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
|Condition or disease|
|Alzheimer's Disease in Down Syndrome|
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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).
|Study Type :||Observational|
|Estimated Enrollment :||270 participants|
|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|
- 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
- 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.
- 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
- 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.
- 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.
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).
- 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.
- 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
- Health Measures [ Time Frame: Over the 2 years of the study ]New-onset seizures or significantly increased frequency of seizures
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
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
|Contact: Duvia Lara Ledesma, MA||(858) firstname.lastname@example.org|
|Contact: Carolyn Revta, MPHemail@example.com|
|United States, Arizona|
|Barrow Neurological Institute||Recruiting|
|Phoenix, Arizona, United States, 85013|
|Contact: Sandy Quintanilla 602-406-7054 firstname.lastname@example.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|
|Atlanta, Georgia, United States, 30322|
|Contact: Helen Smith 404-778-8477 email@example.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 firstname.lastname@example.org|
|Principal Investigator: Cesar Ochoa-Lubinoff, MD|
|Park Ridge, Illinois, United States, 60068|
|Contact: Monika Kapinos 847-723-2243 email@example.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 firstname.lastname@example.org|
|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 email@example.com|
|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|