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Fragile X SyndromePhase 2NCT01855971

"Using Epigallocatechin Gallate (EGCG) and Cognitive Training to Modulate Cognitive Performance in Patients With Fragile X Syndrome" (TESFX)

A Phase 2 study testing EGCG and Cognitive training in people with Fragile X Syndrome, run by Parc de Salut Mar at 1 site in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Fragile X Syndrome
What is being tested?
EGCG and Cognitive training
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
44 participants
Where
1 siteSpain
Study dates
11 Jun 2013to 31 Oct 2015
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

Spain1 site

  • Parc de Salut MAR, Hospital del Mar Medical Research Institute-IMIM

    Barcelona, 08003

Other trials in Spain

About this study

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

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.

Being tested
EGCG, Placebo, Cognitive training
Medical subject headings
Fragile X Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EGCGDietary supplement

    Also called Epigallocatechin-3-gallate (EGCG)

    Life Extension, Mega Green Tea Extract Decaffeinated is a dietary supplement containing EGCG extract (45% EGCG). This extract contains 98% total polyphenols and 45% epigallocatechin-3-gallate (EGCG). EGCG administration in Down syndrome patients will result in an improvement of their cognitive performance.

  • PlaceboDietary supplement

    Also called Matched placebo

    Same capsules containing rice flour. No active treatment is given.

  • Cognitive trainingOther

    Feskits program 3 times per week (1 hour/session) Patients in this arm of the trial carried out computerized online training drawn from the Feskits program (www.feskits.com), chosen to have attention, memory and executive function components. Specifically the sessions included the following exercises: sustained attention, attention/perception, working memory, auditory and visual memory, executive function and language.

Study groups in NCT01855971
Study groupRoleWhat they receive
Fragile X syndrome experimental groupActive comparator1. Administration of 400 mg/day of epigallocatechin-3-gallate (EGCG). Life Extension, Mega Green Tea Extract Decaffeinated, a dietary supplement containing EGCG extract (45% EGCGC). Dosage form: capsules of 200mg Route of administration: orally Dosage: 2 capsules per day (400 mg EGCG/day) Frequency: one capsule in the morning (fasting state) and a second capsule in the afternoon (before dinner). Treatment period: 3 months (from month 1 to month 4) 2. Cognitive training: non-pharmacological cognitive training 3 sessions per week (1 hour per session) by using the Feskits program.
Receives: Dietary Supplement: EGCG; Other: Cognitive training
Fragile X syndrome control groupPlacebo comparator1. Placebo administration. Placebo consists in capsules containing rice flour. Dosage form: capsules Route of administration: orally Dosage: 2 capsules per day Frequency: one capsule in the morning (fasting state) and a second capsule in the afternoon (before dinner). 2. Cognitive training: non-pharmacological cognitive training 3 sessions per week (1 hour per session) by using the Feskits program.
Receives: Dietary Supplement: Placebo; Other: Cognitive training

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Prepulse inhibition of acoustic startle response (PPI)

    Neurophysiology exploration (electroencephalogram)

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  2. The Kaufman Brief Intelligence Test (K-BIT)

    Evaluates the intellectual status and significantly correlates with the WISC-III.The intellectual quotient (IQ) will correspond to the K-BIT standardized total score, which can range from 40 (very low) to 160 (very high).

    Measured: at screening

  3. Changes in psicomotor speed (Motor Screening test (MOT, CANTAB))

    To assess psychomotor speed and accuracy. Participants were instructed to touch a series of crosses that appeared randomly on the screen. Response latency (in milliseconds) (MOT: Mean latency [ms]) will be considered in the present study.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  4. Changes in Simple Reaction Time (SRT; CANTAB)

    explores general alertness and motor speed. Subjects had to press the button on a press pad every time a square appeared in the middle of the screen. Intervals between the examinee's response and the next stimulus were variable during the task.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  5. Changes in Digit Span: forward and backward recall (WAIS-III)

    Forward recall score provides a good measure of verbal attention and working memory span. Backward recall score is predominantly a measure of verbal working memory span. Subjects were required to listen to a series of numbers with randomized presentation, and then repeat them back. The length of the series increased upon the subject's success.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  6. Changes in Spatial Span (SSP): forward and backward recall (CANTAB)

