Assessment of Tecfidera® in Radiologically Isolated Syndrome (RIS)

Study Overview
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Brief Summary
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The purpose of this investigation is to systematically study the efficacy of Tecfidera in those individuals who possess incidental white matter anomalies within the brain following a MRI study that is performed for a reason other than for the evaluation of MS (multiple sclerosis).

Detailed Description
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This is a multi-center, randomized, double-blinded study in which approximately 90 RIS (radiologically isolated syndrome) subjects will be treated with either Tecfidera or placebo for 2 years (1:1 randomization). Study participants, along with the treating and examining physicians, will be blinded to treatment assignment. Central Clinical and Imaging Units will screen all potential study subjects for inclusion/exclusion criteria. We expect to enroll all RIS subjects within the U.S. Following informed consent and verification of entry criteria by the core units, study participants will be randomized 1:1 to either Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) or placebo. Clinical follow-up by the treating physician will occur at weeks 0, 48, 96, 144 and/or End of Study and during or immediately following clinical exacerbations. During clinical visits, comprehensive medical history data will be obtained by the treating physician. All reported acute or progressive clinical events will be adjudicated by the Central Clinical Unit. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to re-evaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made. In addition to the face-to-face visits described above, study participants will be contacted over the telephone at weeks 4, 8, 36, 60, 84, 108, and 132 to assess for medical or treatment difficulties and for study medication compliance. Standardized MRI studies of the brain will be performed at weeks 0, 96, 144 or End of Study. Clinical imaging studies of the brain and/or spinal cord performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the cervical spinal cord with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Official Title
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Multi-center, Randomized, Double-blinded Assessment of Tecfidera® in Extending the Time to a First Attack in Radiologically Isolated Syndrome (RIS) (ARISE)

Conditions
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Multiple Sclerosis (MS)

Intervention / Treatment
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* Drug: Tecfidera
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Males and females meeting 2009 RIS criteria Identified RIS cases with the initial MRI demonstrating anomalies suggestive of demyelinating disease dated > 2009 Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI resulting from an evaluation of a process other than MS CNS white matter anomalies meeting the following MRI criteria: Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum T2-hyperintensities measuring > 3mm2 and fulfilling 3 of 4 Barkhof-Tintoré criteria for dissemination in space CNS anomalies not consistent with a vascular pattern Qualitative determination that CNS anomalies have a characteristic appearance of demyelinating lesions MRI anomalies do not account for clinically apparent neurological impairments in patients Exclusion criteria Women who are pregnant or nursing Incomplete medical history or radiological data History of remitting clinical symptoms consistent with multiple sclerosis lasting > 24 hours prior to CNS imaging revealing anomalies suggestive of MS History of paroxysmal symptoms associated with MS (i.e. Lhermitte's or Uhthoff's phenomena) CNS MRI anomalies are better accounted for by another disease process The subject is unwilling or unable to comply with the requirements of the study protocol Exposure to a disease modifying therapy for MS/RIS within the past 3 months Exposure to high-dose glucocorticosteroid treatment within the past 30 days Participation in other clinical trials involving treatment with a disease-modifying agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tecfidera<br>Tecfidera (120mg by mouth twice daily for 7 days with dose escalation to 240mg by mouth twice daily) | Drug: Tecfidera<br>* Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.<br>* Other names: Dimethyl fumarate;|
| Placebo Comparator: Placebo<br>Placebo by mouth twice daily. | Drug: Placebo<br>* Blinded drug wallets will be dispensed during routine study appointments in 3 month supply, so that compliance can be reconciled at follow up visits and telephone consultations, and recorded in accountability logs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time From Randomization to the First Demyelinating Event (Acute or Development of an Initial Symptom Resulting in a Progressive Clinical Course) | The primary outcome measure for this trial is the time to the first acute or progressive neurological event resulting from CNS demyelination from randomization into the trial. | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lesion Volume on T2-weighted MRI | Change in lesion volume on T2-weighted MRI is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | Baseline, 96 weeks | 
| Number of Newly Enlarging T2 Lesions | Number of newly enlarging T2 lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks | 
| Number of New T2 Lesions | Number of new T2 lesions as measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks | 
| Newly Enlarging T2 Lesions and New T2 Lesions Combined | Newly enlarging T2 lesions and new T2 lesions combined is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks | 
| Number of Contrast Enhancing Lesions | Number of contrast enhancing lesions is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | 96 weeks | 
| Change in the Number of Participants With Brain Atrophy | Change in the number of participants with brain atrophy is measured by follow-up MRI at 96 weeks in the placebo group and in the Tecfidera group. | Baseline, 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiologically Isolated Syndrome (RIS)