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Down Syndrome Biomarker Initiative (DSBI) (DSBI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02141971
Recruitment Status : Completed
First Posted : May 20, 2014
Last Update Posted : May 2, 2017
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Michael Rafii, University of California, San Diego

Tracking Information
First Submitted Date May 16, 2014
First Posted Date May 20, 2014
Last Update Posted Date May 2, 2017
Actual Study Start Date June 1, 2013
Actual Primary Completion Date April 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 13, 2015)
Rate of decline as measured by cognitive, functional and behavioral tests [ Time Frame: 3 years ]
Original Primary Outcome Measures
 (submitted: May 19, 2014)
Rates of change on each specified biochemical biomarker [ Time Frame: 3 years ]
To characterize the cross-sectional and longitudinal trajectory of a set of non-invasive standardized biomarkers in adult subjects with Down syndrome (DS) at all stages of the disease, by applying the same set of biomarkers to each subject once a year across a time span of three years within a longitudinal natural history study. The goal is to characterize cognitive and biomarker trajectories in DS.
Change History
Current Secondary Outcome Measures
 (submitted: December 21, 2016)
  • Rate of conversion will be evaluated among all age groups [ Time Frame: 3 years ]
  • Rate of volume change of whole brain, hippocampus, and other structural Magnetic resonance imaging (MRI) measures. [ Time Frame: 3 years ]
  • Rates of change on each specified biochemical biomarkers [ Time Frame: 3 years ]
  • Rates of change of glucose metabolism as measured by fluorodeoxyglucose positron emission tomography (FDG-PET) imaging [ Time Frame: 2 years ]
  • Extent of amyloid deposition as measured amyloid PET imaging [ Time Frame: 3 years ]
  • Rates of change on retinal amyloid measures. [ Time Frame: 3 years ]
  • Correlations among biomarkers and cognitive change. [ Time Frame: 3 years ]
  • Correlations of Tau deposition as measured by 18F-AV-1451 PET (Tau) imaging with other biomarkers [ Time Frame: 1 year ]
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Down Syndrome Biomarker Initiative (DSBI)
Official Title Down Syndrome Biomarker Initiative: A Natural History Study of Alzheimer's Disease in Down Syndrome (Pilot Study)
Brief Summary

Non-randomized natural history study involving 12 subjects with Down Syndrome, who are aged 30-60 years old. This study will observe 3 different groups: four non-demented subjects between ages 30-40 years old, four non-demented subjects between ages 40-50 years old, and four demented subjects 50-60 years old.

Currently available longitudinal data in DS suggest a high rate of transition to dementia from the late 40s through the early 50s of these individuals. This, together with the universal presence of plaques in DS by their mid 40s makes this age range ideal for studying the development of AD.

Detailed Description

The overall goal of this project is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as the pathology evolves from normal aging through very mild symptoms, to mild cognitive impairment (MCI), to dementia in adults with Down syndrome. This is a pilot study modeled after the Alzheimer's Disease Neuroimaging Initiative (ADNI) to inform the neuroscience community of AD in DS, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios.

AD is the most common dementia in humans and over the next decades will account for a major and increasing morbidity and mortality in the US and worldwide. AD is usually a sporadic disease and the commonly accepted hypothesis as to its etiology is the amyloid cascade hypothesis. There is tremendous activity in the pharmaceutical industry and academia directed towards development of disease modifying treatments, most commonly targeting amyloid, but also tau and other mechanisms. Most efforts are directed towards Mild to Moderate AD or prodromal AD with relatively little work on prevention of AD due to various challenges, including identification of healthy people who would be treated.

Down syndrome is the most common chromosomal disorder in humans, caused by triplication of chromosome 21, accounting for ~1/740 live births in the USA even with routine prenatal screening. In addition to mental retardation and the other classical signs of DS, 100% of people with DS will develop the pathological hallmarks of AD (plaques and tangles) by their 40s and ~80% of people with DS will eventually develop clinical dementia. The primary cause is the triplication of the APP gene on chromosome 21, resulting in 50% greater levels of both APP mRNA and protein. That the disease in DS is indeed AD is supported by pathological, molecular, in-vitro, biomarker and clinical evidence.

People with DS have been followed at major centers in the US and EU for decades with large amounts of clinical and psychometric data gathered and analyzed. There is, however, very little data on CSF biomarkers due to the difficulty of performing lumbar punctures in DS subjects. Only recently has data begun to be gathered from imaging modalities, including Amyloid imaging.

There is no gold standard for the diagnosis of AD in this population and, due to the MR, the standard instruments cannot be used. Most major centers have developed specific instruments that can follow cognitive and functional performance and allow the detection of dementia. The data gathered over the past decades allows the construction of a curve describing the transition to dementia in this population and shows the transition beginning in the mid 40s with a steep slope around the age of 50.

DS is, in effect, a population highly enriched for people who will, with a very high probability develop AD, and it is expected that only with an ADNI-like study can the investigators better understand the trajectory of transition to dementia in this population.

The ultimate goal of this project is to develop treatments for the prevention of AD in this population. Because if the investigators would know at what age the slope of transition to dementia is steepest, a study could be done in a specific age range and require much fewer subjects and time and expense than a study in the general population (where it is currently impossible to determine which healthy individuals will likely develop dementia over the next few years and even if there were, thousands would have to be screened to ID these few). A study in the general population might need to enroll tens of thousands of subjects to observe sufficient transitions to dementia. The investigators estimate that such a study in DS would require about 170 subjects per arm for a 36 month study. Success in such a study would provide the confidence to commit the resources for a larger study in the general population.

As mentioned above, there is minimal CSF data and imaging is only beginning. Thus biomarkers for AD in DS are less developed than in the general population. Additional biomarkers could be helpful in studying AD in DS. A biomarker that could increase the ability to predict transition to dementia in an individual (as opposed to the investigators current ability on a population level) would increase the efficiency of any study. The ability to track the progression or improvement of dementia might also be useful. If a biomarker indicated transition to dementia earlier than any clinical instrument, a prevention study could conceivably be conducted at younger ages with greater chance of success. In addition to DS, such a biomarker would also be useful in the general population.

This study is a pilot study for a larger scale biomarker study which, as described, would enable better understanding of biomarkers and the natural history of AD in DS.

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
blood, urine, cerebrospinal fluid
Sampling Method Probability Sample
Study Population Community sample
  • Down Syndrome
  • Alzheimer's Disease
Intervention Not Provided
Study Groups/Cohorts
  • Non-demented; Ages 30-40
    Four non-demented Down syndrome patients between the ages of 30-40 years old
  • Non-demented; Ages 40-50
    Four non-demented Down syndrome patients between the ages of 40-50 years old
  • Demented; Ages 50-60
    Four demented Down syndrome patients between the ages of 50-60 years old
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 19, 2014)
Original Actual Enrollment Same as current
Actual Study Completion Date April 15, 2017
Actual Primary Completion Date April 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Male and female subjects 30 to 60 years of age inclusive with chromosome karyotype of Down Syndrome due to Trisomy 21.
  • Subjects must have a study partner (parent or other reliable caregiver) who has at least 10 hours of contact and who agrees to accompany the subject to all clinic visits and provide information about the subject's behavior and symptoms.
  • Participant is able to speak/communicate.
  • Subject is willing and has no contraindications to MRI scanning.
  • Participant or parent/legal guardian provides consent.
  • Participant must agree to allow for indefinite storage of his/her data and samples.

Exclusion Criteria:

  • Patients who are anarthric or mute.
  • Patients who do not meet the criteria for the diagnosis of DS.
  • Patients unwilling or unable to participate in all tests and procedures.
  • Unstable medical or behavioral issues.
  • Unable or unwilling to perform MRI and/or PET imaging.
Sexes Eligible for Study: All
Ages 30 Years to 60 Years   (Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
Administrative Information
NCT Number NCT02141971
Other Study ID Numbers DSBI
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Michael Rafii, University of California, San Diego
Study Sponsor Michael Rafii
Collaborators Janssen Research & Development, LLC
Principal Investigator: Michael S. Rafii, MD, PhD University of California, San Diego
PRS Account University of California, San Diego
Verification Date May 2017