinsonian clinical rating scale in monkeys. 8–10,12,14,35 Thus, the rationale for epigallocatechin gallate as a putative disease-modifying agent in multiple system atrophy is well established preclinically. 8–10,12,14,35 The motor examination score of UMSARS was also used in the three most recent trials (of minocycline, 36 rifampicin, 37 and rasagiline, 38 respectively) investigating disease modification in patients with multiple system atrophy. In the trials of rifampicin 37 and rasagiline, 38 a combination of disease onset, expected survival, and UMSARS scores were used as inclusion criteria. Our trial had less complex inclusion criteria: we admitted only freely ambulatory patients to minimise the risk of dropouts, and aimed for a population with mild-to-moderate disease (ie, Hoehn and Yahr stages 1–3) within the full range of motor examination scores of UMSARS. Data from the use of riluzole in patients with amyotrophic lateral sclerosis 39 and from animal models of synucleinopathies suggest that disease modification can be achieved at advanced clinical stages in neurodegenerative diseases. 40 The exclusion criteria of our trial reflected the safety profile of epigallocatechin gallate. 20 We chose a 1-year observation period, which was sufficient in previous trials to investigate disease progression (as shown by motor examination scores on UMSARS) while ensuring patient retention. 1-year progression data for UMSARS motor examination scores from the subset of the European Multiple System Atrophy Study Group's natural history cohort who met our trial's inclusion criteria 31 provided the basis for our power calculation (ie, a sample size of 36 patients per group). 24 The assumptions of the power calculation were supported by data from a post-hoc power calculation in the placebo group of our trial, showing that a group size of 38 patients would be sufficient ( appendix ). The dose of epigallocatechin gallate (1200 mg per day) that we used was substantially higher than doses leading to cognitive improvements in individuals with Down's syndrome (9 mg/kg), 17 and is the highest dose trialled in human beings so far ( NCT01357681 ). Recruitment for our trial was completed within the planned timeframe of 18 months. 24 We recruited more participants than initially planned—a decision that was prospectively approved by the central ethics committee. Blockwise randomisation of patients with parkinsonism-predominant and celebellar-ataxia-predominant disease led to well matched treatment groups at baseline. Demographic and clinical baseline characteristics of the recruited patients are consistent with those of patients in previous large cohort studies, including the fact that patients with celebellar-ataxia-predominant multiple system atrophy tend to have lower motor examination scores on UMSARS at baseline but similar disease progression to those with parkinsonism-predominant disease. 31,41 Compared with the two most recent trials 37,38 of disease modification in patients with multiple system atrophy, we recruited more patients who fulfilled the criteria for probable multiple system atrophy, and compared with the trial 37 of rifampicin we achieved more balanced inclusion of patients with parkinsonism-predominant or celebellar-ataxia-predominant disease in the treatment groups. At 1 year, 86 (93%) of the 92 enrolled patients were still alive—a proportion similar to those in the previous rifampicin 37 and rasagiline 38 trials. However, the frequency of dropouts in our trials was slightly higher than that in previous trials, 37,38 probably because only requiring patients to be able to walk freely led to the inclusion in our trial of patients with more advanced disease. Baseline UMSARS motor examination scores in our trial (roughly 21 points) were higher than those in the trials of rasagiline 38 (roughly 17 points) or rifampicin 37 (roughly 12 points). Even though we over-recruited relative to our sample size calculation, the unexpectedly high frequency of dropouts generates potential concern about the trial's power. However, although the number of trial completers was lower than expected, so was the reported SD for the change in motor examination scores in the placebo group (5·06 rather than 6) in the dataset of trial completers. Furthermore, the 95% CI for the between-group difference for the primary outcome (– 3·71 to 1·83) did not contain the treatment effect of −4 that we expected to detect. These findings suggest that the study was adequately powered to detect a disease-modifying treatment effect of 50% on annual progression of UMSARS motor examination scores and that epigallocatechin gallate does not have this large effect. Epigallocatechin gallate was associated with hepatic adverse events and cessation of treatment in two patients with aminotransferase concentrations more than five-times higher than the upper limit of normal. Changes in aminotransferase concentrations in eight patients in the epigallocatechin gallate group (17% overall) were associated with adverse events. We therefore conclude that 1200 mg epigallocatechin gallate daily is toxic for an substantial proportion of patients with