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Relationship Between Down Syndrome (DS) and Alzheimer's Disease (AD)

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ClinicalTrials.gov Identifier: NCT02759887
Recruitment Status : Unknown
Verified November 2016 by Madelon Petersen, St. Joseph's Hospital and Medical Center, Phoenix.
Recruitment status was:  Recruiting
First Posted : May 3, 2016
Last Update Posted : November 3, 2016
Sponsor:
Collaborators:
Banner Alzheimer's Institute, Phoenix
Translational Genomics Research Institute (TGEN), Phoenix
Information provided by (Responsible Party):
Madelon Petersen, St. Joseph's Hospital and Medical Center, Phoenix

Tracking Information
First Submitted Date  ICMJE April 15, 2016
First Posted Date  ICMJE May 3, 2016
Last Update Posted Date November 3, 2016
Study Start Date  ICMJE November 2016
Estimated Primary Completion Date March 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2016)
  • Florbetapir PET - change between timeframes [ Time Frame: Year 1, Year 2-3 ]
    The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
  • tau PET - change between timeframes [ Time Frame: Year 1, Year 2-3 ]
    The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
  • FDG PET - change between timeframes [ Time Frame: Year 1, Year 2-3 ]
    The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
  • MRI - change between timeframes [ Time Frame: Year 1, Year 2-3 ]
    The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02759887 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2016)
dried blood spot collection (DBSC) analysis - change between timeframes [ Time Frame: Year 1, Year 2-3 ]
(a) Detect and track RNA biomarkers longitudinally from a single dried blood spot (DBS) using next generation RNA sequencing (RNA-Seq) in prospectively assessed DS, DS/AD and NC, (b) Study and identify biomarkers with the greatest rate of change in DS patients who are at differential risk levels for the development of AD dementia, and (c) Correlate the RNA biomarkers with imaging (FDG-PET, FBP (Florbetapir F18)-PET, MRI, tau PET) that are concurrently being gathered in the proposed study populations.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Relationship Between Down Syndrome (DS) and Alzheimer's Disease (AD)
Official Title  ICMJE Longitudinal Assessment of Amyloid Positron Emission Tomography (PET), Fludeoxyglucose F18 (FDG) PET, Tau PET, Magnetic Resonance Imaging (MRI), and Blood Spot Ribonucleic Acid (RNA) in Down Syndrome Individuals With and Without Alzheimer's Dementia and Normal Controls
Brief Summary In order to treat individuals with Down syndrome (DS) better and more efficiently and to gain more insights on its relation to Alzheimer's disease (AD), a comprehensive understanding is needed for its progression in the early or preclinical phase using various biomarkers. DS is a significant risk factor for the early development of AD, with plaques and tangles typically developing by age 35. A better understanding is needed of early markers of the disease in DS patients. Additionally the DS population represents a unique group - due to this elevated risk for AD - to examine biomarkers that may translate in general outside of the DS population to individuals at risk for developing late onset AD. In this proposal, the researchers will assess the longitudinal changes of various biomarkers in a cohort of individuals similar in design to the cross-sectional sectional study in the preliminary data.
Detailed Description This study will recruit from three experimental groups: (1)The DS (adult) group will consist of 15 DS subjects aged 21 and older who do not qualify for the diagnosis of dementia at the beginning of the study. (2)The DS/AD group will consist of 15 DS subjects aged 40 and older who do qualify for the diagnosis of dementia by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Diagnoses will be by standard consensus review of all cases. (3)Normal control (NC) adult will consist of 10 cognitively normal, non-DS individuals, age-matched to the DS group. Blood will be collected to assess apolipoprotein E (ApoE) genotype. Participation in the dried blood spot collection (DBSC) will be an optional sub-study. Only participants and/or their caregivers/legally authorized representatives indicating they wish to have DBSC performed on the consent will provide specimens.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Down Syndrome
  • Alzheimer's Dementia
Intervention  ICMJE
  • Procedure: biospecimen collection
    Blood: ApoE genotyping, comprehensive metabolic panel, RNA sequencing. Urine: beta-hCG (human corionic gonadotropin) testing.
  • Other: cognitive assessments
    Dementia Questionnaire for People with Learning Disabilities; Mini-Mental State Examination; Severe Impairment Battery; Vineland Adaptive Behavior Scale; Arizona Memory Assessment for Intellectual Disability; Kaufman Brief Intelligence Test; Nepsy Mazes; and, Timed Up and Go.
  • Other: caregiver questionnaire
  • Procedure: Florbetapir F18 imaging
    Used in small doses to image brain amyloid-beta deposits in human beings. Radioactivity necessary to create the positron emission tomography (PET) images. Radiation exposure is slightly more than a person would receive from a routine clinical head computed tomography scan.
  • Procedure: MRI
    Magnetic resonance imaging of the head and brain.
  • Procedure: Fludeoxyglucose F18 (FDG)
    Injected intravenously during a PET scan and is a marker for the tissue uptake of glucose; a radiopharmaceutical compound.
  • Procedure: Tau Pet
    Administered during a PET, in small amounts, necessary to create the scan images. Radioactive. The total amount of radiation is about the same that a patient receives from a routine abdominal/pelvis computerized tomography.
    Other Name: F-AV-1451
  • Procedure: Actigraphy
    A non-invasive method of monitoring human rest and activity cycles. A small actigraph unit is worn to measure gross motor activity. The unit is usually worn on the wrist.
    Other Name: actimetry
Study Arms  ICMJE
  • DS adult group
    Consists of 15 DS subjects aged 21 and older who do not qualify for the diagnosis of dementia at the beginning of the study. Interventions include biospecimen collection, cognitive assessments, caregiver questionnaire, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.
    Interventions:
    • Procedure: biospecimen collection
    • Other: cognitive assessments
    • Other: caregiver questionnaire
    • Procedure: Florbetapir F18 imaging
    • Procedure: MRI
    • Procedure: Fludeoxyglucose F18 (FDG)
    • Procedure: Tau Pet
    • Procedure: Actigraphy
  • DS/AD group
    Consists of 15 DS subjects aged 40 and older who do qualify for the diagnosis of dementia by DSM-IV criteria. Diagnoses will be by standard consensus review of all cases. Interventions include biospecimen collection, cognitive assessments, caregiver questionnaire, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.
    Interventions:
    • Procedure: biospecimen collection
    • Other: cognitive assessments
    • Other: caregiver questionnaire
    • Procedure: Florbetapir F18 imaging
    • Procedure: MRI
    • Procedure: Fludeoxyglucose F18 (FDG)
    • Procedure: Tau Pet
    • Procedure: Actigraphy
  • NC adult
    Consists of 10 cognitively normal, non-DS individuals, age-matched to the DS adult group. Interventions include biospecimen collection, cognitive assessments, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.
    Interventions:
    • Procedure: biospecimen collection
    • Other: cognitive assessments
    • Procedure: Florbetapir F18 imaging
    • Procedure: MRI
    • Procedure: Fludeoxyglucose F18 (FDG)
    • Procedure: Tau Pet
    • Procedure: Actigraphy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: April 28, 2016)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2019
Estimated Primary Completion Date March 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria for Non-AD/DS subjects:

  • Subjects with free Trisomy 21.
  • Male or female subjects who are 21 years of age or older.
  • Subjects who are not diagnosed with possible or probable AD or dementia after evaluation NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association) criteria.
  • Subjects who live with or have regular visits from a responsible caregiver willing to provide information about the subject's cognitive status.
  • If the subject is incapable of giving informed consent, the caregiver may consent on behalf of the subject (subject must still confirm assent).

Inclusion criteria for AD/DS subjects:

  • Subjects with free Trisomy 21.
  • Male or female subjects who are 40 and older years of age.
  • Subjects who are diagnosed with possible or probable using NINCDS-ADRDA criteria.
  • Subjects who live with or have regular visits from a responsible caregiver willing to provide information about the subject's cognitive status.
  • If the subject is incapable of giving informed consent, the caregiver may consent on behalf of the subject (subject must still confirm assent).

Inclusion criteria for Normal Controls

  • Cognitively normal, non-DS individuals.
  • Age-matched to the DS group.
  • Subjects who signed an Institutional Review Board-approved informed consent.

Exclusion Criteria: (for all groups)

  • Previous or current diagnosis of a neurodegenerative disorders other than AD or DS, including, but not limited to Parkinson's disease, Pick's disease, fronto-temporal dementia, Huntington's chorea, Creutzfeldt-Jacob disease, normal pressure hydrocephalus, and progressive supranuclear palsy.
  • Previous or current diagnosis of other dementing/neurodegenerative disease (e.g. Parkinson's disease dementia, dementia with Lewy bodies, Lewy body variant AD).
  • Previous or current diagnosis of mixed dementia.
  • Previous or current diagnosis of cognitive impairment resulting from other known etiology.
  • Previous or current diagnosis of clinically significant infarct or possible multi-infarct dementia as defined by the National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neuroscience (NINDS-AIREN) criteria.
  • Previous or current evidence on screening MRI, computed tomography (CT), or other biomarker studies that suggests an alternate etiology (other than probable AD in patients with AD) for cognitive deficit; or in the case of non-AD controls any evidence on screening MRI, CT, or other biomarker studies that suggests the presence of AD pathology. Brain amyloid-β peptides (Aβ) on Amyloid imaging/PET imaging, however, is expected in many non-AD/DS and all AD/DS subjects, and will not be grounds for exclusion.
  • Previous or current clinically significant psychiatric disease, as judged by Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, particularly current major depression or schizophrenia. Patients with dementia who are experiencing behavioral disturbances that may require treatment with psychotropic medications may be entered only after discussion and with the approval of the principal investigator. The investigators should carefully consider whether subjects with behavioral dysfunction will be able to complete the imaging session.
  • Previous or current history of epilepsy or convulsions, except for febrile convulsions during childhood.
  • Current clinically significant hepatic, renal, pulmonary, metabolic, or endocrine disturbances.
  • Current clinically significant cardiovascular disease. Clinically significant cardiovascular disease usually includes one or more of the following: a) cardiac surgery or myocardial infarction within the last 6 months; b) unstable angina; c) coronary artery disease that required an increase in medication within the last 3 months; d) decompensated congestive heart failure; e) significant cardiac arrhythmia or conduction disturbance, particularly those resulting in a trial or ventricular fibrillation, or causing syncope, near syncope, or other alterations in mental status; f) severe mitral or aortic valvular disease; g) uncontrolled high blood pressure; h) congenital heart disease) .
  • Current history of drug or alcohol abuse within the last year, or prior prolonged history of abuse.
  • Current clinically significant infectious disease, including known Acquired Immune Deficiency Syndrome (AIDS) or Human Immunodeficiency Virus (HIV) infection or previous positive test for hepatitis.
  • Women of childbearing potential who are not surgically sterile, not refraining from sexual activity, or not using reliable methods of contraception. Women of childbearing potential must not be pregnant (negative serum beta-hCG [human chorionic gonadotropin] at the time of screening and negative urine beta-hCG on the day of imaging) or lactating at screening. Women must avoid becoming pregnant, and must agree to refrain from sexual activity or to use reliable contraceptive methods for 30 days prior to and 30 days after administration of radiopharmaceutical imaging agents in this study. In order to participate in this study, sexually active females must be either: two or more years post-menopausal or surgically sterilized, or must be using an acceptable form of contraception (oral contraceptives for at least three months or an IUD (intrauterine device) for at least two months prior to the start of the screening visit, or various barrier methods, e.g., diaphragm or combination condom and spermicide).
  • Subjects who, in the opinion of the research team, are otherwise unsuitable for a study of this type.
  • Subjects who have a history of relevant severe drug allergy or hypersensitivity.
  • Subjects who have received an investigational medication within the last 30 days. Additionally, the time between the last dose of the previous experimental medication and enrollment (completion of screening assessments) must be at least equal to 5 times the terminal half-life of the previous experimental medication.
  • Subjects who have ever participated in an experimental study with an amyloid targeting therapy (e.g., immunotherapy, secretase inhibitor) may not be enrolled unless it can be demonstrated that the subject received only placebo in the course of the trial.
  • Current clinically significant medical comorbidities, as indicated by history, physical exam, or laboratory evaluations, that might pose a potential safety risk, interfere with the absorption or metabolism of the study medication, or limit interpretation of the trial results. These include but are not limited to clinically significant hepatic, renal, pulmonary, metabolic or endocrine disease, and cancer.
  • Subjects who have received a radiopharmaceutical for imaging or therapy within the past 7 days prior to the imaging session for this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02759887
Other Study ID Numbers  ICMJE PHX-16-0028-70-03
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Madelon Petersen, St. Joseph's Hospital and Medical Center, Phoenix
Study Sponsor  ICMJE St. Joseph's Hospital and Medical Center, Phoenix
Collaborators  ICMJE
  • Banner Alzheimer's Institute, Phoenix
  • Translational Genomics Research Institute (TGEN), Phoenix
Investigators  ICMJE
Principal Investigator: Marwan N Sabbagh, MD Barrow Neurological Institute
PRS Account St. Joseph's Hospital and Medical Center, Phoenix
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP