Pediatric Exploratory Research Study of EGCG Use and Safety (PERSEUS)

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Pediatric Exploratory Research Study of EGCG Use and Safety (PERSEUS)

Conditions
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Down Syndrome, Fragile X Syndrome

Intervention / Treatment
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* Dietary Supplement: EGCG FontUp
* Other: Placebo FontUp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged 6 to 12 years on day 1 of treatment. Clinical diagnosis of DS (full trisomy 21 or translocated) confirmed by chromosomal analysis (karyotyping) (Cohort I) or molecular diagnosis for FXS (mutations or premutations on the fragile mental retardation 1 gene-Fmr1 of the X chromosome) (Cohort II). A karyotype will be performed if not available in DS population. FXS molecular diagnosis will be performed if not available in FXS population. A body-weight under 50 kg. Parent or legal guardian/representative and caregiver willing to give written informed consent. Mental age ≥ 3 years (Brunet-Lézine scale C version, picture naming and receptive vocabulary of the WPPSI-IV) Study participants must have sufficient vision and hearing to participate in study evaluations. Mild hearing loss will be allowed. Availability of parent/caregiver to accompany the subject to clinical visits, provide information about the subject's behavior and symptoms and ensure compliance with the medication schedule. Subjects must be able to understand basic instructions. Naming and comprehension tasks of the WPPSI-IV will be used as an evaluation Exclusion Criteria: Study participants with a current Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis of any primary psychiatric diagnosis (including autism spectrum disorder). For secondary diagnoses, such as attention deficit hyperactivity disorder, depression and conduct disorder, individuals under a fixed regime of medication (a regime that does not change in the 6 weeks prior to enrollment) are allowed as long as they are considered stable and their medication does not interfere with the progression of the study. Personal history of infantile spasms, of epilepsy, of severe head trauma or Central Nervous System (CNS) infections (e.g. meningitis), with the exception of a single isolated febrile seizure. Subjects with past history of seizures from primary causes (such as West syndrome and Lennox-Gastaut syndrome) or secondary causes. Clinical history of moderate or severe Obstructive Sleep Apnea (OSA) as defined by Apnea-Hypopnea Index (AHI) (>15 events per hour not well controlled by positive airway pressure therapy with stable settings) for at least 3 months prior to screening visit. Subjects with thyroid disease that is not controlled (elevated basal Thyroid-stimulating hormone (TSH) > 10 microU/mL) by thyroid hormone respective therapy. Evidence of active, clinically significant, and unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease. Cardiovascular, Systolic Blood Pressure (SBP) and/or Diastolic Blood Pressure (DBP) outside the 95th percentile for age; resting heart rate above 100 bpm. Cardiovascular, ECG: clinically relevant ECG abnormalities at screening. Auscultation is mandatory part of cardiovascular examination. Clinically significant abnormalities in laboratory test results at screening unless acceptable by the investigator. Life-threatening illness or major surgery in the 3 months prior to the study. Concomitant disease or condition or any clinically significant finding at screening that could interfere with the conduct of the study, or that would, in the opinion of the investigator, could lead to an unacceptable risk to the subject in this study. Patients with risk factors of liver dysfunction such as previous history of liver disease, previous clinically significant hepatic abnormalities in laboratory testing, previous allergy or intolerance with liver disorders or any clinically significant abnormalities in hepatic laboratory testing at screening Participation in other clinical trials in the last 3 months prior to the study. Concomitant use of unapproved medication. Current intake of vitamin supplements, catechins or products containing EGCG (i.e. TEAVIGO, Mega Green Tea capsules Life Extension or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group DS and FXS<br>Cohort 1: a 35 DS children group taking EGCG FontUp. Cohort 2: a 6 FXS children group taking EGCG FontUp. (Experimental open-label) | Dietary Supplement: EGCG FontUp<br>* Intake of 10mg/kg/day of EGCG, in the form of a dietary supplement (FontUp), two times a day.<br>|
| Placebo Comparator: Control group DS<br>Cohort 1: a 35 DS children group taking placebo FontUp. | Other: Placebo FontUp<br>* Intake of placebo, in the form of a dietary supplement (FontUp) (without EGCG), two times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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)(Vineland™-II survey version) | Changes in adaptive behavior A. Communication domain: Sum of A1+A2+A3. Range Score 0-198 A1. Receptive subdomain: Range Score 0-40 A2. Expressive subdomain: Range Score 0-108 A3. Written subdomain: Range Score 0-50 B. Daily living skills domain: Sum of B1+B2+B3. Range Score 0-109 B1. Personal subdomain: Range Score 0-82 B2. Domestic subdomain: Range Score 0-48 B3. Community subdomain: Range Score 0-88 C. Socialization domain: Sum of C1+C2+C3. Range Score 0-180 C1. Interpersonal relationships subdomain: Range Score 0-64 C2. Play and leisure time subdomain: Range Score 0-62 C3. Coping skills subdomain: Range Score 0-60 Total score: Sum of A+B+C. Range Score 0-576 For all measures: a higher score is a better outcome | Days -1,168 and 252 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Down Syndrome (DS), Fragile X Syndrome (FXS), Intellectual Development Disorder (IDD), FontUp, EGCG, Epigallocatechin gallate, Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), Homocysteine, Dietary supplement, Green tea, IMIM, PERSEUS