multiple system atrophy, especially in view of the fact that patients with a priori chronic liver disease were excluded from our trial. Hence, studies of higher doses cannot be safely recommended in human beings, and hepatotoxic effects should be screened for in all studies of epigallocatechin gallate. The main finding of this trial was that, at 12 months, epigallocatechin gallate was not associated with clinically relevant disease modification in patients with multiple system atrophy compared with placebo. We also found no evidence that epigallocatechin gallate had an effect on the secondary clinical outcome measures (ie, UMSARS total score, Clinical Global Impression of Severity, or Clinical Global Impression of Change). This study also included an exploratory MRI sub-study. In the cohort of patients in the imaging sub-study who completed the main study, brain regions affected by multiple system atrophy showed less volume loss in the epigallocatechin gallate group than in the placebo group. In the placebo group, the annual striatal atrophy rate (7·3%) was close to the annual striatal volume loss of roughly 6% reported previously in a single-centre natural history study, 42 whereas striatal volume loss was substantially lower in the epigallocatechin gallate group (3·4%; appendix ). This finding might suggest that epigallocatechin gallate has neuroprotective effects, but other explanations cannot be ruled out—eg, epigallocatechin gallate might reduce brain volume loss by modulating inflammatory processes or increasing cerebral water content rather than by inhibiting neurodegeneration. Surprisingly, an exploratory sensitivity analysis in patients in the imaging sub-study who completed the main study seemed to suggest significant between-group differences favouring epigallocatechin gallate in the primary clinical outcome of change in motor examination scores on UMSARS between baseline and week 52. This finding raises questions about the difference between this group of patients and the full analysis set and the per-protocol study completer set. Selection, matching, or retention of patients did not differ between cohorts. Two of the centres at which the MRI sub-study was done were among the centres recruiting the highest numbers of patients for the trial overall ( appendix ). Previous analyses suggested that trial centres with large numbers of patients might provide data of higher quality than those with fewer patients. 43 On the basis of the atrophy data and suggestion of clinical efficacy from the imaging sub-study, atrophy rates might be a promising biomarker in future studies, and inhibition of α-synuclein aggregation warrants further investigation in multiple system atrophy and other synucleinopathies. The PROMESA trial had several limitations. Even though the study included the highest number of participants so far completing a randomised controlled trial of disease modification in both subtypes of multiple system atrophy, the goal of reducing disease progression by 50% might have been too ambitious. The trial was not powered to detect smaller changes. Furthermore, the number of dropouts was higher than expected. Only four of the 12 centres recruited ten or more patients. Study centres that recruited small numbers of patients might have introduced increased variability to the dataset. Overall, larger numbers of patients, longer observation periods, and larger trial sites, could have enabled disease-modifying efficacy to be detected. For the software used see www.randomization.com Contributors JL, AG, WHO, GKW, UM, and GUH designed the study, which was set up by JL, SM, MSc, SE-S, CE, FP, KB, BE-W, and GUH. JL, SM, MSc, CT, MSü, KE, BM, AL, ML, JC, AM, JK, FG, DP, SE-S, CE, FP, KB, BE-W, and GUH had roles in trial conduct performance. UM supervised the statistical analysis. HJ-H did the blinded imaging analyses. IR did the statistical analyses. GUH was the principal clinical investigator. JL was the sponsor delegated person of this trial, in which the Klinikum der Universität München of Ludwig-Maximilians-Universität München was the sponsor. JL, AG, WHO, WP, CT, GKW, IR, and GUH were on the blinded data review committee and the writing committee. JL, IR, and GUH wrote the first draft of the paper, which was revised by all authors. PROMESA Study Group Elisabeth André, Christiane Blankenstein, Monica Canelo, Marco Düring, Jens Ebentheuer, Christopher Fricke, Alexander Gerbes, Stefan Groiss, Doreen Gruber, Christian Hartmann, Thomas Kirchner, Daniel Kroneberg, Martin Kunz, Stefan Lorenzl, Alexia Moldovan, Anna Noda, Heidi Pape, Gesine Respondek, Eva Schäffer, Alfons Schnitzler, Walter Schulz-Schaeffer, Johannes Schwarz, Cornelia Skowronek, Alexander Storch, Vera Tadic, Dávid Vadász, Benno Zimmermann, Martina Schneider Declaration of interests JL has received grants from ParkinsonFonds Deutschland, the German Neurology Foundation, the Lüneburg Foundation, the Bischof Dr Karl Golser Foundation, the Dr Arthur Arnstein Foundation, and the German Parkinson Society; non-financial support from Taiyo International and AbbVie; and personal fees from Aesku, Bayer Vital, the Willi Gross Foundation, Axon