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

Down Syndrome Clinical Trial

— PERSEUS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03624556
• Other study ID #: PERSEUS/1
• Status: Completed
• Phase: N/A
• Start date: January 29, 2018
• Est. completion date: November 30, 2020

Study information

• Verified date: June 2021
• Source: Parc de Salut Mar
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: November 30, 2020
• Est. primary completion date: March 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 12 Years

Eligibility

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.

Related Conditions & MeSH terms

• Down Syndrome
• Fragile X Syndrome
• Syndrome

Intervention

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

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

Locations

Country	Name	City	State
Spain	IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)	Barcelona

Sponsors (5)

Lead Sponsor	Collaborator
Parc de Salut Mar	Hospital Infantil Universitario Niño Jesús, Madrid, Spain, Hospital Universitario Marqués de Valdecilla, Institut Jerome Lejeune, Instituto Hispalense de Pediatría, Sevilla, Spain

Country where clinical trial is conducted

Spain, 

References & Publications (20)

Altafaj X, Dierssen M, Baamonde C, Martí E, Visa J, Guimerà J, Oset M, González JR, Flórez 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. — View Citation

Altafaj X, Martín ED, Ortiz-Abalia J, Valderrama A, Lao-Peregrín 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. — View Citation

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. — View Citation

Benavides-Piccione R, Dierssen M, Ballesteros-Yáñez I, Martínez de Lagrán M, Arbonés 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. — View Citation

de Sola S, de la Torre R, Sánchez-Benavides G, Benejam B, Cuenca-Royo A, Del Hoyo L, Rodríguez J, Catuara-Solarz S, Sanchez-Gutierrez J, Dueñas-Espin I, Hernandez G, Peña-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. — View Citation

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

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. Epub 2006 Dec 4. — View Citation

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. — View Citation

Guedj F, Sébrié 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. — View Citation

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. — View Citation

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:S16-22. doi: 10.1002/bdra.20776. Epub 2011 Mar 4. Review. — View Citation

Martínez-Cué C, Martínez P, Rueda N, Vidal R, García S, Vidal V, Corrales A, Montero JA, Pazos Á, Flórez J, Gasser R, Thomas AW, Honer M, Knoflach F, Trejo JL, Wettstein JG, Hernández MC. Reducing GABAA a5 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. — View Citation

Mégarbané A, Ravel A, Mircher C, Sturtz F, Grattau Y, Rethoré 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. Review. — View Citation

Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry. 2006 Sep;67(17):1849-55. Epub 2006 Jul 31. Review. — View Citation

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. — View Citation

Pujol J, del Hoyo L, Blanco-Hinojo L, de Sola S, Macià D, Martínez-Vilavella G, Amor M, Deus J, Rodríguez J, Farré 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. — View Citation

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. Epub 2007 Jan 19. — View Citation

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

Ruiz-Mejias M, Martinez de Lagran M, Mattia M, Castano-Prat P, Perez-Mendez L, Ciria-Suarez L, Gener T, Sancristobal B, García-Ojalvo J, Gruart A, Delgado-García 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. — View Citation

Vicari S, Carlesimo GA. Short-term memory deficits are not uniform in Down and Williams syndromes. Neuropsychol Rev. 2006 Jun;16(2):87-94. Epub 2006 Aug 9. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Exploratory Outcome: Blood folate concentration	Exploratory biomarkers: determination of folate in blood samples	Months -1, 3 and 6
Other	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
Other	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
Other	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
Other	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: cognitive functioning scale module. Range score 0-100; generic core module. Range score 0-100; family impact module. Range score 0-100 For all measures: a higher score is a better outcome	Baseline, months 6 and 9
Other	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: bedtime resistance. Range score 0-36; sleep behavior. Range score 0-24; night waking. Range score 0-8; morning wake up. 0-16 For all items except item 19, a higher score is a better outcome	Baseline, months 6 and 9
Other	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)).; Irritability. Range score 0-45; Hyperactivity. Range score 0-48; Lethargy/Withdrawal. Range score 0-21; Stereotypy. Range score 0-48; Inappropriate Speech. Range score 0-12 For all measures: a higher score is a worst outcome	Baseline, months 6 and 9
Other	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
Other	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
Primary	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)
Primary	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.
Primary	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.
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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