MAIN STUDY: SWITCH SUB-STUDY: SWITCH-JCV

Study Overview
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Brief Summary
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MAIN STUDY: The purpose of this study is to determine if teriflunomide will be safe and effective to prevent relapses in patients with relapsing types of MS when switching from natalizumab to teriflunomide in patients at risk for PML. This is a two center interventional study of patients who have had 12 or more continuous infusions of natalizumab , who are anti-JCV-ab positive, and who had been free of clinical relapses during prior 12 months of natalizumab therapy who will be switching to teriflunomide. SUB-STUDY: To study the number of patients experiencing a reduction in the anti-JCV antibody Index value in patients who had received at least one dose of teriflunomide during participation in the SWITCH protocol (main study).

Detailed Description
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MAIN STUDY: Teriflunomide (TFM) is the primary metabolite of leflunomide, which is marketed worldwide for the treatment of rheumatoid arthritis. Teriflunomide inhibits dihydroorotate dehydrogenase( DHODH), the forth enzyme in the de novo synthesis pathway of pyrimidines. Activated T-lymphocytes utilize both the de novo pyrimidine and salvage pathways of pyrimidines ribonucleotide synthesis.After mitogen stimulation, teriflunomide inhibits in vitro T cell proliferation, DNA and RNA synthesis and expression of cell surface and nuclear antigens that are directly involved in T-cell activation and proliferation. Natalizumab (NTZ) is a FDA approved treatment for relapsing-forms of multiple sclerosis (MS) with pivotal studies showing an annualized relapse-rate (ARR) reduction of 68%, a reduction of new Gadolinium enhancing (Gd+) lesions by 92% and a reduction of disability of 42% compared to placebo. NTZ is highly effective in controlling MS but the risk of developing progressive multifocal leukoencephalopathy (PML) increases with the duration of the use of natalizumab. It can have a serious and life threatening complication in about 1 in 500 to 1 in 250 patients who have had more that 18 infusions due PML and who have a detected antibody (Ab) for the JC virus. The risk of PML is much greater in patients who have had prior immunosuppressive (IS) treatment. The combination of detected anti-JCV Ab , duration of NTZ treatment of greater than 24 months and prior IS increases the risk of development PML to an incidence of 11 per 1000 treated patients. So there is a need to have an alternative MS disease modifying treatment (DMT) to use for patients at risk to develop PML from NTZ treatment that might be sufficiently effective for MS so as not to have the patients' MS worsen while lowering or eliminating the risk of PML. SUB-STUDY: John Cunningham virus (JCV) is the responsible organism for the development of progressive multifocal encephalopathy (PML). Multiple sclerosis (MS) patients treated with natalizumab (NTZ), who have evidence of exposure to JCV have a significantly elevated risk, as high as 12/1000 patients, of developing PML, necessitating the elective transition of patients off NTZ. JCV is a member of the polyoma virus family, and closely related to BK virus. BK virus has been found to be a significant threat to destroy transplanted kidneys and there is growing evidence that treatment with leflunomide, the pro-drug of teriflunomide (TFM) clears BKV from the kidney. Main study assessed the clinical efficacy of TFM in MS patients transitioned off NTZ solely because they have evidence of exposure to JCV, as determined by the presence of serum anti-JCV immunoglobulin G (IgG). Previous work by other investigators has demonstrated a close correlation between positive anti-JCV antibody titers and the presence of active JCV infection. There is evidence that JCV is closely related to its fellow polyoma virus BKV, and that BKV is cleared by treatment with the TFM pro-drug leflunomide, we propose to determine if treatment of the JCV antibody positive patients currently enrolled in the approved protocol results in reduction in, or reversion to negative, of the anti-JCV antibody titer as measured by the JCV antibody Index, a commercially available assay which is used internationally as the standard for evidence of JCV exposure in NTZ-treated patients.

Official Title
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MAIN STUDY: Switching Relapsing Multiple Sclerosis Patients Treated With Natalizumab at Risk for Progressive Multifocal Leukoencephalopathy to Teriflunomide: Is This Safe and Effective? SUB-STUDY: Analysis of JCV Antibody Index in MS Patients Treated With Teriflunomide

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: teriflunomide


Participation Criteria
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Eligibility Criteria
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MAIN STUDY Inclusion Criteria: Male and female patients, age 21 to 60 with relapsing forms of MS, treated with natalizumab for 12 consecutive months or longer with anti-JCV Ab positive during that time period. Able to understand and sign Informed Consent Document. Stable disease during treatment with natalizumab. No clinical relapses for at least 12 months. Stable MRI on follow-up MRI scans for prior 12 months without evidence of new or enlarging T-2 hyperintensities or Gd+ lesions. No clinical evidence by imaging or cerebrospinal fluid (CSF) for PML. No evidence of significant cognitive limitation or psychiatric disorder. Expanded Disability Status Scale (EDSS) of 1.0 to 6.0 inclusive. Exclusion Criteria: Any mental condition of such that patient is unable to understand the nature, scope and possible consequences of the study. Patients that are known HIV positive. Patients with a known history of hepatitis. Known history of active tuberculosis not adequately treated, or a positive ppd skin test or positive quantiferon gold. Any persistent or severe infection. Any malignancy within 5 years, except for Basal or Squamous cell skin lesions, which have been surgically excised, with no evidence of metastasis. Clinically relevant or unstable cardiovascular, neurological (i.e. progressive weakness, increasing hypesthesia), endocrine, or other major systemic diseases. History of drug or alcohol abuse within the past year. Any significant depression or psychiatric disease (BDI II greater than 25) within the past year. Any significant lab abnormality as deemed by the investigator including but not limited to the following: Hypoproteinemia with serum albumin < 3.0g/dl. Serum creatinine >133umol/L (or >1.5 mg/dl) Hematocrit <24% and/or Absolute white blood cell count < 4,000 cells/mm3 (µl) and/or Platelet Count <150,000 cells/mm3 (µl) and /or Absolute neutrophil < 1,500 cells/mm3 (µl) Liver function impairment or persisting elevations of serum glutamate pyruvate transaminase (SGPT)/ Alanine transaminase (ALT), serum glutamate oxaloacetate transaminase (SGOT)/ aspartate aminotransferase (AST), or direct bilirubin greater than 1.5 fold the upper limit of normal. Any confounding illness or other diseases of the spine or bone that would impair evaluation of the patient or treatment effects. Any clinical, CSF or MRI evidence for PML. Prior treatment with immunosuppressive drugs except for past use of intravenous steroids to treat MS relapses. Pregnant or breast feeding women. Women of childbearing potential not protected by effective contraceptive method of birth control and/or are unwilling or unable to be tested for pregnancy. In the conception of a child during the course of the trial. Known history of hypersensitivity to teriflunomide or leflunomide. Persisting elevations (confirmed by retest) of serum amylase or lipase greater than 2-fold the upper limit of normal. Known history of chronic pancreatic disease or pancreatitis. Prior use within 4 weeks before randomization or concomitant use of phenytoin, warfarin, tolbutamide, cholestyramine, or products containing St. John's Wort SUB-STUDY Eligibility Criteria for JCV sub-study: Must have been enrolled in the SWITCH protocol and received at least 1 dose of 14mg TFM during the study period. Must be willing to sign written, informed consent for this JCV sub-study and follow protocol requirements.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriflunomide<br>Teriflunomide 14 mg oral teriflunomide daily | Drug: teriflunomide<br>* 14 mg oral teriflunomide daily<br>* Other names: Aubagio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAIN STUDY: Number of Participants Relapse Free at 24 Months | Number of patients relapses free by month 24. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MAIN STUDY: Time to Return of Radiological Evidence of Multiple Sclerosis Activity With New Gadolinium Enhancing (Gd+) Lesions on Cranial MRI. | Mean time to first Gadolinium enhancing (GAD+) lesion in months. | 24 months | 
| MAIN STUDY: Expanded Disability Status Scale (EDSS) Sustained Progression for 3 Months as Measured by at Least 0.5 Increase From Baseline or 1 in Any EDSS Set Score | Mean time to 3-month sustained disability worsening (SDW) in months. SDW is defined as an increase of ≥ 1 point for patients with EDSS of 1.0-5.0, and ≥ 0.5 points for patients with an EDSS of 5.5-6.0, sustained for 3 months. Patients with ≥ 1 point increase in EDSS in whom a second measure was not obtained 3 months later were not included as SDW. | 24 months | 
| MAIN STUDY: Mean Time to New T2 or Enlarging T2 Hyperintensities on Monthly Sentinel Brain MRIs | Mean time of new T2 or enlarging T2 Lesions | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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teriflunomide, natalizumab, relapsing multiple sclerosis