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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

Primary Purpose

Down Syndrome (DS)

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Epigallocatechin-3-gallate (EGCG)
Sponsored by
Parc de Salut Mar
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Down Syndrome (DS) focused on measuring APP function (amyloid precursor protein, cognitive stimulation, alzheimer disease. program

Eligibility Criteria

14 Years - 29 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Dietary Supplement: Epigallocatechin-3-gallate (EGCG)

Placebo

Arm Description

EGCG normally works as a 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.

No active treatment is given.

Outcomes

Primary Outcome Measures

Change in Cognitive Evaluation
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.
Change in Amyloidosis Biomarkers
APP derived amyloid peptides in plasma (INNO-BIA)

Secondary Outcome Measures

Treatment compliance
Change in Biomarkers of lipid oxidation
LDL (Low density lipoproteins), HDL (High density lipoprotein, cholesterol, triglycerides oxidized-LDL (Pentra Autoanalyzer, and ELISA Mercodia for LDLox
Change in DYRK1A activity biomarkers
Plasma homocysteine (Abbot AxyM), transthyretrin (ELISA) FOXO1 (DNA-binding ELISA nuclear extract from lymphocytes)
COMT val158met genetic polymorphism (catechol methyl transferase) (Taqman)
Change in AST (SGOT -serum glutamic oxaloacetic transaminase-) and ALT (SGPT- Serum Glutamic Pyruvate Transaminase-) (Pentra Autoanalyzer, and ELISA Mercodia for LDLox)
Change in Body Composition by electrical impedance (TANITA-MC-180)
Changes in Neurophysiology
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).
Changes in Neuroimaging
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.

Full Information

First Posted
September 26, 2012
Last Updated
February 10, 2016
Sponsor
Parc de Salut Mar
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1. Study Identification

Unique Protocol Identification Number
NCT01699711
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Parc de Salut Mar

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Down Syndrome (DS)
Keywords
APP function (amyloid precursor protein, cognitive stimulation, alzheimer disease. program

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
87 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dietary Supplement: Epigallocatechin-3-gallate (EGCG)
Arm Type
Active Comparator
Arm Description
EGCG normally works as a 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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
No active treatment is given.
Intervention Type
Dietary Supplement
Intervention Name(s)
Epigallocatechin-3-gallate (EGCG)
Intervention Description
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 Outcome Measure Information:
Title
Change in Cognitive Evaluation
Description
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.
Time Frame
From predose baseline to 19 months (end of treatment)
Title
Change in Amyloidosis Biomarkers
Description
APP derived amyloid peptides in plasma (INNO-BIA)
Time Frame
From predose baseline to 19 months (end of treatment)
Secondary Outcome Measure Information:
Title
Treatment compliance
Time Frame
Predose baseline 3, 7, 13 months
Title
Change in Biomarkers of lipid oxidation
Description
LDL (Low density lipoproteins), HDL (High density lipoprotein, cholesterol, triglycerides oxidized-LDL (Pentra Autoanalyzer, and ELISA Mercodia for LDLox
Time Frame
Predose baseline: 3, 7, 13 months
Title
Change in DYRK1A activity biomarkers
Description
Plasma homocysteine (Abbot AxyM), transthyretrin (ELISA) FOXO1 (DNA-binding ELISA nuclear extract from lymphocytes)
Time Frame
Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).
Title
COMT val158met genetic polymorphism (catechol methyl transferase) (Taqman)
Time Frame
Predose baseline
Title
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).
Title
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).
Title
Changes in Neurophysiology
Description
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).
Time Frame
Predose baseline: 7, 13 months
Title
Changes in Neuroimaging
Description
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.
Time Frame
Predose baseline: 7, 13 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
29 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)
City
Barcelona
ZIP/Postal Code
08003
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
27302362
Citation
de la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, Xicota L, Janel N, Catuara-Solarz S, Sanchez-Benavides G, Blehaut H, Duenas-Espin I, Del Hoyo L, Benejam B, Blanco-Hinojo L, Videla S, Fito M, Delabar JM, Dierssen M; TESDAD study group. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jul;15(8):801-810. doi: 10.1016/S1474-4422(16)30034-5.
Results Reference
derived

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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

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