Neuroscience, and Ionis. AG reports non-financial support from MODAG, and holds patents licensed to MODAG for water-soluble derivatives of 3·5-diphelyl-diazole compounds (PCT EP 16/081084 patent family) and drugs that inhibit protein aggregation in diseases linked to protein aggregation or neurodegenerative diseases (EP 2307381 patent family). WHO reports grants from Parkinson Fonds Deutschland, the Michael J Fox Foundation for Parkinson's Research, the Charitable Hertie Foundation, and Stichting Parkinson Fonds The Netherlands. WP has received consultancy and lecture fees in relation to clinical drug programmes for Parkinson's disease from AbbVie, AstraZeneca, BIAL, Biogen, Biohaven, Britannia, Grünenthal, Intec, Ipsen, Lundbeck, Novartis, Neuroderm, Orion, Oxford Biomedica, Prexton, Regenera, Roche, Sunovion, Sun Pharma, Takeda, Teva, UCB, and Zambon, and has received royalties for books from Thieme, Wiley Blackwell, Oxford University Press, and Cambridge University Press. CT has received consultancy fees from Britannia, UCB, Benevolent, Novartis, Roche, and Orion, grants from the Michael J Fox Foundation for Parkinson's Research, and Horizon 2020, speaker fees from UCB, Otsuka, and Gruenenthal, author fees from a book for patients with Parkinson's disease from Schattauer; and licence fees for use of the PDSS-2-scale. GKW is the president of the Bischof Dr Karl Golser Foundation, one of the study funders. KE has received grants from the German Parkinson Society and the Michael J Fox Fundation for Parkinson's Research, advisory board fees from Bial, Grünenthal, Mundipharma, and Zambon, and speaker fees from Bial, Desitin, Grünenthal, Mundipharma, UCB, and Zambon. BM has received personal fees from Roche, Biogen, and UCB; grants, personal fees, and non-financial support from the Michael J Fox Foundation for Parkinson's Research; and grants from the EU (Horizon 2020), grants Deutsche Forschungsgemeinschaft, Deutsche Parkinson Vereinigung, and Parkinson Fonds Deutschland. ML has received personal fees from Bayer Healthcare, Medtronic, UCB, AbbVie, and Grünenthal. JC has received grants from St Jude Medical and Medtronic, personal fees from Bayer, UCB, AbbVie, Desitin, Zambon, Thieme Verlag, and Kohlhammer Verlag. AM has received personal fees from Pharm Allergan, Ipsen, Merz, Actelion, GlaxoSmithKline, Desitin, Teva, grants from Pharm Allergan, Ipsen, Merz, Actelion, Possehl-Stiftung, Margot und Jürgen Wessel Stiftung, the German Tourette Syndrome Association, Interessenverband Tourette Syndrom, Deutsche Forschungsgemeinschaft (projects 1692/3-1, 4-1, SFB 936, and FOR 2698), and Innovationsausschuss of the Gemeinsamer Bundesausschuss (Translate NAMSE), and royalties for the book Neurogenetics from Oxford University Press. JK has received personal fees from UCB, Bial, NeuroDerm, Novartis, Zambon, AbbVie, Teva, Medtronic, Desitin, Boehringer Ingelheim, GlaxoSmithKline, Merz, and Hoffmann-La Roche. DB has received grants from UCB, Lundbeck, the Michael J Fox Foundation for Parkinson's Research, Janssen, the German Parkinson's Disease Association, the German Ministry for Economics and Energy, the German Federal Ministry of Education and Research, Parkinson Fonds Deutschland, Teva, EU, Novartis, and the Damp Foundation, and personal fees from UCB, Lundbeck, BIAL, Bayer, AbbVie, Biogen, and Zambon. FP has received a grant from the Arthur Arnstein Foundation. HJ-H has served as a consultant for Novartis. GUH reports grants from Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research, ParkinsonFonds Germany, the German Academic Exchange Service, the NOMIS foundation, the Bavarian Ministry for Education, Culture, Science and Art, and the EU and European Federation of Pharmaceutical Industries and Associations' Innovative Medicines Initiative, and personal fees from the German Center for Neurodegenerative Diseases. All other authors declare no competing interests. The study protocol, statistical analysis plan, informed consent form, and study data, including deidentified participant data and a data dictionary defining each field in the set, will be made available to others upon formal request and receipt of a signed material transfer agreement. Requests should be directed to the corresponding author. Data will only be shared via individual secured network connections. Acknowledgments This study was funded by ParkinsonFonds Deutschland, the German Parkinson Society, the German Neurology Foundation, the Lüneburg Foundation, the Bischof Dr Karl Golser Foundation, and the Dr Arthur Arnstein Foundation. One of three batches of epigallocatechin gallate was provided for free by Taiyo International. We thank the patients and their families for their participation, Florian Krismer for providing the data for the power calculation from the European Multiple System Atrophy Study Group's database, Katie Göttlinger for proofreading the manuscript, Jason Hassenstab for strategic advice, and Scott Berry for revision of the trial statistics.
Research Areas and Centers
- Research Area: Medical Genetics
DFG Research Classification Scheme
- 2.23-02 Molecular Biology and Physiology of Nerve and Glial Cells
