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Multiple SclerosisRISEMSNCT03586986

Risk Factors in Early Multiple Sclerosis

An observational study of Multiple Sclerosis and Magnetic Resonance Imaging, run by University of Colorado, Denver at 1 site in United States.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 30 years
What is being tested?
Brain MRI
How many people
300 participants
Where
1 siteUnited States
Study dates
26 Jul 2018to May 2024
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 30 years
  • All sexes
  • Adult

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.

Who may be able to join

  • FDR Inclusion Criteria
  • Male and female
  • All races and ethnicities
  • Ages 18-30
  • Must have a parent, sibling or child with MS fulfilling McDonald 2017 criteria
  • No symptoms suggestive of MS on formal screen
Show all 14Show fewer
  • Ability to undergo a non-contrast MRI and venipuncture, and perform an environmental screen, mood screen and cognitive test
  • Non-FDR Inclusion Criteria
  • Male and female
  • All races and ethnicities
  • Ages 18-30
  • Must NOT have a FDR (parent, sibling, child) or second degree relative (grandparent, aunt or uncle) with MS fulfilling McDonald 2017 criteria
  • No symptoms suggestive of MS on formal screen
  • Ability to undergo venipuncture and perform an environmental screen.

Who cannot join

  • FDR Exclusion Criteria
  • Symptoms suggestive of MS on formal screen
  • Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's
  • Non-FDR Exclusion Criteria
  • Symptoms suggestive of MS on formal screen
  • Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

Trial locations and contacts

1 site in 1 country.

John R Corboy, MD contact

303-724-2187 ext. 42196

john.corboy@ucdenver.edu

Sydney Lipton, BA contact

sydney.lipton@cuanschutz.edu

United States1 site, 1 recruiting

  • University of Colorado Anschutz Medical Campus

    Aurora, Colorado, 80045

    John Corboy, MD, 303-724-2187, john.corboy@ucdenver.edu

    John Corboy, MD

    Recruiting

Other trials in United States

About this study

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.

Read the 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).

Being tested
Brain MRI
Keywords
First degree relative
Medical subject headings
Multiple Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Brain MRIDiagnostic test

    Also called Blood analysis, Bioscreen, Symbol Digit Modality Test (SDMT)

    Perform brain MRI; draw blood; fill out bioscreen questionnaire; perform SDMT

Study groups in NCT03586986
Study groupRoleWhat they receive
FDR with abnormal brain MRIFirst degree relatives fulfilling lesions disseminated in space on MRI
Receives: Diagnostic Test: Brain MRI
FDR with normal brain MRIFirst degree relatives not fulfilling lesions disseminated in space on MRI
Receives: Diagnostic Test: Brain MRI
Non-FDRAge and sex-matched controls to FDRs noted above

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Discovery of Lesions disseminated in space on brain MRI

    Lesions disseminated in space on brain MRI. The presence or absence of these lesions will only be measured once at the initial visit.

    Measured: At the subject's Initial Visit

Secondary outcomes (14)

  1. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  2. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  3. Define risk stratification algorithm for prediction of MS

    The investigators will measure the prevalence of vitamin D deficiencies, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  4. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  5. Define risk stratification algorithm for prediction of MS

    The investigators will measure the presence of the viral infection Epstein-Barr virus, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  6. Define risk stratification algorithm for prediction of MS

    The investigators will measure the presence of the viral infection Cytomegalovirus, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  7. Define risk stratification algorithm for prediction of MS

    The investigators will measure the presence of the viral infection Herpes Simplex I, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  8. Define risk stratification algorithm for prediction of MS

    The investigators will measure the presence of the viral infection Herpes Simplex II, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  9. Define risk stratification algorithm for prediction of MS

    The investigators will measure the presence of the viral infection Varicella zoster virus, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  10. Define risk stratification algorithm for prediction of MS

    The investigators will measure the prevalence of CNS damage marker Neurofillament light, with the goal of defining an expanded risk stratification scheme.

    Measured: Within 4 months of the Initial Visit

  11. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  12. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  13. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

  14. Define risk stratification algorithm for prediction of MS

    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.

    Measured: Within 4 months of the Initial Visit

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jul 2018
  2. Study start26 Jul 2018
  3. Primary completionMay 2024 (estimated)
  4. Study completionMay 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Case-control
Time perspective
Prospective
Enrolment
300 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03586986
Sponsor's protocol ID
17-1884
Acronym
RISEMS
Status last verified
Feb 2023
First submitted
15 May 2018
Last updated
6 Feb 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Bar-Or A. Multiple sclerosis and related disorders: evolving pathophysiologic insights. Lancet Neurol. 2016 Jan;15(1):9-11. doi: 10.1016/S1474-4422(15)00342-7. Epub 2015 Dec 8. No abstract available.

    PubMed 26700897

  • Solomon AJ, Corboy JR. The tension between early diagnosis and misdiagnosis of multiple sclerosis. Nat Rev Neurol. 2017 Sep;13(9):567-572. doi: 10.1038/nrneurol.2017.106. Epub 2017 Aug 11. No abstract available.

    PubMed 28799551

  • Signori A, Schiavetti I, Gallo F, Sormani MP. Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. 2015 Jun;22(6):960-6. doi: 10.1111/ene.12690. Epub 2015 Mar 19.

    PubMed 25786797

  • Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009 Nov;8(11):987-97. doi: 10.1016/S1474-4422(09)70237-6. Epub 2009 Sep 10.

    PubMed 19748319

  • Kavaliunas A, Manouchehrinia A, Stawiarz L, Ramanujam R, Agholme J, Hedstrom AK, Beiki O, Glaser A, Hillert J. Importance of early treatment initiation in the clinical course of multiple sclerosis. Mult Scler. 2017 Aug;23(9):1233-1240. doi: 10.1177/1352458516675039. Epub 2016 Oct 17.

    PubMed 27754943

  • Giovannoni G. The neurodegenerative prodrome in multiple sclerosis. Lancet Neurol. 2017 Jun;16(6):413-414. doi: 10.1016/S1474-4422(17)30127-8. No abstract available.

    PubMed 28504102

  • Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, Hauser SL, Pelletier D. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009 Mar 3;72(9):800-5. doi: 10.1212/01.wnl.0000335764.14513.1a. Epub 2008 Dec 10.

    PubMed 19073949

  • Okuda DT, Siva A, Kantarci O, Inglese M, Katz I, Tutuncu M, Keegan BM, Donlon S, Hua le H, Vidal-Jordana A, Montalban X, Rovira A, Tintore M, Amato MP, Brochet B, de Seze J, Brassat D, Vermersch P, De Stefano N, Sormani MP, Pelletier D, Lebrun C; Radiologically Isolated Syndrome Consortium (RISC); Club Francophone de la Sclerose en Plaques (CFSEP). Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One. 2014 Mar 5;9(3):e90509. doi: 10.1371/journal.pone.0090509. eCollection 2014.

    PubMed 24598783

  • Rojas JI, Patrucco L, Miguez J, Besada C, Cristiano E. Brain atrophy in radiologically isolated syndromes. J Neuroimaging. 2015 Jan-Feb;25(1):68-71. doi: 10.1111/jon.12182. Epub 2014 Oct 13.

    PubMed 25307993

  • Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J; Swiss Multiple Sclerosis Cohort Study Group. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-870. doi: 10.1002/ana.24954.

    PubMed 28512753

  • Weinstock-Guttman B, Zivadinov R, Mahfooz N, Carl E, Drake A, Schneider J, Teter B, Hussein S, Mehta B, Weiskopf M, Durfee J, Bergsland N, Ramanathan M. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflammation. 2011 Oct 4;8:127. doi: 10.1186/1742-2094-8-127.

    PubMed 21970791

  • Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. doi: 10.1001/jama.296.23.2832.

    PubMed 17179460

  • Salzer J, Hallmans G, Nystrom M, Stenlund H, Wadell G, Sundstrom P. Smoking as a risk factor for multiple sclerosis. Mult Scler. 2013 Jul;19(8):1022-7. doi: 10.1177/1352458512470862. Epub 2012 Dec 20.

    PubMed 23257617

  • De Stefano N, Cocco E, Lai M, Battaglini M, Spissu A, Marchi P, Floris G, Mortilla M, Stromillo ML, Paolillo A, Federico A, Marrosu MG. Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis. Ann Neurol. 2006 Apr;59(4):634-9. doi: 10.1002/ana.20767.

    PubMed 16498621

  • Gabelic T, Ramasamy DP, Weinstock-Guttman B, Hagemeier J, Kennedy C, Melia R, Hojnacki D, Ramanathan M, Zivadinov R. Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis. AJNR Am J Neuroradiol. 2014 Jan;35(1):106-12. doi: 10.3174/ajnr.A3653. Epub 2013 Jul 25.

    PubMed 23886745

Questions about this trial

What is this clinical trial studying?

An observational study of Multiple Sclerosis and Magnetic Resonance Imaging, run by University of Colorado, Denver at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 6 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact John R Corboy, MD (303-724-2187 ext. 42196, john.corboy@ucdenver.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Discovery of Lesions disseminated in space on brain MRI (time frame: At the subject's Initial Visit). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03586986, which also lists 19 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2023; AzTrials last refreshed its copy on 26 Oct 2026.

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