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Central Vein Sign: a Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04495556
Recruitment Status : Not yet recruiting
First Posted : August 3, 2020
Last Update Posted : August 5, 2020
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
University of Pennsylvania
Cedars-Sinai Medical Center
Information provided by (Responsible Party):
The Cleveland Clinic

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.


Condition or disease Intervention/treatment
Multiple Sclerosis Diagnostic Test: MRI

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Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Central Vein Sign: a Diagnostic Biomarker in Multiple Sclerosis
Estimated Study Start Date : August 2020
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
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
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
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
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.




Primary Outcome Measures :
  1. MRI Outcomes [ Time Frame: Change assessed over 24 months. First scan at baseline (first study visit) and the second scan at 24 months or the last study visit. ]

    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.



Secondary Outcome Measures :
  1. Clinical Outcomes - McDonald Criteria 2017 [ Time Frame: McDonald criteria will be reviewed at baseline, month 12 and month 24 visits. ]
    Determination of a diagnosis of MS using the McDonald Criteria 2017 will be conducted by a central adjudication committee. McDonald diagnostic criteria for MS are clinical, radiographic, and laboratory criteria used in the diagnosis of multiple sclerosis. Members of the adjudication committee will separately review the clinical data, laboratory testing, and study MRIs of each participant at baseline, 12 months, and 24 months.

  2. Clinical Outcomes - Relapses [ Time Frame: Relapses will be assessed at month 6, month 12, month 18 and month 24. ]
    Relapses will be assessed at every study visit after baseline to look for disease progression and disability. Proportion of people who do not have clinical relapses of MS at 24 months, will help us determine if CVS yields specificity for MS among individuals with atypical presentation.

  3. Clinical Outcomes - Lab results - Cerebrospinal Fluid Testing [ Time Frame: Lab results will be collected at baseline, month 6, month 12, month 18 and month 24. ]
    Lab results will be collected at every study visit whenever available. May include recording of: cerebrospinal fluid testing (CSF).

  4. Lab results - Neuromyelitis Optica Antibodies (NMO-IgG) [ Time Frame: Lab results will be collected at baseline, month 6, month 12, month 18 and month 24. ]
    Lab results will be collected at every study visit whenever available. May include recording of: neuromyelitis optica antibodies (NMO-IgG).

  5. Lab results - Myelin oligodendrocyte glycoprotein (MOG) testing. [ Time Frame: Lab results will be collected at baseline, month 6, month 12, month 18 and month 24. ]
    Lab results will be collected at every study visit whenever available. May include recording of: myelin oligodendrocyte glycoprotein (MOG) testing.

  6. Patient reported Outcomes - Change in Neuro-QoL (Quality of Life in Neurological disorders) using Neuro-QoL short forms to assess Physical Domains, from baseline to month 24. [ Time Frame: Assessed over 24 months. Neuro-QoL at baseline, month 12 and month 24 study visits. ]

    The Neuro-QoL (short forms) instrument will be used to measure quality of life as related to neurological disease.

    11 subscales, each is scored separately, there is no composite score.

    Physical Domains include:

    Upper Extremity Function (Fine Motor, ADL), Lower Extremity Function (Mobility), Fatigue, and Sleep Disturbance.


  7. Change in Neuro-QoL using Neuro-QoL short forms to assess Mental Domains, from baseline to month 24 [ Time Frame: Assessed over 24 months. Neuro-QoL at baseline, month 12 and month 24 study visits. ]

    The Neuro-QoL (short forms) instrument will be used to measure quality of life as related to neurological disease.

    11 subscales, each is scored separately, there is no composite score.

    Mental Domains include:

    Cognition Function, Stigma, Anxiety, Depression and Positive Affect and Well-being.


  8. Change in Neuro-QoL using Neuro-QoL short forms to assess Social Domains, from baseline to month 24 [ Time Frame: Assessed over 24 months. Neuro-QoL at baseline, month 12 and month 24 study visits. ]

    The Neuro-QoL (short forms) instrument will be used to measure quality of life as related to neurological disease.

    11 subscales, each is scored separately, there is no composite score.

    Social Domains include:

    Ability to Participate in Social Roles and Activities, and Satisfaction with Social Roles and Activities.