    Forward recall is predominantly a measure of visual attention and memory span. Participants were shown a sequence of squares that turned into a different color, one at each time, in a specific temporal order and spatial location. The examinee had to reproduce the sequence by touching on the screen the squares in the same order as they were presented. The length of the sequence increases in accordance to the subject's correct answers. Participants were shown a sequence of squares that turned into a different color, one at each time, in a specific temporal order and spatial location. The examinee had to reproduce the sequence by touching on the screen the squares in the same order as they were presented. The length of the sequence increases in accordance to the subject's correct answers.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  7. Changes in executive function (Word fluency test)

    Subjects were asked to generate as many words as possible in 1 minute belonging to the specified category of "animals" (open ranged: 0 to n1). High scores (number of words) (Semantic Word Fluency) indicate greater verbal fluency ability.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  8. Changes in in executive function (Tower of London-Drexel University (ToLDx))

    This test requires moving three different colored balls across three different sized pegs in order to replicate a goal configuration. Movements follow strict rules. Two training tasks were followed by 10 problems of increasing complexity. The task finalized after the examinee failed to solve two consecutive problems.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  9. Changes in in executive function (Weigl Color-Form Sort Test)

    This is a set-shifting task that assesses the ability to categorize across two dimensions: color and shape. Instructions for administration and scoring were taken from Strauss \& Lewin. Test material consisted of 12 tokens: four circles, four triangles, and four squares, and shapes were colored blue, red, yellow or green. The 12 tokens were displayed unsorted in front of the examinee. In the first trial the examinee is required to sort the tokens in a way that they go together (color or shape).

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  10. Changes in executive function (Cats & Dogs Test)

    This is a Stroop-like task assessing response inhibition, based on the original Day-Night task. In this test, a sequence of 16 pictures, 8 cats and 8 dogs arranged in a prefixed order, are presented to the examinee on a single strip of card. The task consists of two trials with two different conditions: a control trial and an experimental-inhibition trial.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  11. Changes in memory and learning (Paired Associates Learning (PAL, CANTAB))

    In this task the participants are required to learn associations between an abstract visual pattern and its location. Each participant is presented with a number of white boxes, arranged in a circle around an empty central space in the screen. Each box "opens" to reveal what is underneath (empty, or with a unique abstract pattern) in a randomized order until the participant has revealed all the contents. Next, a single pattern is presented in the center of the screen and the subject is instructed to touch the box where that pattern has been shown during the presentation phase of the trial. The task increases in difficulty from 1 to 8 patterns.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  12. Changes in memory and learning (Pattern Recognition Memory (PRM, CANTAB))

    Participants are presented with a series of two blocks of 12 abstract visual patterns that appear sequentially in the center of the computer screen. Patterns are designed so that they cannot easily be given verbal labels. Each pattern is shown for 3 seconds. In each of the 12 recognition trials, two patterns are presented: one familiar (from the series that the participants have already seen) and one novel pattern. The participant have to recognize the previously seen pattern. The same procedure is repeated with a second block of 12 new patterns but this time the recognition trial started 20 minutes after the presentation of this second block to provide a measure of delayed recall.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  13. Changes in memory and learning (Cued Recall Test)

    The test consisted of a list of 12 items, which have to be verbally recalled by the examinee during 3 trials of free and cued recall. The test start with a learning phase where the examinee is required to learn the list of 12 items using 12 images. Four pictures are presented at a time, one in each quadrant of a card. First, the examinee have to name each of the four pictures in the card, and secondly assign each picture according to a verbal category-cue given by the examiner.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  14. Changes in language (Boston Naming Test )

    The test consists of 60 black and white pictures graded in naming difficulty. Each picture is presented individually. The examinee is asked to name each item, and when unable to do so spontaneously, the examiner provides semantic and/or phonemic cues.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  15. Changes in language (Token Test )

    Test materials consists of 20 tokens in two shapes (circles and rectangles), two sizes (big and small), and five colors (red, black, yellow, white, and green). The tokens are laid out according to a fixed configuration in front of the examinee. The test requires the examinee to touch the tokens according to the oral commands provided by the examiner. Thirty-six commands are divided into six stages of increasing complexity.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  16. Changes in Adaptive Behavior in daily living

