A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome

Abstract

Background & Aims: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS. Methods We conducted preclinical studies in Fmr1 knockout mice (Fmr1-/y) using novel objectrecognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESFXS; NCT01855971). Twenty-seven subjects with FXS (18-55 years) were administered of EGCG (5-7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation. Results Preclinical studies showed an improvement in memory in the novel object recognition paradigm. We found that FXS patients receiving EGCG+CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo+CT. Conclusions Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS.

Function of Green Tea Catechins in the Brain: Epigallocatechin Gallate and its Metabolites

“…Several studies including animal, human, and cell cultures support the potential neuroprotective activities of green tea catechins against neurological disorders. Very recently, EGCG was found to be safe and potential in improving cognition using both preclinical (mice) and clinical (human) studies [68]. The concentrations of EGCG, which is the main and the most active component among catechins, are very low in human and rat plasma and EGCG disappears within several hours from systemic circulation (<8 h) due to fast and extensive metabolism (methylation, glucuronidation, and sulfation) and microbial metabolism and degradation, resulting in the formation of various microbial ring-fission metabolites, which are detectable (>8 h) in the plasma and urine [30,31,33].…”

Retinal Thickness Analysis in Progressive Multiple Sclerosis Patients Treated With Epigallocatechin Gallate: Optical Coherence Tomography Results From the SUPREMES Study

“…Furthermore, treatment with EGCG and glatiramer acetate in EAE mice delayed disease onset, reduced clinical disability and reduced inflammatory infiltrates ( 25 ). In clinical trials, oral intake of EGCG was associated with improved muscle metabolism during moderate exercise in RRMS ( 26 ) and improved cognitive rehabilitation in genetic disorders ( 27 , 28 ).…”

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

“…In human clinical trials, green tea extracts and EGCG were shown to be safe for use in children and adults, including during prolonged periods (Kumar et al, 2016;de la Torre et al, 2020;Vilela et al, 2020), which reinforces the treatment potential of those components.…”

“…In a study conducted in 2012, EGCG (300 mg) improved neurological effects during alpha, beta, and theta brainwave stimulation, promoting, among other effects, increased calmness and reduced stress self-evaluated by healthy individuals over periods of 120 min (Scholey et al, 2012). These studies are corroborated by a more recent phase 1 trial conducted by de la Torre et al (2020). EGCG improved cognition and functional competence when combined with cognitive training during a 3-month follow-up (de la Torre et al, 2020).…”