Estrogen Receptors Beta (ER-B) as Therapeutic Targets for the Improvement of Cognitive Performance in Fragile-X (TESXF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Parc de Salut Mar
Sponsor:
Information provided by (Responsible Party):
Parc de Salut Mar
ClinicalTrials.gov Identifier:
NCT01855971
First received: May 9, 2013
Last updated: September 19, 2013
Last verified: September 2013
  Purpose

Fragile X syndrome (FXS) present 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.


Condition Intervention Phase
Fragile X Syndrome
Dietary Supplement: Epigallocatechin-3-gallate (EGCG)
Dietary Supplement: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Estrogen Receptors Beta (ER-B) as Therapeutic Targets for the Improvement of Cognitive Performance in Fragile-X (TESXF)

Resource links provided by NLM:


Further study details as provided by Parc de Salut Mar:

Primary Outcome Measures:
  • Therapeutic response and treatment efficacy [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Therapeutic response and treatment efficacy will be evaluated with Clinical Global Impressions-Improvement (CGI-I) scale.


Secondary Outcome Measures:
  • Neurophysiology [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Prepulse inhibition (PPI) of acoustic startle response

  • Phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Concentrations of PI3K/mTOR in human lymphocites.

  • Lipid Oxidation Biomarkers [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Concentration in plasma of oxidized- LDL.

  • Body analysis composition [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Bioimpedance body analysis composition

  • Analytical chemistry [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: Yes ]
    Blood (clinical chemistry, hematology, coagulation) and urine analysis

  • Attention [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Attention will be evaluated with CANTAB battery (Cambridge Cognition).

  • Psychomotor Speed and Manual Skills [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Psychomotor Speed and Manual Skills will be evaluated with Motor Screening test (MOT) CANTAB.

  • Episodic Memory [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Episodic Memory will be evaluated with CANTAB battery (Cambridge Cognition).

  • Executive Functions [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Executive Functions will be evaluated with CANTAB battery (Cambridge Cognition).

  • Language [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Language will be evaluated with Boston Naming Test and with Token Test (TT).

  • Extracellular signal-regulated kinase 1 (ERK) activity in human lymphocytes [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Concentrations of Kinase 1(ERK) activity in human lymphocytes.

  • Quality of Life Evaluation [ Time Frame: From baseline to 7 months ] [ Designated as safety issue: No ]
    Quality of Life will be evaluated with Kidscreen-27.


Estimated Enrollment: 40
Study Start Date: June 2013
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Epigallocatechin-3-gallate (EGCG)
EGCG normally works as a dietary supplement. EGCG administration in Down syndrome patients will result in an improvement of their cognitive performance. A daily oral dose containing 9 mg/kg (range 6.9-12.7) of EGCG is given during three months.
Dietary Supplement: Epigallocatechin-3-gallate (EGCG)
EGCG normally works as a dietary supplement. EGCG administration in Down syndrome patients will result in an improvement of their cognitive performance. A daily oral dose containing 9 mg/kg (range 6.9-12.7) of EGCG is given during three months.
Other Name: Epigallocatechin-3-gallate (EGCG)
Placebo Comparator: Placebo
No active substance is given.
Dietary Supplement: Placebo
No active treatment is given.
Other Name: Matched placebo

Detailed Description:

Rare diseases leading to intellectual disability, such as Fragile X syndrome (FXS), where alterations in synaptic plasticity are involved, may benefit from treatments targeting Estrogen Receptors beta (ER-β). Estrogens 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 (EGCG is an ATP-inhibitor of PI3K, and mTOR and ERK1/2) altered in FXS and improves memory recognition in a FXS animal model. 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

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have been diagnosed of Fragile X syndrome (FXS), aged between 18-40 years, have given the consent to participate (official custody).
  • To understand and accept experimental procedures and signing and informed consent (parents and/or tutors)
  • Subjects with age comprised between 18 and 40 years
  • Use of contraceptive methods in female subjects
  • 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

Exclusion 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 three months before the study;
  • Regular ingestion of medication in the month 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 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 vegetarian diet.
  • Practice of physical exercise for more than 2 hours per day or energy consumption of more than 3000 kcal per week.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01855971

Contacts
Contact: De la Torre Rafael, PharmD 0034933160484 rtorre@imim.es

Locations
Spain
Parc de Salut MAR, Hospital del Mar Medical Research Institute-IMIM Recruiting
Barcelona, Spain, 08003
Contact: Rafael de la Torre, PharmD    0034933160484    rtorre@imim.es   
Principal Investigator: Rafael de la Torre, PharmD         
Sub-Investigator: Magi Farre, MD         
Sponsors and Collaborators
Parc de Salut Mar
Investigators
Principal Investigator: Rafael de la Torre, PhamD Parc de Salut Mar
  More Information

No publications provided

Responsible Party: Parc de Salut Mar
ClinicalTrials.gov Identifier: NCT01855971     History of Changes
Other Study ID Numbers: TESXF
Study First Received: May 9, 2013
Last Updated: September 19, 2013
Health Authority: Spain: Ethics Committee

Additional relevant MeSH terms:
Fragile X Syndrome
Mental Retardation, X-Linked
Genetic Diseases, X-Linked
Mental Retardation
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Estrogens
Epigallocatechin gallate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antimutagenic Agents
Anticarcinogenic Agents
Antineoplastic Agents
Therapeutic Uses
Neuroprotective Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 20, 2014