Double-blind, Randomised, Placebo-controlled Parallel Group Study to Investigate the Effect of EGCG Supplementation on Disease Progression of Patients With Multiple System Atrophy (MSA)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 92
- 试验地点
- 12
- 主要终点
- Change of Score in Motor Examination (ME) of the Unified MSA Rating Scale (UMSARS-ME) From V1 to V7.
研究概览
简要总结
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.
详细描述
5 Introduction Multiple System Atrophy (MSA) is a slowly progressing neurodegenerative disease that is characterized by i) a hypokinetic movement disorder which defines MSA of the parkinsonian type (MSA-P) or by ii) cerebellar symptoms which define MSA of the cerebellar type (MSA-C). In both types the movement disorder can be accompanied by vegetative symptoms such as orthostatic hypotension. In contrast to Parkinson's disease (PD), the effect of dopaminergic medication on the parkinsonian symptoms is very limited. In spite of several efforts, no disease modifying therapy has been identified so far. Several lines of evidence including epidemiological, in vitro, and in vivo data, suggest that Epigallocatechin gallate (EGCG) might be able to delay disease progression of MSA by modifying several aspects in the pathogenesis of MSA such as protein aggregation, oxidative stress and iron accumulation. Therefore, this study is designed to investigate the influence of EGCG on disease progression in patients with MSA. To assess the effect on disease progression, clinical evaluation and MR-imaging will be applied in a bi-center, prospective, placebo-controlled, double-blind randomized phase III trial. The primary outcome measure will be the change in motor symptoms from V1 to V7 measured by the UMSARS-ME comparing placebo- vs. verum-treated patients. The secondary efficacy endpoint will be the change from V1 to V7 in the total UMSARS score, in the CGI score and in MRI parameters (global and regional atrophy / iron deposition) comparing placebo- vs. verum-treated patients.
5.1 Background The disease: MSA is a synucleinopathy that is suitable for various reasons as a model disease to investigate disease-modifying effects in α-synuclein (aSyn)-dependent neurodegeneration. The disease progression is more rapid compared to PD and therefore allows the observation of clinically relevant effects in shorter observation periods. As no potent symptomatic treatment of MSA is currently available, the influence of symptomatic active substances on clinical data is limited and placebo can be used as comparator. This solves the potential ethical problem of having to deprive patients of such symptomatic treatment during the study and underlines the high medical need for a symptomatic treatment. Another important argument for neuroprotection studies in MSA is that in three independent studies EMSA, NNIPPS, MEMSA a very similar disease progression was observed over a defined period of time, which enables a precise power analysis with sample sizes and follow-up periods that are suitable for an investigator initiated trial (IIT).
The therapeutic target: An increasing amount of data suggests that toxic oligomers from misfolded, disease-specific proteins play a potentially important role in the neuronal cell death in neurodegenerative diseases. Specifically in MSA, oligomeric aSyn aggregate species appear to be crucially involved in the pathogenetic mechanisms.
The pharmacological compound: Epidemiological data suggest that ingredients in tea may be neuroprotective for synucleinopathies in man. Regular consumption of tea reduces the risk of contracting PD by about 50%. Also for MSA, a clear trend in the sense of a positive effect of tea consumption on the risk of disease development was observed (OR = 0.5, 95% CI: 0.22-1.5, p = 0.09). EGCG, a polyphenol that is for example found in green tea, inhibits the formation of toxic aSyn oligomers in vitro and transforms aSyn oligomers by direct interaction in alternative, non-toxic oligomer species. Furthermore, EGCG shows a neuroprotective effect in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) mouse model of PD. In addition, EGCG is an antioxidant and an iron chelator and therefore has more potential beneficial effects on synucleinopathies.
The pharmacokinetic properties of EGCG were tested in humans in the serum and in rodents in serum and organs, including the brain in detail. It was found that repeated oral application of doses of EGCG result in a significant increase in serum levels in healthy adults compared to a single dose. The proposed daily dose of 1200 mg of EGCG is comparable to about 15 to 30 cups of green tea (depending on the mode of preparation) (Prof. F. Paul, Berlin, pers. comm.). Animal experiments in rodents have shown that after a single i.v. dose of EGCG, the substance is found in the brain in significant quantities.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •"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.
排除标准
- •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
研究组 & 干预措施
Placebo
Placebo
干预措施: Placebo (Drug)
EGCG as putative neuroprotective agent
Treatment with 800 mg - 1200 mg EGCG as putative neuroprotective agent
干预措施: EGCG as putative neuroprotective agent (Drug)
结局指标
主要结局
Change of Score in Motor Examination (ME) of the Unified MSA Rating Scale (UMSARS-ME) From V1 to V7.
时间窗: 52 weeks
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.
次要结局
- 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)
- Effect of Treatment (Epigallocatechin Gallate vs Placebo) on Safety and Tolerability: Discontinuation Rates Because of Hepatotoxicity(52 weeks)
- Number of Participants Achieving Each Clinical Global Impression of Severity (CGI-S): Illness Level at Visit 5(Visit 5 (30 weeks after Baseline Visit))
- Number of Participants Achieving Each Clinical Global Impression of Severity (CGI-S): Illness Level at Visit 6(48 weeks after baseline visit)
- Number of Participants Achieving Each Clinical Global Impression of Severity (CGI-S): Illness Level at Visit 7(52 weeks after baseline visit)
- Number of Participants Achieving Each Clinical Global Impression of Improvement (CGI-I): Improvement Level at Visit 7 Compared to the Baseline Visit(Visit 7: 52 weeks after baseline visit)
- Clinical Safety and Tolerability of EGCG Measured by Death Rates(52 weeks)
- Number of Participants Achieving Each Clinical Global Impression of Severity (CGI-S): Illness Level at Visit 1(At baseline visit (max. 4 weeks after the screening visit))
- Number of Participants Achieving Each Clinical Global Impression of Improvement (CGI-I): Efficacy Index (Therapeutic Effect of Treatment With Medication and Associated Side Effects) at Visit 7 Compared to the Baseline Visit(Visit 7: 52 weeks after baseline visit)
研究者
Dr. Johannes Levin
Sponsor delegated person
Ludwig-Maximilians - University of Munich