Clinical trial NCT01855971: "Using Epigallocatechin Gallate (EGCG) and Cognitive Training to Modulate Cognitive Performance in Patients With Fragile X Syndrome" (TESFX)
Official title: Estrogen Receptors Beta (ER-B) as Therapeutic Targets for the Improvement of Cognitive Performance in Fragile-X (TESXF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fragile X Syndrome
Lead sponsor: Parc de Salut Mar
Sponsor class: OTHER
First posted: 2013-05-17
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study lasts 7 months :

* from day 0 to month 1, patients will receive placebo, in order to avoid the placebo effect of the treatment.
* from month 1 to month 4 : patients will be divided in two cohorts, one group receiving ECGC (experimental group), and the other placebo (control group).
* from mont 4 to month 7 : no treatment in given, only effects of cessation of treatment are observed.

Patients from both arms will receive Cognitive training.
Primary purpose: TREATMENT

Brief summary: Fragile X syndrome (FXS) presents alterations in synaptic plasticity that produce intellectual disability. can produce improvement. Estrogens (targeting Estrogen Receptors beta (ER-β) can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth, and health benefits derived from flavonoids, as the flavonol epigallocatechin gallate (EGCG), phytoestrogens of natural origin are partially explained by their interaction with membrane ER. Selective ER-β flavonoids are thus good candidates for their therapeutic evaluation in intellectual disabilities. EGCG also targets central intracellular transduction signals altered in FXS and improves memory recognition in a FXS animal model(adenosine triphosphate (ATP)-inhibitor of phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK1/2). This study targets the synaptic plasticity alterations that underlie the learning and memory impairment but also the computational disability in FXS. The hypothesis is that EGCG can act by favoring the physiological processes involved in cognition.


Eligibility criteria: Inclusion Criteria:

* Molecular diagnosis of Fragile X syndrome (FXS)
* Males and females aged 12 to 60 years.
* Study participants must understand and accept experimental procedures and assent to participate in the study signing an informed consent.
* Parents or caregivers have to understand and accept experimental procedures and sign informed consent form.
* Use of effective contraceptive methods in female participants
* Regular menstrual cycle (26-32 days duration) in female subjects
* Moderate mental disability (IQ\>40)
* Body mass index (BMI) comprised between 18.5 and 29.9 kg/m2, and body weight between 50 and 100 kg.
* Non-smokers
* Electroencephalogram record and general blood and urine analysis performed at screening visit should be within normal values. Minor or occasional variations in normal values are allowed if, in the opinion of Principal Investigator, taking into account the state of the science, they are not clinically significant, they do not pose risk for the subjects and they do not interfere in the evaluation of the investigational product. These variations and their non-relevance should be justified by writing.

Exclusion Criteria:

* Not fulfil inclusion criteria.
* Subjects with neurological disease other than FXS, relevant medical disease, co-morbid mental disorder or currently taking any treatment that could interfere with cognitive function or alter any key biomarkers and biochemical parameters analyzed.
* Having suffered from any major illness or undergoing major surgery in the last 12 months preceding the study.
* Regular ingestion of psychotropic drugs in the three months preceding the study. Exceptions were made for single doses of symptomatic medication administered up to the week preceding the trial.
* Current ingestion of vitamin supplements or catechins or non steroidal antiinflammatory drug (NSAID) in the two weeks preceding the study.
* History or clinical proof of gastrointestinal, hepatic or renal problems or any other cause that may alter processes of absorption, distribution, metabolism, or excretion of the drug, or that might suggest gastrointestinal irritation to drug.
* Subjects following a cognitive training.

Primary outcomes:
measure: Change in Prepulse inhibition of acoustic startle response (PPI)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: The Kaufman Brief Intelligence Test (K-BIT)
timeFrame: at screening
measure: Changes in psicomotor speed (Motor Screening test (MOT, CANTAB))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Simple Reaction Time (SRT; CANTAB)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Digit Span: forward and backward recall (WAIS-III)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Spatial Span (SSP): forward and backward recall (CANTAB)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in executive function (Word fluency test)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in in executive function (Tower of London-Drexel University (ToLDx))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in in executive function (Weigl Color-Form Sort Test)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in executive function (Cats & Dogs Test)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in memory and learning (Paired Associates Learning (PAL, CANTAB))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in memory and learning (Pattern Recognition Memory (PRM, CANTAB))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in memory and learning (Cued Recall Test)
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in language (Boston Naming Test )
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in language (Token Test )
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Adaptive Behavior in daily living
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Quality of life (Kidscreen-27 (parents version))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: change sin quality of sleep (the Pittsburgh Sleep Quality Index (PSQI))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in disrupting behavior (the Aberrant Behavior Checklist (ABC-C))
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
Secondary outcomes:
measure: Changes in Phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) concentration
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in Lipid Oxidation Biomarkers
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in body analysis composition
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: changes in clinical chemistry biomarkers
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: changes in hematology biomarkers
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: changes in coagulation biomarkers
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: changes in urine analysis
timeFrame: From presdose baseline to 3 and 6 months (after treatment)
measure: Changes in extracellular signal-regulated kinase 1 (ERK) biomarker
timeFrame: From baseline to 7 months
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Parc de Salut MAR, Hospital del Mar Medical Research Institute-IMIM
Study officials:
affiliation: Parc de Salut Mar
name: Rafael de la Torre, PhamD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991 May 31;65(5):905-14. doi: 10.1016/0092-8674(91)90397-h.
citation: Vignes M, Maurice T, Lante F, Nedjar M, Thethi K, Guiramand J, Recasens M. Anxiolytic properties of green tea polyphenol (-)-epigallocatechin gallate (EGCG). Brain Res. 2006 Sep 19;1110(1):102-15. doi: 10.1016/j.brainres.2006.06.062. Epub 2006 Jul 21.
citation: Yang J, Han Y, Sun H, Chen C, He D, Guo J, Yu C, Jiang B, Zhou L, Zeng C. (-)-Epigallocatechin gallate suppresses proliferation of vascular smooth muscle cells induced by high glucose by inhibition of PKC and ERK1/2 signalings. J Agric Food Chem. 2011 Nov 9;59(21):11483-90. doi: 10.1021/jf2024819. Epub 2011 Oct 14.