Central Vein Sign: a Diagnostic Biomarker in Multiple Sclerosis

NCT04495556 | Active Not Recruiting DMC

• 2 other identifiers: 20-0631U01NS116776-01
• Study Type: observational
• Target: 420
• Locations: 2 countries
• Sites: 11

Brief Summary

The need for improved diagnostic methods in Multiple Sclerosis (MS) is widely recognized. Although Magnetic Resonance Imaging (MRI) is a longstanding tool for detecting MS lesions, diagnostic inaccuracies persist. Up to 20% of people diagnosed with MS (1 in 5) are later found not to have the disease. This is highly consequential, as more than two-thirds of misdiagnosed patients are unnecessarily exposed to risks from disease-modifying therapies, which in rare cases can be life-threatening. Moreover, the current standard in MS diagnosis - the McDonald criteria, which combine clinical symptoms and MRI findings - were developed from studies in people with typical clinical presentations of MS. This reduces the specificity of these criteria, rendering them uninformative for the nearly half of MS patients who present to neurologists with atypical or nonclassical symptoms. Timeliness of MS diagnosis is also key, as diagnostic delay is common in cases of relapsing-remitting MS and can carry severe and lifelong consequences. The CentrAl Vein Sign in MS (CAVS-MS) study has been designed to assess whether Central Vein Sign (CVS) criteria can help address some of these unmet diagnostic needs. It will specifically explore the role of presentation type by enrolling a mixed population of patients with typical clinical presentations (n = 200) and those with atypical presentations, including suggestive MRI findings in the absence of neurologic symptoms (n = 200) across North America.

Conditions

Multiple Sclerosis

Keywords

Multiple Sclerosis; MS; MRI; Central Vein Sign; CVS; Diagnostic Biomarker; Autoimmune disease

Outcome Measures

Primary Outcomes (1)

• MRI Outcomes

  MRI will be done to assess sensitivity and specificity of the CVS for multiple sclerosis. MRI will be done at baseline or start of the study and at month 24, end of study. Central veins will be counted and lesions will be considered CVS+ using specified criteria. CVS will be determined using Select6, Select3\*, and automated lesion analysis with inclusion and exclusion of periventricular lesions.

  Change assessed over 24 months. First scan at baseline (first study visit) and the second scan at 24 months or the last study visit.

Secondary Outcomes (9)

• Clinical Outcomes - McDonald Criteria 2017

  McDonald criteria will be reviewed at baseline, month 12 and month 24 visits.

• Clinical Outcomes - Relapses

  Relapses will be assessed at month 6, month 12, month 18 and month 24.

• Clinical Outcomes - Lab results - Cerebrospinal Fluid Testing

  Lab results will be collected at baseline, month 6, month 12, month 18 and month 24.

• Lab results - Neuromyelitis Optica Antibodies (NMO-IgG)

  Lab results will be collected at baseline, month 6, month 12, month 18 and month 24.

• Lab results - Myelin oligodendrocyte glycoprotein (MOG) testing.

  Lab results will be collected at baseline, month 6, month 12, month 18 and month 24.

Other Outcomes (1)

• Economics outcomes

  Done at all 5 study visits - baseline, month 6, month 12, month 18 and month 24.

Study Arms (2)

Typical

Patients with typical symptom onset including: acute unilateral optic neuritis, double vision due to an internuclear ophthalmoplegia or sixth nerve palsy, facial sensory loss or trigeminal neuralgia in a young adult (\<40 years of age), cerebellar ataxia and nystagmus, partial myelopathy, sensory symptoms in a CNS (central nervous system) pattern, Lhermitte's symptom, asymmetric limb weakness, urge incontinence or erectile dysfunction, or other neurological presentation considered to be typical by the site investigator.

Diagnostic Test: MRI

Atypical

Patients with atypical onset including: bilateral optic neuritis or unilateral optic neuritis with a poor visual recovery, complete gaze palsy or fluctuating ophthalmoparesis, intractable nausea, vomiting, or hiccups, complete transverse myelopathy with bilateral motor and sensory involvement, encephalopathy, subacute cognitive decline, headache or meningismus, isolated fatigue or asthenia, constitutional symptoms, other clinical presentations considered atypical by the site investigator (examples include: vague or patchy sensory symptoms, pain, short lasting bilateral blurred vision, etc.), or absence of clinical symptoms with MRI features suggestive of MS.

