Risk Factors in Early Multiple Sclerosis (RISEMS)

February 2, 2023 updated by: University of Colorado, Denver
The central hypothesis of this protocol is that it is possible, using First Degree Relatives (FDRs) of patients with Multiple Sclerosis (MS) and assessing a variety of both known and unknown risk factors for MS, to define a risk algorithm for earliest signs of development of MS. The plan will be to do an abbreviated brain Magnetic Resonance Imaging (MRI) scan in asymptomatic, young FDRs, analyze blood for a variety of immunological, genetic, neuroaxonal damage, metabolic, viral serology and other markers, and have FDRs fill out a detailed bioscreen questionnaire about lifestyle factors and perform a cognitive screening test. The investigators will then compare the results of the various blood/other studies in FDRs with and without an MRI showing signs signs concerning for MS, as well as age-and sex-matched NON-FDRs who will have blood drawn and fill out the questionnaire. With this preliminary cross-sectional study, the investigators hope to begin to identify a risk stratification model for those at highest risk of developing MS, ie FDRs, with a long-term goal of developing a longitudinal study to increase sensitivity and specificity of the risk model.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Specific Aims, among asymptomatic first degree relatives (FDRs), aged 18-30, of multiple sclerosis (MS) patients:

  1. Determine the prevalence of brain MRI lesions disseminated in space (DIS), consistent with MS
  2. Gather data on potential risk factors or early signs related to MS development, including markers for: genes, immunological function, environmental factors, neuroaxonal damage, Vitamin D levels, lipid metabolism, activity levels, mood abnormalities, and cognitive function. From this, develop a risk factor score, incorporating all relevant potential markers of increased risk of DIS.
  3. To use this pilot, cross-sectional study as a base for development of a long-term, longitudinal, multi-center study to determine genetic and environmental risks for pre-symptomatic MS
  4. To create and maintain a biobank of specimens for future analysis as other potential biomarkers become available.
  5. Evaluate for potential dissemination in time (DIT) and dissemination in space (DIS) in asymptomatic FDRs through longitudinal assessment.

Sequences to include

  1. Whole brain T1-weighted images acquired using 3-Dimensional fast spoiled-gradient recalled acquisitions (T1-3D-FSPGR) with 1 mm slice thickness and isotropic voxel dimensions.
  2. Whole brain 3-Dimensional Double Inversion Recovery (DIR) acquisition with 1.5 mm slice thickness.
  3. Whole brain T2-weighted Fluid Attenuated Inversion Recovery (FLAIR ) images with 1 mm slice thickness and isotropic voxel dimensions will be combined with
  4. Whole brain T2*-weighted segmented echo-planar imaging (segEPI) images with <=1 mm slice thickness and isotropic voxel dimensions to obtain FLAIR* images.

Blood analysis for:

  1. Single Nucleotide Polymorphism analysis of greater than 200 known mutations associated with risk of MS, and do an human leukocyte antigen (HLA) analysis
  2. CD20 on CD4+ cell analysis
  3. B Cell Anergy analysis Lipid levels
  4. Viral serologies (HSV, EBV, CMV, VZV)
  5. Neurofilament Light
  6. Vitamin D levels

Bioscreen analysis based on that from the Diabetes Autoimmunity Study in the Young (DAISY); and to include the Godin Leisure-Time Exercise Questionnaire (GLTEQ), which has been validated in both adults and children and a validated dietary/food frequency questionnaire. In addition perform a cognitive screen with a Symbol Digit Modality test.

Blood will also be stored for future potential analysis, including peripheral blood mononuclear cells, serum, and Ribonucleic acid (RNA).

Study Type

Observational

Enrollment (Anticipated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • University of Colorado Anschutz Medical Campus
        • Contact:
        • Principal Investigator:
          • John Corboy, MD
        • Principal Investigator:
          • Jill Norris, PhD
        • Principal Investigator:
          • Enrique Alvarez, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 30 years (ADULT)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The population will be a total of 300 women and men, of all races and ethnicities, between the ages of 18-30, inclusive, who have no symptoms of MS, but have at least one FDR with documented MS fulfilling McDonald 2017 criteria. FDRs with one or more siblings/parents with MS will be included, and more than one FDR of a proband MS patient will be allowed. A control group of age- and sex-matched controls who have no known family members with MS (out to first cousins and grandparents) will have blood drawn and fill out the environmental questionnaire, but will not undergo a brain/spine MRI. The controls will be matched 1:1:1 for those FDRs with positive MRI scans suggesting pre-symptomatic MS and those age-and sex-matched FDRs who do NOT have positive MRI scans suggesting pre-symptomatic MS.

Description

Inclusion Criteria:

  • FDR Inclusion Criteria

    1. Male and female
    2. All races and ethnicities
    3. Ages 18-30
    4. Must have a parent, sibling or child with MS fulfilling McDonald 2017 criteria
    5. No symptoms suggestive of MS on formal screen
    6. Ability to undergo a non-contrast MRI and venipuncture, and perform an environmental screen, mood screen and cognitive test

  • Non-FDR Inclusion Criteria

    1. Male and female
    2. All races and ethnicities
    3. Ages 18-30
    4. Must NOT have a FDR (parent, sibling, child) or second degree relative (grandparent, aunt or uncle) with MS fulfilling McDonald 2017 criteria
    5. No symptoms suggestive of MS on formal screen
    6. Ability to undergo venipuncture and perform an environmental screen.

Exclusion Criteria:

  • FDR Exclusion Criteria

    1. Symptoms suggestive of MS on formal screen
    2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

  • Non-FDR Exclusion Criteria

    1. Symptoms suggestive of MS on formal screen
    2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
FDR with abnormal brain MRI
First degree relatives fulfilling lesions disseminated in space on MRI
Diagnostic test: Brain MRI
Perform brain MRI; draw blood; fill out bioscreen questionnaire; perform SDMT
Other Names:
  • Blood analysis
  • Bioscreen
  • Symbol Digit Modality Test (SDMT)
FDR with normal brain MRI
First degree relatives not fulfilling lesions disseminated in space on MRI
Diagnostic test: Brain MRI
Perform brain MRI; draw blood; fill out bioscreen questionnaire; perform SDMT
Other Names:
  • Blood analysis
  • Bioscreen
  • Symbol Digit Modality Test (SDMT)
Non-FDR
Age and sex-matched controls to FDRs noted above

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Discovery of Lesions disseminated in space on brain MRI
Time Frame: At the subject's Initial Visit
Lesions disseminated in space on brain MRI. The presence or absence of these lesions will only be measured once at the initial visit.
At the subject's Initial Visit

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the prevalence of specific genetic markers including, single nucleotide polymorphism analysis of more than 200 known mutations and analysis of HLA-DRB1 variants, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the prevalence of immunological markers including, CD4, CD8, CD40, CD19 and CD20 with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the prevalence of vitamin D deficiencies, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the prevalence of lipid markers including, total cholesterol, high and low density lipoproteins, and triglycerides, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the presence of the viral infection Epstein-Barr virus, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the presence of the viral infection Cytomegalovirus, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the presence of the viral infection Herpes Simplex I, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the presence of the viral infection Herpes Simplex II, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the presence of the viral infection Varicella zoster virus, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure the prevalence of CNS damage marker Neurofillament light, with the goal of defining an expanded risk stratification scheme.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will measure activity level, using the Godin Leisure-time Exercise questionnaire, with the goal of defining an expanded risk stratification scheme. Weekly frequencies of strenuous, moderate, and light activities (i.e. number of times per week an individual performs these activities) are multiplied by nine, five, and three, respectively. Total weekly leisure activity is calculated in arbitrary units by summing the products of the separate components, as shown in the following formula: Weekly leisure activity score = (9 × Strenuous) + (5 × Moderate) + (3 × Light). As there is no limit for the number of times a participant can perform an exercise per week, the maximum score is boundless. While, a sedentary individual may exhibit the minimum score of 0.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will evaluate cognitive functions using the Perceived Stress Scale, with the goal of defining an expanded risk stratification scheme. This will be used to evaluate stress domains. Individual scores on the Perceived Stress Scale can range from 0 to 40 with higher scores indicating higher perceived stress. Scores ranging from 0-13 would be considered low stress. Scores ranging from 14-26 would be considered moderate stress. Scores ranging from 27-40 would be considered high perceived stress.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will evaluate cognitive functions using University of Colorado's NeuroQol Depression Scale, with the goal of defining an expanded risk stratification scheme. This assessment will be used to evaluate depression domains. The minimum raw score is 8, which represents better (desirable) self-reported health, and the maximum score is 40, which represents worse (undesirable) self-reported health. These raw scores will be converted to T-scores, with 36.9 being the minimum and 75.0 being the maximum T-score.
Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
Time Frame: Within 4 months of the Initial Visit
The investigators will evaluate cognitive functions using University of Colorado's NeuroQol Anxiety Scale, with the goal of defining an expanded risk stratification scheme. This assessment will be used to measure anxiety domains, with the highest raw score of 40 representing worse (undesirable) self-reported anxiety, and a raw score of 8 representing better (desirable) self-reported anxiety. These raw scores will be converted to T-scores, with 36.4 being the minimum and 76.8 being the maximum T-score.
Within 4 months of the Initial Visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Collaborators

Colorado School of Public Health

Investigators

  • Principal Investigator: John R Corboy, MD, University of Colorado - Anschutz Medical Campus

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 26, 2018

Primary Completion (ANTICIPATED)

May 1, 2024

Study Completion (ANTICIPATED)

May 1, 2024

Study Registration Dates

First Submitted

May 15, 2018

First Submitted That Met QC Criteria

July 12, 2018

First Posted (ACTUAL)

July 16, 2018

Study Record Updates

Last Update Posted (ACTUAL)

February 6, 2023

Last Update Submitted That Met QC Criteria

February 2, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 17-1884

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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