<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01699711</url>
  </required_header>
  <id_info>
    <org_study_id>TESDAD</org_study_id>
    <nct_id>NCT01699711</nct_id>
  </id_info>
  <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</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Parc de Salut Mar</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Parc de Salut Mar</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, is postulated to modulate&#xD;
      dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and amyloid beta&#xD;
      precursor protein (APP) gene overexpression in the brains of Down syndrome mouse models. The&#xD;
      clinical study is aimed at demonstrating that normalization of Dyrk1A and APP functions is a&#xD;
      therapeutic approach to improve cognitive performance and decelerate AD (Alzheimer's disease)&#xD;
      like progression.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>February 2012</start_date>
  <completion_date type="Actual">March 2015</completion_date>
  <primary_completion_date type="Actual">June 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Cognitive Evaluation</measure>
    <time_frame>From predose baseline to 19 months (end of treatment)</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Amyloidosis Biomarkers</measure>
    <time_frame>From predose baseline to 19 months (end of treatment)</time_frame>
    <description>APP derived amyloid peptides in plasma (INNO-BIA)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment compliance</measure>
    <time_frame>Predose baseline 3, 7, 13 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Biomarkers of lipid oxidation</measure>
    <time_frame>Predose baseline: 3, 7, 13 months</time_frame>
    <description>LDL (Low density lipoproteins), HDL (High density lipoprotein, cholesterol, triglycerides oxidized-LDL (Pentra Autoanalyzer, and ELISA Mercodia for LDLox</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in DYRK1A activity biomarkers</measure>
    <time_frame>Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).</time_frame>
    <description>Plasma homocysteine (Abbot AxyM), transthyretrin (ELISA) FOXO1 (DNA-binding ELISA nuclear extract from lymphocytes)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>COMT val158met genetic polymorphism (catechol methyl transferase) (Taqman)</measure>
    <time_frame>Predose baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in AST (SGOT -serum glutamic oxaloacetic transaminase-) and ALT (SGPT- Serum Glutamic Pyruvate Transaminase-) (Pentra Autoanalyzer, and ELISA Mercodia for LDLox)</measure>
    <time_frame>Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Body Composition by electrical impedance (TANITA-MC-180)</measure>
    <time_frame>Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Neurophysiology</measure>
    <time_frame>Predose baseline: 7, 13 months</time_frame>
    <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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Neuroimaging</measure>
    <time_frame>Predose baseline: 7, 13 months</time_frame>
    <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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">87</enrollment>
  <condition>Down Syndrome (DS)</condition>
  <arm_group>
    <arm_group_label>Dietary Supplement: Epigallocatechin-3-gallate (EGCG)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>No active treatment is given.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Epigallocatechin-3-gallate (EGCG)</intervention_name>
    <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.</description>
    <arm_group_label>Dietary Supplement: Epigallocatechin-3-gallate (EGCG)</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Have been diagnosed of DS neurological disease, aged between 14-29 years.&#xD;
&#xD;
          -  Have given the consent to participate (official custody).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with neurological disease other than DS, relevant medical disease, co-morbid&#xD;
             mental disorder or currently taking any treatment that could interfere with cognitive&#xD;
             function or alter any key biomarkers and biochemical parameters analyzed.&#xD;
&#xD;
          -  Having suffered from any major illness or undergoing major surgery in the last three&#xD;
             months before the study.&#xD;
&#xD;
          -  Regular ingestion of medication in the month preceding the study (exceptions for&#xD;
             single doses of symptomatic medication administered up to the week preceding the&#xD;
             trial).&#xD;
&#xD;
          -  Current ingestion of vitamin supplements or catechins or AINE in the two weeks&#xD;
             preceding the study.&#xD;
&#xD;
          -  History of gastrointestinal, hepatic or renal problems or any other cause that may&#xD;
             alter processes of absorption, distribution, metabolism, or excretion of the drug, or&#xD;
             that might suggest gastrointestinal irritation to drug.&#xD;
&#xD;
          -  Subjects following a vegetarian diet.&#xD;
&#xD;
          -  Practice of physical exercise for more than 2 hours per day or energy&#xD;
             consume/consumption of more than 3000 kcal per week.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>29 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>IMIM (Institut Hospital del Mar d'Investigacions Mèdiques)</name>
      <address>
        <city>Barcelona</city>
        <zip>08003</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>September 26, 2012</study_first_submitted>
  <study_first_submitted_qc>October 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>February 10, 2016</last_update_submitted>
  <last_update_submitted_qc>February 10, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 11, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Parc de Salut Mar</investigator_affiliation>
    <investigator_full_name>Rafael de la Torre</investigator_full_name>
    <investigator_title>PhD</investigator_title>
  </responsible_party>
  <keyword>APP function (amyloid precursor protein, cognitive stimulation, alzheimer disease. program</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Down Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epigallocatechin gallate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01699711
org study id: TESDAD
nct id: NCT01699711
lead sponsor: 
has dmc: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change in Cognitive Evaluation
time frame: From predose baseline to 19 months (end of treatment)
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.
measure: Change in Amyloidosis Biomarkers
time frame: From predose baseline to 19 months (end of treatment)
description: APP derived amyloid peptides in plasma (INNO-BIA)
measure: Treatment compliance
time frame: Predose baseline 3, 7, 13 months
measure: Change in Biomarkers of lipid oxidation
time frame: Predose baseline: 3, 7, 13 months
description: LDL (Low density lipoproteins), HDL (High density lipoprotein, cholesterol, triglycerides oxidized-LDL (Pentra Autoanalyzer, and ELISA Mercodia for LDLox
measure: Change in DYRK1A activity biomarkers
time frame: Predose baseline 4 , 7 and 13 and 19 moths (end of treatment plus 6 months).
description: Plasma homocysteine (Abbot AxyM), transthyretrin (ELISA) FOXO1 (DNA-binding ELISA nuclear extract from lymphocytes)
measure: COMT val158met genetic polymorphism (catechol methyl transferase) (Taqman)
time frame: Predose baseline
measure: 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).
measure: 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).
measure: Changes in Neurophysiology
time frame: Predose baseline: 7, 13 months
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).
measure: Changes in Neuroimaging
time frame: Predose baseline: 7, 13 months
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.
arm group label: Dietary Supplement: Epigallocatechin-3-gallate (EGCG)
arm group type: Active Comparator
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 group label: Placebo
arm group type: Placebo Comparator
description: No active treatment is given.
intervention type: Dietary Supplement
intervention name: Epigallocatechin-3-gallate (EGCG)
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.
arm group label: Dietary Supplement: Epigallocatechin-3-gallate (EGCG)
arm group label: Placebo
criteria: 
gender: All
minimum age: 14 Years
maximum age: 29 Years
healthy volunteers: No
facility: 
country: Spain
responsible party type: Principal Investigator
investigator affiliation: Parc de Salut Mar
investigator full name: Rafael de la Torre
investigator title: PhD
mesh term: Down Syndrome
mesh term: Epigallocatechin gallate