  9. Patient reported Outcomes - PDDS (patient determined disease steps) [ Time Frame: PDDS will be assessed at all the 5 study visits - baseline, month 6, 12, 18 and 24. ]
    The PDDS is a patient reported outcome that captures overall MS disability. It will be collected and baseline, month 6, month 12, month 18, and month 24. PDDS scores will be recorded and sustained worsening will be considered for worsening of 1 point or greater confirmed at 3 months.


Other Outcome Measures:
  1. Economics outcomes [ Time Frame: Done at all 5 study visits - baseline, month 6, month 12, month 18 and month 24. ]
    Health care expenditures will be measured using Healthcare Resource Utilization (HRU) forms. Total costs for patients over the 24-month follow up period will be assessed using information from all 5 study visits. At each encounter, patients will report emergency care visits and inpatient hospitalizations which have occurred within the past 6-months. Costs accrued over each 6-month period will be used to estimate overall 24-month costs.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Criteria

Inclusion Criteria:

Inclusion criteria for participants with typical presentations will include:

  1. Age 18 to 65 inclusive
  2. Referral to a study academic site for a clinical suspicion of MS
  3. 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.
  4. Able to provide written informed consent to participate in the study
  5. 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
  6. Onset of typical neurological symptoms within 10 years of screening.

Inclusion criteria for participants with atypical presentations will include:

  1. Age 18 to 65 inclusive
  2. Referral to a study academic site for a suspicion of MS
  3. 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
  4. Able to provide written informed consent to participate in the study
  5. 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
  6. Onset of atypical neurological symptoms within 10 years of screening.

Exclusion Criteria:

Exclusion criteria for both typical and atypical populations will include:

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

Information from the National Library of Medicine

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): NCT04495556


Contacts
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Contact: Praneeta C Raza, MD, MSc 216-445-9692 razap@ccf.org

Locations
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United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Contact: Natalie Ayala       natalie.ayala@cshs.org   
Principal Investigator: Nancy Sicotte, MD         
University of Southern California
Los Angeles, California, United States, 90089
Contact: Christina Azevedo, MD       cazevedo@usc.edu   
Principal Investigator: Christina Azevedo, MD         
University of California San Francisco
San Francisco, California, United States, 94115
Contact: Jennifer Arjona       jennifer.arjona@ucsf.edu   
Principal Investigator: Roland Henry, MD         
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
Contact: Courtney Knapp       courtney.knapp@cuanschutz.edu   
Principal Investigator: Enrique Alvarez, MD         
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
Contact: Lesa Moemeka       lesa.moemeka@yale.edu   
Principal Investigator: Erin Logbrake, MD         
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21218
Contact: Anna DuVal       aduval1@jhmi.edu   
Principal Investigator: Peter Calabresi, MD         
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Contact: Carly O'Donnell       carly.ODonnell@pennmedicine.upenn.edu   
Principal Investigator: Russell Shinohara, PhD         
United States, Texas
The University of Texas at Austin
Austin, Texas, United States, 78759
Contact: Sarah Campbell       scampbell@austin.utexas.edu   
Principal Investigator: Leorah Freeman, MD         
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05405
Contact: Emily Azalone       emily.azalone@uvmhealth.org   
Principal Investigator: Andrew Solomon, MD         
Canada, Ontario
St. Michael's Hospital of Unity Health Toronto
Toronto, Ontario, Canada, M5B1W8
Contact: Melanie Guenette       Melanie.Guenette@unityhealth.to   
Principal Investigator: Jiwon Oh, MD         
Sponsors and Collaborators
The Cleveland Clinic
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
University of Pennsylvania
Cedars-Sinai Medical Center
Investigators
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Principal Investigator: Daniel Ontaneda, MD, PhD The Cleveland Clinic
Principal Investigator: Nancy Sicotte, MD Cedars-Sinai Medical Center
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Responsible Party: The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT04495556    
Other Study ID Numbers: 20-063
1U01NS116776-01 ( U.S. NIH Grant/Contract )
First Posted: August 3, 2020    Key Record Dates
Last Update Posted: August 5, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The Cleveland Clinic:
Multiple Sclerosis
MS
MRI
Central Vein Sign
CVS
Diagnostic Biomarker
Autoimmune disease
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases