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| Name | Class |
|---|---|
| Hospital Infantil Universitario Niño Jesús, Madrid, Spain | OTHER |
| Instituto Hispalense de PediatrÃa, Sevilla, Spain | UNKNOWN |
| Hospital Universitario Marqués de Valdecilla | OTHER |
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To evaluate safety and tolerability of epigallocatechin gallate (EGCG) in children from 6 to 12 years old with Intellectual Developmental Disorders (IDD) (Down syndrome or Fragile X syndrome).
This project first objective is to evaluate the safety and tolerability of the EGCG molecule (extracted form green tea) on children from 6 to 12 years old with Intellectual Development Disorder (Down syndrome and Fragile X syndrome).
The secondary objective is to evaluate the benefits of the EGCG on attention, memory, executive functions, language and adaptive behaviour of these children. Dyrk1A and homocysteine in plasma will also be quantified, using them as biomarkers of efficacy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental group DS and FXS | Experimental | Cohort 1: a 35 DS children group taking EGCG FontUp. Cohort 2: a 6 FXS children group taking EGCG FontUp. (Experimental open-label) |
|
| Control group DS | Placebo Comparator | Cohort 1: a 35 DS children group taking placebo FontUp. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EGCG FontUp | Dietary Supplement | Intake of 10mg/kg/day of EGCG, in the form of a dietary supplement (FontUp), two times a day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Safety Outcome Measure : Adverse Events | Medical evaluations of incidence, nature, severity and causality of Adverse Events and Serious Adverse Events (SAE). | From day -5 to day 252 (through study completion) |
| Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in liver function | The finding of an elevated alanine transaminase (ALT) or aspartate transaminase (AST) (>3xULN), elevated total bilirubin (>2xULN) | Days -5, 5, 42, 84, 126, and 168. |
| Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in thyroid function | Elevated TSH (>10 microU/mL) or any decrease of free T4 below the lower limit of normal values (<0.8 ng/dL) | Days -5, 42, 84, 126, and 168. |
| Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in renal function | Serum creatinine will be measured at various time points and an increase exceeding x1.5 ULN (upper limit of normal values) that is confirmed by a repeat testing within 3 days. | Days -15, 84, and 168 |
| Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with Electroencephalography (EEG): Clinical significant changes in cerebral activity | Electroencephalogram recording to detect epileptiform abnormalities and/or seizure activity and/or pro-convulsive effects in pediatric participants, enabling a deeper understanding of the pharmacological effects of the intervention. | Days -15, 84, and 168 |
| Measure | Description | Time Frame |
|---|---|---|
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Expressive language | Assessed by Picture Naming (PN) (WPPSI-IV). It is a verbal Comprehension subtest. It has 24 items. The child should name the drawings shown in the stimulus book. PN measures expressive language, ability and language development. Range score 0-24. Higher score is better outcome. | Days -15, 168 and 252 |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory Outcome: Efficacy Biomarkers analysis in plasma | Dyrk1A and homocysteine (markers of efficacy); and Catechins and EGC concentrations (EGCG metabolites). | Baseline, months 3 and 6 |
| Exploratory Outcome: Blood folate concentration |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IMIM (Institut Hospital del Mar d'Investigacions Mèdiques) | Barcelona | 08003 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16876833 | Background | Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry. 2006 Sep;67(17):1849-55. doi: 10.1016/j.phytochem.2006.06.020. Epub 2006 Jul 31. | |
| 19636252 | Background | Megarbane A, Ravel A, Mircher C, Sturtz F, Grattau Y, Rethore MO, Delabar JM, Mobley WC. The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genet Med. 2009 Sep;11(9):611-6. doi: 10.1097/GIM.0b013e3181b2e34c. |
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| ID | Term |
|---|---|
| D004314 | Down Syndrome |
| D005600 | Fragile X Syndrome |
| D008607 | Intellectual Disability |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D000015 | Abnormalities, Multiple |
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| Institut Jerome Lejeune |
| OTHER |
Cohort I (Down Syndrome children): Phase II Randomized, double-blind, placebo-controlled, parallel groups to evaluate safety and tolerability of EGCG in children. The experimental group will take 10mg/kg/day of FontUp (EGCG on a dietary supplement with chocolate like shake flavor, two times a day) while the placebo group will take the same product but without the EGCG in it, taken with the same posology.
Cohort II (Fragile X syndrome children): exploratory open label study (pilot study) to assess safety and tolerability of EGCG. These patients will receive 10mg/kg/day of FontUp.
This cohort will only be recruited in Spanish sites.
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The treatment consists in FontUp (EGCG on a dietary supplement with chocolate like shake flavor) taken dissolved in 100mL of water two times a day (breakfast and afternoon snack). The placebo treatment is the same product but without the EGCG in it, taken with the same posology.
| Placebo FontUp | Other | Intake of placebo, in the form of a dietary supplement (FontUp) (without EGCG), two times a day. |
|
| Safety Outcome Measure: Measure: Number of participants with treatment-related adverse events with supporting evidence with Electrocardiogram: Clinical significant changes in QTcF | A QTcF (Fridericia's correction) value (mean of the three measurements) exceeding 500 ms when confirmed in repeat measurement within 15-30 minutes will be recorded as SAE. A QTcF value exceeding a change from screening (mean of three time-matched measurements) of 60 ms when confirmed in repeat measurement within 15-30 minutes will be recorded as SAE. | Days -56 and 168 |
| Safety Outcome Measure: Measure: Number of participants with treatment-related adverse events with supporting evidence with Echocardiogram: Clinical significant changes in size of the chambers of the heart. | Doppler echocardiogram is used to look at how blood flows through the heart chambers, heart valves, and blood vessels. The movement of the blood reflects sound waves to a transducer. The ultrasound computer then measures the direction and speed of the blood flowing through heart and blood vessels. | Days -56 and 168 |
| Safety Outcome Measure: Measure: Number of participants with treatment-related adverse events with supporting evidence with Echocardiogram: Clinical significant changes in pumping function of the heart. | This measure is known as an ejection fraction or EF. | Days -56 and 168 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Receptive language | Assessed by Receptive Vocabulary (RV)(WPPSI-IV). It is a verbal comprehension subtest. It has 31 items. The child selects the picture that best represents the word the examiner reads aloud. RV measures receptive language ability and language development. Range score 0-40. Higher score is better outcome. | Days -1,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Memory and Learning | Assessed by Sentence Repetition (NEPSY-II): This subtest is designed to assess the ability to repeat sentences of increasing complexity and length. The child is read a series of sentences and asked to recall each sentence immediately after it is presented. Range score 0-34. Higher score is better outcome. | Days -1,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Working Memory (WM) | Assessed by Picture memory (WPPSI-IV). This subtest measures visual WM. It has 35 items. The child views a stimulus page of pictures for a specified time and then selects these pictures from options on a response page, for which a set of stimuli is viewed and then recognized from among a set of responses. Range score 0-35. Higher score is better outcome. | Days -1,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Verbal Fluency (VF) | Subjects are asked to generate as many words as possible in 1 minute belonging to the category of "animals". No range score. A higher score is better outcome. | Days -1,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in inhibition behavior | Assessed by Cats & Dogs Test. 16 pictures presented on a single strip of card (two trials with two conditions, control and experimental-inhibition). Measures of task accuracy in the experimental inhibition trial (total number of correct responses, range score 0-16) and total time performance (in seconds) were included in the analyses. | Days -1,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in mental flexibility | Assessed by Dimensional Change Card Sort (DCCS). Sort a series of bivalent test cards, according to one dimension(colour) or another(shape). Range score 0-24, higher score is better outcome. | Days -1,84,168 and 252 |
| Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Visual-spatial Process | Assessed by Blocks Design(WPPSI-IV). It is a visual spatial subtest which has 17 items. It measures ability to analyze and synthesize abstract visual stimuli. Range score 0-34, higher score is better outcome. | Days -1,168 and 252 |
| Functional Outcome Measure : IDD-CHILD Vineland Adaptive Behavior Scales Scale Parent/Caregiver Interview Form, Second Edition (VABS-II)(Vinelandâ„¢-II survey version) | Changes in adaptive behavior
For all measures: a higher score is a better outcome | Days -1,168 and 252 |
Exploratory biomarkers: determination of folate in blood samples
| Months -1, 3 and 6 |
| Exploratory Outcome Targeted metabolomics | In the PERSEUS project spot urine samples will be collected to further evaluate the metabolome of subjects with Down syndrome, seeking biomarkers of treatment efficacy or those differentiating responders and non-responders. Analysis will be focused in the biosynthesis and metabolism of neurotransmitters, the kynurenine pathway and the hypothalamic-hypophyseal-adrenal axis. | Months -1, 3 and 6 |
| Exploratory Outcome: Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) | Evaluating changes in executive performance. BRIEF-P is a widely used caregiver questionnaire of everyday skills reflective of abilities in the executive domain. It generates a range of scales, including scales specific to working memory and inhibitory control.Raw scores and T-scores will be derived for the following scales: inhibit, shift, emotional control, initiate, working memory, plan/organize, organization of materials and monitor. | Baseline, months 6 and 9 |
| Exploratory Outcome: Observed Memory Questionnaire Parent Form (OMQ-PF) | Evaluating changes in memory performance. OMQ-PF is a 27-item questionnaire designed to ascertain parental perceptions about their child's memory function. All items are rated on a 5-point Likert (from 1- Strongly agree to 5-Strongly disagree OR 1- Never to 5- Always). | Baseline, months 6 and 9 |
| Exploratory Outcome: Paediatric Quality of Life Inventory (PedsQL) | Evaluating Quality of life. The PedsQL measurement model was designed to integrate the merits of generic and disease-specific instruments to evaluate quality of life. Three modules will be used:
| Baseline, months 6 and 9 |
| Exploratory Outcome: Children's Sleep habits questionnaire (CSHQ) | Rebound effects after discontinuation of treatment measures: evaluating changes sleep disturbances. CSHQ is a 22-item parent-report questionnaire that encompasses eight domains:
| Baseline, months 6 and 9 |
| Exploratory Outcome: Aberrant Behavior Checklist (ABC) | Rebound effects after discontinuation of treatment measures: evaluating changes in disrupting behaviors. The ABC-C is a 58-item rating scale used to assess maladaptive behaviors across five original dimensions or subscales (Items are evaluated on a four-point Liker scale ranging from 0 (not at all a problem) to 3 (the problem is severe in degree)).
| Baseline, months 6 and 9 |
| Exploratory Outcome: Mediterranean Diet Quality Index for children and adolescents (KidMed Questionnaire) | KIDMED index includes 16 questions based on the principles of the Mediterranean diet, where higher scores indicate greater adherence to healthy diet. Range score -4 -16. | Baseline, months 6 and 9 |
| Exploratory Outcome: Changes in Cognitive composite Z-score | This variable will be created by computing the sum of the Z-scores from tests that make up IDD-CHILD battery described in secondary outcome measures. No range score. A higher score is better outcome. | Baseline, months 6 and 9 |
| 21381186 | Background | Khoshnood B, Greenlees R, Loane M, Dolk H; EUROCAT Project Management Committee; EUROCAT Working Group. Paper 2: EUROCAT public health indicators for congenital anomalies in Europe. Birth Defects Res A Clin Mol Teratol. 2011 Mar;91 Suppl 1(Suppl 1):S16-22. doi: 10.1002/bdra.20776. Epub 2011 Mar 4. |
| 16967345 | Background | Vicari S, Carlesimo GA. Short-term memory deficits are not uniform in Down and Williams syndromes. Neuropsychol Rev. 2006 Jun;16(2):87-94. doi: 10.1007/s11065-006-9008-4. Epub 2006 Aug 9. |
| 17237124 | Background | Ronan A, Fagan K, Christie L, Conroy J, Nowak NJ, Turner G. Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region. J Med Genet. 2007 Jul;44(7):448-51. doi: 10.1136/jmg.2006.047373. Epub 2007 Jan 19. |
| 17145134 | Background | Dowjat WK, Adayev T, Kuchna I, Nowicki K, Palminiello S, Hwang YW, Wegiel J. Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci Lett. 2007 Feb 8;413(1):77-81. doi: 10.1016/j.neulet.2006.11.026. Epub 2006 Dec 4. |
| 11555628 | Background | Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, Guimera J, Oset M, Gonzalez JR, Florez J, Fillat C, Estivill X. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. Hum Mol Genet. 2001 Sep 1;10(18):1915-23. doi: 10.1093/hmg/10.18.1915. |
| 17663443 | Background | Belichenko PV, Kleschevnikov AM, Salehi A, Epstein CJ, Mobley WC. Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol. 2007 Oct 1;504(4):329-45. doi: 10.1002/cne.21433. |
| 23165261 | Background | Dierssen M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci. 2012 Dec;13(12):844-58. doi: 10.1038/nrn3314. |
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| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |
| D038901 | X-Linked Intellectual Disability |
| D025064 | Sex Chromosome Disorders |
| D040181 | Genetic Diseases, X-Linked |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |