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Down Syndrome Clinical Trials - Study of Alzheimer's Disease in Down Syndrome (LIFE-DSR)

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ClinicalTrials.gov Identifier: NCT04149197
Recruitment Status : Recruiting
First Posted : November 4, 2019
Last Update Posted : November 4, 2019
Sponsor:
Collaborator:
Alzheimer's Disease Cooperative Study (ADCS)
Information provided by (Responsible Party):
LuMind IDSC Foundation

Brief Summary:
This is an observational, multi-center, longitudinal cohort study to characterize adults with DS ages 25 years and above enrolled at specialized care centers. The aim is to assess changes in cognition, behavior, function and health over approximately 24 months. Blood will be collected for the development of plasma AD biomarkers useful in the DS population.

Condition or disease
Alzheimer's Disease in Down Syndrome

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Detailed Description:

Adults with DS face a markedly increased risk of Alzheimer's Disease (AD). DS, the most common genetic cause of AD, is due to trisomy for all or part of a third copy of chromosome 21. It is typically associated with the presence of a number of abnormal clinical phenotypes, including craniofacial anatomy, and is universally characterized by mild to moderate intellectual disability. Almost all adults with DS develop AD-like neuropathology by the age of 40. While dementia may not be universal, the prevalence of AD in DS increases from 9% to 23% between the ages of 35 and 49 years, 55% in those between 50 and 59 years, and estimates place it as greater than 75% in those 60 years of age and above. The average age at which dementia is diagnosed is 55 years . Given shared clinical and neuropathological features, and in view of shared genetic risk, this disorder is now termed AD in DS (AD-DS).

Among the genes on chromosome 21 triplicated in DS the evidence is compelling that increased gene dose for amyloid precursor protein (APP), with increased levels of the APP protein and its products, is necessary for AD-DS. Other chromosome 21 genes may impact AD-DS as may genes on other chromosomes, including variants that also increase the probability of AD, but a uniquely important role is played by increased dose for APP. Given the APP gene dose-dependence of AD-DS, and the recognition that a rare form of FAD is due to APP gene duplication, it is not surprising that AD and AD-DS share common neuropathologies, including accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Indeed, the neuropathological hallmarks of AD-DS are very similar if not identical to AD. Thus, like AD, beta-amyloid (Aβ) - principally Aβ42 - is the isoform of Aβ that dominates in diffuse deposits and then in mature plaques; Aβ40 accumulates around cerebral vessels with significantly higher frequencies in DS than in AD, recapitulating the congophilic angiopathy of AD. However, distinct from AD, Aβ accumulation in DS occurs in young people with deposition in diffuse plaques in those in the teenage years, decades earlier than in both aged controls and individuals with AD. As in AD, amyloid deposition appears before NFT formation and is present significantly before the development of dementia. An important question is whether it is possible to prevent or mitigate the cognitive deficits and other symptoms associated with AD-DS. Ascertaining the preclinical and prodromal stages of the dementia could be particularly valuable. This approach has significantly advanced the field in studies on other cases of genetically caused AD, i.e. those with familial AD (FAD) due to mutations in APP or in its processing enzymes Presenilin 1 and 2. Given this rationale, we will characterize the preclinical and prodromal stages of AD-DS by conducting longitudinal observations that incorporate medical history and measures of cognition, behavior, and function in adults with DS aged 25 years and above. The goal is to chart the cognitive, behavioral and functional status of a population at high risk for AD-DS.

Specialty centers in the U.S. care for large populations of persons with DS and form the team of recruiting sites in this study. The DS-CTN is a clinical research and trials network of specialty centers in the U.S. expertly equipped to conduct work extending from design, to execution, to analysis and publication of research that benefits the DS population through discovery and delivery of effective treatments. The DS-CTN currently consists of 11 member sites in the U.S. specializing in DS, and is comprised of scientific investigators and clinicians, largely but not exclusively from academic research centers, whose focus is on clinical trials in the DS population. The DS-CTN will support this observational study through enrollment and longitudinal follow-up of participants. DS-CTN member sites will also support this study by contributing expert feedback into protocol and data entry field development, while also offering important feedback and input on the conduct and flow of the study. The DS-CTN will be responsible for the analysis and publication of the study data.

Males and females, aged 25 and older, with a diagnosis of DS, typically supported by karyotype analysis documenting full trisomy for chromosome 21 or complete unbalanced translocation of chromosome 21.

Enrollment will be balanced by the following age strata: 25 to 34 years old (target 10% of enrollment), 35 to 44 (target 40% of enrollment), 45 to 54 (target 40% of enrollment), and 55 years and older (target 10% of enrollment).


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Study Type : Observational
Estimated Enrollment : 270 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Down Syndrome Clinical Trials Network (DS-CTN) Study of Alzheimer's Disease in Down Syndrome
Actual Study Start Date : June 30, 2019
Estimated Primary Completion Date : March 30, 2022
Estimated Study Completion Date : September 30, 2022





Primary Outcome Measures :
  1. Cognitive Measure [ Time Frame: Over the 2 years of the study ]

    -Severe Impairment Battery (SIB) with the Shoebox test - The SIB was developed to assess the skills of people with severe dementia. The SIB evaluates cognitive abilities at the lower end of the range. Range of total possible score: 0 - 100

    Subscale Ranges:

    • Social Interaction - 0 - 6
    • Orientation - 0 - 8
    • Visuospatial Ability - 0 - 8
    • Construction - 0 - 12
    • Language - 0 - 56
    • Memory - 0 - 16
    • Praxis - 0 - 8
    • Attention - 0 - 15
    • Orienting to name - 0 - 4

    Higher scores reflect better performance for each subscale. Scores above 60 mean the participant completes the Shoebox Memory Test.


  2. Cognitive Measure [ Time Frame: Over the 2 years of the study ]

    - The Down Syndrome-Mental Status Examination (DS-MSE) is a test battery used to measure a broad range of skills including to recall of personal information, orientation to season and day of the week, short-term memory, language, visuospatial construction, and praxis. Range of total possible score: 0 - 62

    Subscale ranges:

    • Introduction: 0 - 2
    • Orientation: 0 - 12
    • Verbal Repetition: 0 - 8
    • Naming for the Identity of 3 Objects: 0 - 3
    • Verbal Comprehension: 0 - 12
    • Immediate Memory for Location: 0 - 3
    • Naming: 0 - 8
    • Visuospatial Construction: 0 - 8
    • Delayed Memory for Location: 0 - 3
    • Apraxia: 0 - 4

    Higher scores reflect better performance for each subscale.


  3. Behavioral Measure [ Time Frame: Over the 2 years of the study ]

    Dementia Questionnaire for People with Learning Disabilities (DLD) - Measures specific cognitive and functional deterioration as a result of dementia, and functional deterioration as a result of severe sensory or psychiatric problems. Range of total possible scores: 0 - 100 50 Questions with a possible range of 0 - 2 per question. Higher scores reflect worse performance.

    Score Calculation:

    Categories are mixed throughout the questionnaire. To calculate the score at the end, scores on each page are added up and categorizes into Cognitive Scores, or SCS (categories 1 - 3: Short-term memory, Long-term memory, and Spatial & Temporal Orientation) and Social Scores, or SOS (Categories 4 - 8: Speech, Practical Skills, Mood, Activity & Interest, Behavioral Disturbance).


  4. Behavioral Measure [ Time Frame: Over the 2 years of the study ]
    Neuropsychiatric Inventory (NPI) evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). The score for each subscale is the product of severity and frequency and the total score is the sum of all subscales.

  5. Functional Measure [ Time Frame: Over the 2 years of the study ]

    Vineland-3 is an adaptive behavior measure used to assess intellectual/developmental/other disabilities. Total score range: 0 - 140

    • Expressive Communication: 0 - 98
    • 49 questions - range: 0 - 2 per Q
    • Written Communication: 0 - 76
    • 38 questions - range: 0 - 2 per Q
    • Personal Daily Living Skills - 0 - 110
    • 55 questions - range: 0 - 2 per Q
    • A basal is established when four consecutive items score 2 in a domain
    • A ceiling is established with four consecutive items score 0 in a domain
    • Questions for each section are administered until basal & ceiling are established
    • If no basal established, go from first question to ceiling in the domain
    • If no ceiling established, go from basal to final question in the domain
    • For questions where the respondent has not observed the behavior, calculate an estimate %
    • (No. of questions estimated/No. of questions answered) x 100 = % estimated
    • Raw score for each domain:
    • (Highest-numbered basal item x 2) + Points between basal & ceiling

  6. Health Measures [ Time Frame: Over the 2 years of the study ]
    New-onset seizures or significantly increased frequency of seizures

  7. Health Measures [ Time Frame: Over the 2 years of the study ]
    Changes in mood or behavior, including depression or psychosis, viewed as significant in the opinion of the caregiver or clinician.


Secondary Outcome Measures :
  1. Exploratory Outcome Measures [ Time Frame: Over the 2 years of the study ]
    To derive a preliminary composite measure from the scales being used in LIFE-DSR that is most sensitive to change in this population and which can be validated in a future prospective study.

  2. Exploratory Outcome Measures [ Time Frame: Over the 2 years of the study ]
    To integrate and further validate a novel and highly sensitive multidomain instrument for AD-DS upon its completion (Professor A. Strydom, Kings College, London). This instrument is being developed under a separate protocol and upon its validation will be integrated into LIFE-DSR to evaluate its responsiveness to change in clinically important domains.

  3. Exploratory Outcome Measure [ Time Frame: Over the 2 years of the study ]
    To evaluate the difference in sensitivity for changes reflective of onset of AD-DS between preliminary composite measure and this multidomain instrument.

  4. Exploratory Outcome Measure [ Time Frame: Over the 2 years of the study ]
    To derive potential screening measures, from the larger test batteries, that might be best used for screening of significant AD dementia risk. These could then be further validated in a future prospective study.

  5. Exploratory Outcome Measure [ Time Frame: Over the 2 years of the study ]
    To obtain and bank plasma samples for future development of sensitive translational biomarkers, such as those related to amyloid or tau.


Biospecimen Retention:   Samples With DNA
A blood sample will be collected at the baseline, Month 12 and Month 24 visits for banking of plasma for future biomarker studies, which may include analysis of AD biomarkers such as amyloid beta (Aβ) or tau. In addition to biomarker analysis, future genotyping studies may also be conducted. Apolipoprotein E (APOE) (e4 +/-) genotype and other genetic variations are associated with the risk of onset of AD. Therefore, this blood sample collected at baseline, Month 12 and Month 24 will also include banking of buffy coat for future gene analyses which may include APOE testing of e2, e3, and e4 alleles as well as other genes associated with AD


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   25 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Males and females, aged 25 and older, with a diagnosis of DS, typically supported by karyotype analysis documenting full trisomy for chromosome 21 or complete unbalanced translocation of chromosome 21.
Criteria

Inclusion Criteria:

  • Age 25 years or older
  • Diagnosis of DS, typically supported by karyotype analysis documenting full trisomy for chromosome 21 or complete unbalanced translocation of chromosome 21. Karyotype analysis is not required for study entry
  • Participants, or Legal Authorized Representative, and their study partner if applicable, in the opinion of the investigator, are able to understand and willing to sign written informed consent.
  • Participants must have a study partner who has frequent interaction with the participant on a regular basis, will agree to participate in annual clinic visits, can provide accurate responses to questions about the participant, and facilitate participation in the study visits, in the opinion of site PI or study coordinator.
  • Participant and study partner must be capable of reliably completing study assessments.

Exclusion Criteria:

  • Participants and study partners who, in the opinion of the investigator, are not able to complete trial procedures or adhere to the schedule of study assessments will be excluded from study participation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04149197


Contacts
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Contact: Duvia Lara Ledesma, MA (858) 246-5466 dlaraledesma@ucsd.edu
Contact: Carolyn Revta, MPH 858-229-4967 crevta@ucsd.edu

Locations
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United States, Arizona
Barrow Neurological Institute Recruiting
Phoenix, Arizona, United States, 85013
Contact: Sandy Quintanilla    602-406-7054    sandy.quintanilla@dignityhealth.org   
Principal Investigator: Anna Burke, MD         
United States, California
University California Irvine Not yet recruiting
Irvine, California, United States, 92697
Principal Investigator: Ira Lott, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Helen Smith    404-778-8477    hsmith3@emory.com   
Principal Investigator: Amy Talboy, MD         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Melissa Baer    312-563-6636    melissa_r_baer@rush.edu   
Principal Investigator: Cesar Ochoa-Lubinoff, MD         
Advocate Health Recruiting
Park Ridge, Illinois, United States, 60068
Contact: Monika Kapinos    847-723-2243    monika.kapinos@advocatehealth.com   
Principal Investigator: Brian Chicoine, MD         
United States, Kentucky
University Of Kentucky Not yet recruiting
Lexington, Kentucky, United States, 40536
Principal Investigator: Frederick Schmitt, PhD         
United States, Maryland
Kennedy Krieger Institute Not yet recruiting
Baltimore, Maryland, United States, 21205
Principal Investigator: George Capone, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Ashlee Campbell    671-726-7954    acampbell18@mgh.harvard.edu   
Principal Investigator: Stephanie Santoro, MD         
Massachusetts General Hospital Not yet recruiting
Charlestown, Massachusetts, United States, 02129
Principal Investigator: Diana Rosas, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Jane Ann Baker    919-668-4576    janeann.baker@duke.edu   
Principal Investigator: Priya Kishnani, PhD         
United States, Ohio
Cincinnatti Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229
Principal Investigator: Anna Esbensen, MD, PhD         
Case Western Reserve University Not yet recruiting
Cleveland, Ohio, United States, 044106
Principal Investigator: Alberto Costa, MD, PhD         
Sponsors and Collaborators
LuMind IDSC Foundation
Alzheimer's Disease Cooperative Study (ADCS)

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Responsible Party: LuMind IDSC Foundation
ClinicalTrials.gov Identifier: NCT04149197     History of Changes
Other Study ID Numbers: ADC-059-LIFE-DSR
First Posted: November 4, 2019    Key Record Dates
Last Update Posted: November 4, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by LuMind IDSC Foundation:
Down Syndrome
Alzheimer's Disease
Additional relevant MeSH terms:
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Alzheimer Disease
Down Syndrome
Syndrome
Disease
Pathologic Processes
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn