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

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ClinicalTrials.gov Identifier: NCT03624556
Recruitment Status : Recruiting
First Posted : August 10, 2018
Last Update Posted : September 17, 2018
Sponsor:
Collaborators:
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Instituto Hispalense de Pediatría, Sevilla, Spain
Hospital Universitario Marqués de Valdecilla
Institut Jerome Lejeune
Information provided by (Responsible Party):
Rafael de la Torre, Parc de Salut Mar

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Down Syndrome Fragile X Syndrome Dietary Supplement: EGCG FontUp Other: Placebo FontUp Not Applicable

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
Official Title: Pediatric Exploratory Research Study of EGCG Use and Safety (PERSEUS)
Actual Study Start Date : January 29, 2018
Estimated Primary Completion Date : June 29, 2019
Estimated Study Completion Date : September 1, 2019


Arm Intervention/treatment
Experimental: Experimental group DS and FXS
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
Intake of 10mg/kg/day of EGCG, in the form of a dietary supplement (FontUp), two times a day.

Placebo Comparator: Control group DS
Cohort 1: a 35 DS children group taking placebo FontUp.
Other: Placebo FontUp
Intake of placebo, in the form of a dietary supplement (FontUp) (without EGCG), two times a day.




Primary Outcome Measures :
  1. Safety Outcome Measure : Adverse Events [ Time Frame: From day -5 to day 252 (through study completion) ]
    Medical evaluations of incidence, nature, severity and causality of Adverse Events and Serious Adverse Events (SAE).

  2. Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in liver function [ Time Frame: Days -5, 5, 42, 84, 126, and 168. ]
    The finding of an elevated alanine transaminase (ALT) or aspartate transaminase (AST) (>3xULN), elevated total bilirubin (>2xULN)

  3. Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in thyroid function [ Time Frame: Days -5, 42, 84, 126, and 168. ]
    Elevated TSH (>10 microU/mL) or any decrease of free T4 below the lower limit of normal values (<0.8 ng/dL)

  4. Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with blood analysis: Changes in renal function [ Time Frame: Days -15, 84, and 168 ]
    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.

  5. Safety Outcome Measure: Number of participants with treatment-related adverse events with supporting evidence with Electroencephalography (EEG): Clinical significant changes in cerebral activity [ Time Frame: Days -15, 84, and 168 ]
    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.

  6. Safety Outcome Measure: Measure: Number of participants with treatment-related adverse events with supporting evidence with Electrocardiogram: Clinical significant changes in QTcF [ Time Frame: Days -56 and 168 ]

    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.


  7. 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. [ Time Frame: Days -56 and 168 ]
    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.

  8. 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. [ Time Frame: Days -56 and 168 ]
    This measure is known as an ejection fraction or EF.


Secondary Outcome Measures :
  1. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Expressive language [ Time Frame: Days -15, 168 and 252 ]
    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.

  2. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Receptive language [ Time Frame: Days -1,168 and 252 ]
    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.

  3. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Memory and Learning [ Time Frame: Days -1,168 and 252 ]
    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.

  4. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Working Memory (WM) [ Time Frame: Days -1,168 and 252 ]
    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.

  5. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Verbal Fluency (VF) [ Time Frame: Days -1,168 and 252 ]
    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.

  6. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in inhibition behavior [ Time Frame: Days -1,168 and 252 ]
    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.

  7. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in mental flexibility [ Time Frame: Days -1,84,168 and 252 ]
    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.

  8. Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Visual-spatial Process [ Time Frame: Days -1,168 and 252 ]
    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.

  9. Functional Outcome Measure : IDD-CHILD Vineland Adaptive Behavior Scales Scale Parent/Caregiver Interview Form, Second Edition (VABS-II)(Vineland™-II survey version) [ Time Frame: Days -1,168 and 252 ]

    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



Other Outcome Measures:
  1. Exploratory Outcome: Efficacy Biomarkers analysis in plasma [ Time Frame: Baseline, months 3 and 6 ]
    Dyrk1A and homocysteine (markers of efficacy); and Catechins and EGC concentrations (EGCG metabolites).

  2. Exploratory Outcome: Blood folate concentration [ Time Frame: Months -1, 3 and 6 ]
    Exploratory biomarkers: determination of folate in blood samples

  3. Exploratory Outcome Targeted metabolomics [ Time Frame: Months -1, 3 and 6 ]
    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.

  4. Exploratory Outcome: Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) [ Time Frame: Baseline, months 6 and 9 ]
    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.

  5. Exploratory Outcome: Observed Memory Questionnaire Parent Form (OMQ-PF) [ Time Frame: Baseline, months 6 and 9 ]
    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).

  6. Exploratory Outcome: Paediatric Quality of Life Inventory (PedsQL) [ Time Frame: Baseline, months 6 and 9 ]

    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:

    1. cognitive functioning scale module. Range score 0-100
    2. generic core module. Range score 0-100
    3. family impact module. Range score 0-100 For all measures: a higher score is a better outcome

  7. Exploratory Outcome: Children's Sleep habits questionnaire (CSHQ) [ Time Frame: Baseline, months 6 and 9 ]

    Rebound effects after discontinuation of treatment measures: evaluating changes sleep disturbances.

    CSHQ is a 22-item parent-report questionnaire that encompasses eight domains:

    1. bedtime resistance. Range score 0-36
    2. sleep behavior. Range score 0-24
    3. night waking. Range score 0-8
    4. morning wake up. 0-16 For all items except item 19, a higher score is a better outcome

  8. Exploratory Outcome: Aberrant Behavior Checklist (ABC) [ Time Frame: Baseline, months 6 and 9 ]

    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)).

    1. Irritability. Range score 0-45
    2. Hyperactivity. Range score 0-48
    3. Lethargy/Withdrawal. Range score 0-21
    4. Stereotypy. Range score 0-48
    5. Inappropriate Speech. Range score 0-12 For all measures: a higher score is a worst outcome

  9. Exploratory Outcome: Mediterranean Diet Quality Index for children and adolescents (KidMed Questionnaire) [ Time Frame: Baseline, months 6 and 9 ]
    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.

  10. Exploratory Outcome: Changes in Cognitive composite Z-score [ Time Frame: Baseline, months 6 and 9 ]
    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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03624556


Contacts
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Contact: Rafaël de la Torre Fornell, PhD 933160484 ext +34 rtorre@imim.es

Locations
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Spain
IMIM (Institut Hospital del Mar d'Investigacions Mèdiques) Recruiting
Barcelona, Spain, 08003
Contact: Rafael De la Torre Fornell, PhD    0034933160484    rtorre@imim.es   
Principal Investigator: Rafael de la Torre, PhD         
Sponsors and Collaborators
Parc de Salut Mar
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Instituto Hispalense de Pediatría, Sevilla, Spain
Hospital Universitario Marqués de Valdecilla
Institut Jerome Lejeune

Publications:

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Responsible Party: Rafael de la Torre, Director of the Neurosciences Department in Institut Hospital d'Investigacions Mèdiques (IMIM), PharmD, PhD, Parc de Salut Mar
ClinicalTrials.gov Identifier: NCT03624556     History of Changes
Other Study ID Numbers: PERSEUS/1
First Posted: August 10, 2018    Key Record Dates
Last Update Posted: September 17, 2018
Last Verified: September 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rafael de la Torre, Parc de Salut Mar:
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

Additional relevant MeSH terms:
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Syndrome
Down Syndrome
Fragile X Syndrome
Disease
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Mental Retardation, X-Linked
Sex Chromosome Disorders
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System