Diagnostic Test: MRI

Interventions

MRI DIAGNOSTIC_TEST

The study will include MRI at baseline (first study visit) and month 24 (final study visit). MRI at month 24 (end of study) will be used to determine McDonald Criteria and final review of CVS.

Atypical; Typical

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The study will recruit a total 400 participants. The study will include 200 patients presenting with typical first syndromes and will enroll an additional 200 patients with atypical presentations and radiological suspicion of the disease. Participants will be recruited from the patient populations followed at eleven different sites including: Cleveland Clinic, Johns Hopkins University, University of California San Francisco, University of Texas Austin, University of Colorado Denver, University of Toronto (St. Michael's Hospital), University of Vermont, University of Pennsylvania, Cedars Sinai Medical Center, University of Southern California, and Yale University. Study investigators will confirm eligibility criteria, and participants will then be enrolled into the study.

You may qualify if:

• Age 18 to 65 inclusive
• Referral to a study academic site for a clinical suspicion of MS
• Onset with typical symptom onset including: acute unilateral optic neuritis, double vision due to an internuclear ophthalmoplegia or sixth nerve palsy, facial sensory loss or trigeminal neuralgia in a young adult (\<40 years of age), cerebellar ataxia and nystagmus, partial myelopathy, sensory symptoms in a CNS pattern, Lhermitte's symptom, asymmetric limb weakness, urge incontinence or erectile dysfunction, or other neurological presentation considered to be typical by the site investigator.
• Able to provide written informed consent to participate in the study
• For participants referred for clinical suspicion of multiple sclerosis who had workup prior to referral or who are taking disease-modifying therapies for MS, digital availability of diagnostic cranial MRI with gadolinium within 3 months of initial symptoms
• Onset of typical neurological symptoms within 10 years of screening.
• Age 18 to 65 inclusive
• Referral to a study academic site for a suspicion of MS
• Onset with atypical onset including: bilateral optic neuritis or unilateral optic neuritis with a poor visual recovery, complete gaze palsy or fluctuating ophthalmoparesis, intractable nausea, vomiting, or hiccups, complete transverse myelopathy with bilateral motor and sensory involvement, encephalopathy, subacute cognitive decline, headache or meningismus, isolated fatigue or asthenia, constitutional symptoms, other clinical presentations considered atypical by the site investigator (examples include: vague or patchy sensory symptoms, pain, short lasting bilateral blurred vision, etc.), or absence of clinical symptoms with MRI features suggestive of MS
• Able to provide written informed consent to participate in the study
• For participants referred for clinical suspicion of multiple sclerosis who had workup prior to referral or who are taking disease-modifying therapies for MS, digital availability of diagnostic cranial MRI with gadolinium within 3 months of initial symptoms
• Onset of atypical neurological symptoms within 10 years of screening.

You may not qualify if:

• Contraindication to MRI studies; metal or metal implants incompatible with MRI
• Inability to tolerate MRI due to claustrophobia or known excessive movement (e.g. tremor)
• Contraindication to use of gadolinium containing contrast agents (allergy or renal failure)
• Treatment with systemic corticosteroids in the 4 weeks preceding enrollment.

Sponsors & Collaborators

• The Cleveland Clinic: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• University of Pennsylvania: collaborator
• Cedars-Sinai Medical Center: collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (11)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

University of Southern California

Los Angeles, California, 90089, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21218, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63130, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

The University of Texas at Austin

Austin, Texas, 78759, United States

Location

University of Vermont

Burlington, Vermont, 05405, United States

Location

St. Michael's Hospital of Unity Health Toronto

Toronto, Ontario, M5B1W8, Canada

Location

MeSH Terms

Conditions

Multiple Sclerosis; Autoimmune Diseases

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Immune System Diseases

Study Officials

• Daniel Ontaneda, MD, PhD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

• Nancy Sicotte, MD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

• Pascal Sati, PhD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Neurologist, Mellen Center for Multiple Sclerosis

Study Record Dates

• First Submitted: July 23, 2020
• First Posted: August 3, 2020
• Study Start: June 11, 2020
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027
• Last Updated: October 2, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); CA (1)