    ABAS-II is designed, according to AAMS guidelines, for evaluating adaptive skills in people with mental disabilities of a wide age range and across multiple environments. The ABAS-II tool for adults (ages 16 to 89) includes 5 subscales which assesses the individual's competence (in terms of behavior frequency) in 10 different skill áreas.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  17. Changes in Quality of life (Kidscreen-27 (parents version))

    This instrument assesses quality of life from the child and adolescent's perspective in terms of their physical, mental, and social well-being, higher scores corresponding to a greater quality of life. The questionnaire measures five dimensions.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  18. change sin quality of sleep (the Pittsburgh Sleep Quality Index (PSQI))

    This questionnaire evaluates the quality and patterns of sleep in older adults. It assesses sleep performance over the previous month across seven different domains: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. Parents will self-report all answers to each of the seven areas.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  19. Changes in disrupting behavior (the Aberrant Behavior Checklist (ABC-C))

    The ABC-C is a 58-item questionnaire for caregivers designed to assess the presence and severity of psychiatric symptoms and behavioral disturbance commonly exhibited by individuals with IDD. The questionnaire explores problem behaviors across 5 domains.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

Secondary outcomes (8)

  1. Changes in Phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) concentration

    Concentrations of PI3K/mTOR in human lymphocites.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  2. Changes in Lipid Oxidation Biomarkers

    Concentrations in plasma of oxidized- LDL.

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  3. Changes in body analysis composition

    Bioimpedance body analysis composition (TANITA)

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  4. changes in clinical chemistry biomarkers

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  5. changes in hematology biomarkers

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  6. changes in coagulation biomarkers

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  7. changes in urine analysis

    Measured: From presdose baseline to 3 and 6 months (after treatment)

  8. Changes in extracellular signal-regulated kinase 1 (ERK) biomarker

    Concentrations of Kinase 1(ERK) activity in human lymphocytes.

    Measured: From baseline to 7 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 May 2013 (estimated)
  2. Study start11 Jun 2013
  3. Primary completion31 Jul 2015
  4. Study completion31 Oct 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
44 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01855971
Sponsor's protocol ID
TESXF
Status last verified
May 2019
First submitted
9 May 2013
Last updated
10 May 2019
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Adachi N, Tomonaga S, Tachibana T, Denbow DM, Furuse M. (-)-Epigallocatechin gallate attenuates acute stress responses through GABAergic system in the brain. Eur J Pharmacol. 2006 Feb 15;531(1-3):171-5. doi: 10.1016/j.ejphar.2005.12.024. Epub 2006 Feb 2.

    PubMed 16457806

  • Berry-Kravis E, Knox A, Hervey C. Targeted treatments for fragile X syndrome. J Neurodev Disord. 2011 Sep;3(3):193-210. doi: 10.1007/s11689-011-9074-7. Epub 2011 Feb 19.

    PubMed 21484200

  • Campbell EL, Chebib M, Johnston GA. The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors. Biochem Pharmacol. 2004 Oct 15;68(8):1631-8. doi: 10.1016/j.bcp.2004.07.022.

    PubMed 15451406

  • Gross C, Berry-Kravis EM, Bassell GJ. Therapeutic strategies in fragile X syndrome: dysregulated mGluR signaling and beyond. Neuropsychopharmacology. 2012 Jan;37(1):178-95. doi: 10.1038/npp.2011.137. Epub 2011 Jul 27.

    PubMed 21796106

  • Levenga J, de Vrij FM, Oostra BA, Willemsen R. Potential therapeutic interventions for fragile X syndrome. Trends Mol Med. 2010 Nov;16(11):516-27. doi: 10.1016/j.molmed.2010.08.005. Epub 2010 Sep 21.

    PubMed 20864408

  • Van Aller GS, Carson JD, Tang W, Peng H, Zhao L, Copeland RA, Tummino PJ, Luo L. Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. Biochem Biophys Res Commun. 2011 Mar 11;406(2):194-9. doi: 10.1016/j.bbrc.2011.02.010. Epub 2011 Feb 15.

    PubMed 21300025

  • 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.

    PubMed 1710175

  • 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.

    PubMed 16859659

  • 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.

    PubMed 21973165

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing EGCG and Cognitive training in people with Fragile X Syndrome, run by Parc de Salut Mar at 1 site in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Prepulse inhibition of acoustic startle response (PPI) (time frame: From presdose baseline to 3 and 6 months (after treatment)). The study lists 19 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01855971, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2019.

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