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

NCT03624556 | Completed

• 1 other identifier: PERSEUS/1
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

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).

Conditions

Down Syndrome; Fragile X Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (9)

• Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Expressive language

  Days -15, 168 and 252

• Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Receptive language

  Days -1,168 and 252

• Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Memory and Learning

  Days -1,168 and 252

• Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Working Memory (WM)

  Days -1,168 and 252

• Cognitive Outcome Measure : IDD-CHILD Battery. Cognitive changes in Verbal Fluency (VF)

  Days -1,168 and 252

Other Outcomes (10)

• Exploratory Outcome: Efficacy Biomarkers analysis in plasma

  Baseline, months 3 and 6

• Exploratory Outcome: Blood folate concentration

  Months -1, 3 and 6

• Exploratory Outcome Targeted metabolomics

  Months -1, 3 and 6

Study Arms (2)

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)

Dietary Supplement: EGCG FontUp

Control group DS

PLACEBO COMPARATOR

Cohort 1: a 35 DS children group taking placebo FontUp.

Other: Placebo FontUp

Interventions

EGCG FontUp DIETARY_SUPPLEMENT

Intake of 10mg/kg/day of EGCG, in the form of a dietary supplement (FontUp), two times a day.

Experimental group DS and FXS

Placebo FontUp OTHER

Intake of placebo, in the form of a dietary supplement (FontUp) (without EGCG), two times a day.

Control group DS

Eligibility Criteria

• Age: 6 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Parc de Salut Mar: lead
• Hospital Infantil Universitario Niño Jesús, Madrid, Spain: collaborator
• Instituto Hispalense de Pediatría, Sevilla, Spain: collaborator
• Hospital Universitario Marqués de Valdecilla: collaborator
• Institut Jerome Lejeune: collaborator

Study Sites (1)

IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)

Barcelona, 08003, Spain

Location

Related Publications (20)

• 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.

  PMID: 16876833 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.

  PMID: 19636252 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.

  PMID: 21381186 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.

  PMID: 16967345 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.

  PMID: 17237124 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.

  PMID: 17145134 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.

  PMID: 11555628 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.

  PMID: 17663443 BACKGROUND

• Dierssen M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci. 2012 Dec;13(12):844-58. doi: 10.1038/nrn3314.

  PMID: 23165261 BACKGROUND

• Ji J, Lee H, Argiropoulos B, Dorrani N, Mann J, Martinez-Agosto JA, Gomez-Ospina N, Gallant N, Bernstein JA, Hudgins L, Slattery L, Isidor B, Le Caignec C, David A, Obersztyn E, Wisniowiecka-Kowalnik B, Fox M, Deignan JL, Vilain E, Hendricks E, Horton Harr M, Noon SE, Jackson JR, Wilkens A, Mirzaa G, Salamon N, Abramson J, Zackai EH, Krantz I, Innes AM, Nelson SF, Grody WW, Quintero-Rivera F. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet. 2015 Nov;23(11):1473-81. doi: 10.1038/ejhg.2015.71. Epub 2015 May 6.

  PMID: 25944381 BACKGROUND

• Benavides-Piccione R, Dierssen M, Ballesteros-Yanez I, Martinez de Lagran M, Arbones ML, Fotaki V, DeFelipe J, Elston GN. Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/- mouse. Neurobiol Dis. 2005 Oct;20(1):115-22. doi: 10.1016/j.nbd.2005.02.004.

  PMID: 16137572 BACKGROUND

• Pujol J, del Hoyo L, Blanco-Hinojo L, de Sola S, Macia D, Martinez-Vilavella G, Amor M, Deus J, Rodriguez J, Farre M, Dierssen M, de la Torre R. Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome. Cortex. 2015 Mar;64:148-56. doi: 10.1016/j.cortex.2014.10.012. Epub 2014 Oct 28.

  PMID: 25461715 BACKGROUND

• de Sola S, de la Torre R, Sanchez-Benavides G, Benejam B, Cuenca-Royo A, Del Hoyo L, Rodriguez J, Catuara-Solarz S, Sanchez-Gutierrez J, Duenas-Espin I, Hernandez G, Pena-Casanova J, Langohr K, Videla S, Blehaut H, Farre M, Dierssen M; TESDAD Study Group. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials. Front Psychol. 2015 Jun 4;6:708. doi: 10.3389/fpsyg.2015.00708. eCollection 2015.

  PMID: 26089807 BACKGROUND

• Ruiz-Mejias M, Martinez de Lagran M, Mattia M, Castano-Prat P, Perez-Mendez L, Ciria-Suarez L, Gener T, Sancristobal B, Garcia-Ojalvo J, Gruart A, Delgado-Garcia JM, Sanchez-Vives MV, Dierssen M. Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex. J Neurosci. 2016 Mar 30;36(13):3648-59. doi: 10.1523/JNEUROSCI.2517-15.2016.

  PMID: 27030752 BACKGROUND

• Ruben K, Wurzlbauer A, Walte A, Sippl W, Bracher F, Becker W. Selectivity Profiling and Biological Activity of Novel beta-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors. PLoS One. 2015 Jul 20;10(7):e0132453. doi: 10.1371/journal.pone.0132453. eCollection 2015.

  PMID: 26192590 BACKGROUND

• Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bittles AH. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet. 2002 Nov;62(5):390-3. doi: 10.1034/j.1399-0004.2002.620506.x.

  PMID: 12431254 BACKGROUND

• Martinez-Cue C, Martinez P, Rueda N, Vidal R, Garcia S, Vidal V, Corrales A, Montero JA, Pazos A, Florez J, Gasser R, Thomas AW, Honer M, Knoflach F, Trejo JL, Wettstein JG, Hernandez MC. Reducing GABAA alpha5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome. J Neurosci. 2013 Feb 27;33(9):3953-66. doi: 10.1523/JNEUROSCI.1203-12.2013.

  PMID: 23447605 BACKGROUND

• Pons-Espinal M, Martinez de Lagran M, Dierssen M. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A. Neurobiol Dis. 2013 Dec;60:18-31. doi: 10.1016/j.nbd.2013.08.008. Epub 2013 Aug 20.

  PMID: 23969234 BACKGROUND

• Altafaj X, Martin ED, Ortiz-Abalia J, Valderrama A, Lao-Peregrin C, Dierssen M, Fillat C. Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2013 Apr;52:117-27. doi: 10.1016/j.nbd.2012.11.017. Epub 2012 Dec 5.

  PMID: 23220201 BACKGROUND

• Guedj F, Sebrie C, Rivals I, Ledru A, Paly E, Bizot JC, Smith D, Rubin E, Gillet B, Arbones M, Delabar JM. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One. 2009;4(2):e4606. doi: 10.1371/journal.pone.0004606. Epub 2009 Feb 26.

  PMID: 19242551 BACKGROUND

MeSH Terms

Conditions

Down Syndrome; Fragile X Syndrome; Intellectual Disability

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; X-Linked Intellectual Disability; Sex Chromosome Disorders; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of the Neurosciences Department in Institut Hospital d'Investigacions Mèdiques (IMIM), PharmD, PhD

Model Details: 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.

Study Record Dates

• First Submitted: June 6, 2018
• First Posted: August 10, 2018
• Study Start: January 29, 2018
• Primary Completion: March 29, 2020
• Study Completion: November 30, 2020
• Last Updated: June 11, 2021

Record last verified: 2021-06

Locations

ES (1)