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Completed

NCT Number: NCT01699711

Normalization of dyrk1A and APP Function as an Approach to Improve Cognitive Performance and Decelerate AD Progression in DS Subjects: Epigallocatechin Gallate as Therapeutic Tool

Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is postulated to modulate dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and amyloid beta precursor protein (APP) gene overexpression in the brains of Down syndrome mouse models. The clinical study is aimed at demonstrating that normalization of Dyrk1A and APP functions is a therapeutic approach to improve cognitive performance and decelerate AD (Alzheimer's disease) like progression.

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Key information

Conditions

Down Syndrome (DS) Abnormalities, Multiple Alzheimer Disease Brain Diseases Central Nervous System Diseases Chromosome Disorders Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dementia Down Syndrome Genetic Diseases, Inborn Intellectual Disability Mental Disorders Nervous System Diseases Neurobehavioral Manifestations Neurocognitive Disorders Neurodegenerative Diseases Neurologic Manifestations Tauopathies

Age range

14 year–29 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)

Barcelona, 08003, Spain

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Have been diagnosed of DS neurological disease, aged between 14-29 years.
  • Have given the consent to participate (official custody).

Exclusion criteria

  • Subjects with neurological disease other than DS, relevant medical disease, co-morbid mental disorder or currently taking any treatment that could interfere with cognitive function or alter any key biomarkers and biochemical parameters analyzed.
  • Having suffered from any major illness or undergoing major surgery in the last three months before the study.
  • Regular ingestion of medication in the month preceding the study (exceptions for single doses of symptomatic medication administered up to the week preceding the trial).
  • Current ingestion of vitamin supplements or catechins or AINE in the two weeks preceding the study.
  • History of gastrointestinal, hepatic or renal problems or any other cause that may alter processes of absorption, distribution, metabolism, or excretion of the drug, or that might suggest gastrointestinal irritation to drug.
  • Subjects following a vegetarian diet.
  • Practice of physical exercise for more than 2 hours per day or energy consume/consumption of more than 3000 kcal per week.

Treatment and study plan

Epigallocatechin-3-gallate (EGCG)

Dietary Supplement

EGCG administration in Down syndrome patients will result in an improvement of their cognitive performance. A daily oral dose containing 9 mg/kg (range 6.9-12.7) of EGCG is given during twelve months.

Primary outcomes

  1. Change in Cognitive Evaluation

    Time frame: From predose baseline to 19 months (end of treatment)

    a.Intelligence Quotient [Kaufman (K-BIT)], b.Attention [Spatial Span direct series (SSP), Choice Reaction Time (CRT) CANTAB battery]c. Psychomotor Speed [ (MOT) CANTAB battery] d.Episodic Memory [visuospatial: Paired Associates Learning (PAL) and visual: Pattern Recognition Memory (PRM) CANTAB battery; visuospatial learning Cued Recall Test (CRT) ] e.Executive Functions [working memory: SSP CANTAB battery; verbal semantic fluency; inhibition: Cats and Dogs; planning: Tower of London-Drexel (TOLDX) mental flexibility: Weigl Card Sorting Test ] f.Language:[ Expressive language: Boston naming test (BNT) ; Receptive language: Token Test (TT) g.Functional, quality of life and neuropsychiatric evaluation [Adaptative Behaviour Assessment System (ABAS-II): Dementia Questionnaire for People with Intellectual Disabilities (DMR): Neuropsychiatric Inventory (NPI); quality of life: Kidscreen; semi-structured interview to evaluate subjective effects concerning relevant changes.

  2. Change in Amyloidosis Biomarkers

    Time frame: From predose baseline to 19 months (end of treatment)

    APP derived amyloid peptides in plasma (INNO-BIA)

Secondary outcomes

  1. Treatment compliance

    Time frame: Predose baseline 3, 7, 13 months

  2. Change in Biomarkers of lipid oxidation

    Time frame: Predose baseline: 3, 7, 13 months

    LDL (Low density lipoproteins), HDL (High density lipoprotein, cholesterol, triglycerides oxidized-LDL (Pentra Autoanalyzer, and ELISA Mercodia for LDLox

  3. Change in DYRK1A activity biomarkers

    Time frame: Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).

    Plasma homocysteine (Abbot AxyM), transthyretrin (ELISA) FOXO1 (DNA-binding ELISA nuclear extract from lymphocytes)

  4. COMT val158met genetic polymorphism (catechol methyl transferase) (Taqman)

    Time frame: Predose baseline

  5. Change in AST (SGOT -serum glutamic oxaloacetic transaminase-) and ALT (SGPT- Serum Glutamic Pyruvate Transaminase-) (Pentra Autoanalyzer, and ELISA Mercodia for LDLox)

    Time frame: Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).

  6. Change in Body Composition by electrical impedance (TANITA-MC-180)

    Time frame: Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).

  7. Changes in Neurophysiology

    Time frame: Predose baseline: 7, 13 months

    Parameters to be evaluated: (i) Motor threshold at Rest (MTR) for the Abductor Pollicis Brevis ( APB) muscle determination (ii) Basal single pulse response at rest for the APB at 110 of the MTR required, and (iii) Percentage of increase and decrease of the amplitude of the APB after double pulse, short and long pulse interval after transcranial magnetic stimulation (TMS).

  8. Changes in Neuroimaging

    Time frame: Predose baseline: 7, 13 months

    Regional brain morphology and volume (FLAIR) sequence to assess possible white matter tissue macroscopic lesions), brain function in disease-specific neural systems: Intrinsic functional organization (i.e., functional connectivity) in the resting-state within the neural systems.

Sponsors and collaborators

Lead sponsor

Parc de Salut Mar

Other

Registry information

Important dates

Study start
2012
Primary completion
2014
Study completion
2015
First posted
Oct 4, 2012
Registry last updated
Feb 11, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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