Tysabri Effects on Cognition and Neurodegeneration in Multiple Sclerosis

Study Overview
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Brief Summary
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The long-term objective is to further establish the role of Tysabri in preventing neurological degeneration in multiple sclerosis (MS) and to establish powerful and efficient new markers for neurological degeneration in MS. The study intends to correlate cognition with two instruments and their measurements-MRI and OCT (optical coherence tomography).

Detailed Description
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The specific aims are: To determine the effects of Tysabri on cognition (memory, thought processes, etc.) To determine the effects of Tysabri on specific MRI markers for cognitive dysfunction To determine the effects of Tysabri on retinal nerve fiber layer thickness (RNFL) using optical coherence tomography (OCT), a special instrument used in ophthalmology

Official Title
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Tysabri Effects on Cognition and Neurodegeneration in Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Tysabri


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 through 60 years of age inclusive Diagnosis of relapsing remitting multiple sclerosis Prior to treatment phase, have had disease activity with at least 1 documented relapse during the previous year OR 2 documented relapses during the previous 2 years OR one or more new MRI lesions (Gd+ and/or T2 hyperintense) An Expanded Disability Status Scale (EDSS) score of 0-4.5 inclusive Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to treatment Never been treated with Tysabri/natalizumab. Exclusion Criteria: Another type of MS other than relapsing remitting multiple sclerosis (RRMS) A history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome/immunocompromised A history or presence of cancer (except for successfully treated basal or squamous cell carcinoma of skin) Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively Have received any live or live attenuated vaccines (including for varicella-zoster virus or Measles) within the last 2 months Have received total lymphoid irradiation or bone marrow transplantation Have been treated with: corticosteroids or adrenocorticotropic hormones (ACTH) within the last month, IFN-β or glatiramer acetate within the last 3 months, immunosuppressive medications such as azathioprine or methotrexate within the last 6 months, immunoglobulins and/or monoclonal antibodies (including natalizumab) within the last 6 months, or cladribine, cyclophosphamide or mitoxantrone at any time. Any medically unstable condition or a progressive neurological disorder, other than MS, which may affect participation in the study History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal or other major disease Unable to undergo MRI scans, including claustrophobia, have a pacemaker or history of hypersensitivity to gadolinium-DTPA Have had a relapse within 30 days prior AND/OR not stabilized from a previous relapse History of severe allergic or anaphylactic reactions or known drug hypersensitivity to natalizumab/Tysabri A clinically significant infectious disease, such as cellulitis, pneumonia, septicemia History of progressive multifocal leukoencephalopathy(PML) Participation in any clinical research study evaluating another investigational drug or therapy within the last 6 months History of Tysabri therapy Abnormal screening blood test Females who are not postmenopausal for at least 1 year, surgically sterile or willing to practice effective contraception during the study Nursing mothers, pregnant women, and women planning to become pregnant while on study

Ages Eligible for Study
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Minimum Age: 18 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: Tysabri<br>Natalizumab 300 mg IV every 4 weeks | Drug: Tysabri<br>* Infuse TYSABRI® 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP over approximately one hour. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP. Tysabri will be infused every four weeks.<br>* Other names: Natalizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognitive Function Over Time | Cognitive function was assessed using the oral version of the Symbol Digit Modalities Test (SDMT). The number of correct responses in 90 seconds was recorded (possible range 0-110). For analysis, SDMT scores were converted to z-scores using published age and education based norms. A negative z-score indicates a SDMT score below the mean based on the age and education based norms, for example a z-score of -2 = 2 standard deviations below the mean; a positive z-score indicating a score above the mean. Higher scores indicate better cognitive function. | Baseline, 48 weeks, 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Over Time in Retinal Nerve Fiber Layer Thickness | Retinal Nerve Fiber Layer (RNFL) thickness was measured using spectral domain OCT scans by a trained technician. Scans were performed without pupil dilation. | Baseline, 24, 48, 72, and 96 weeks | 
| Change Over Time in Brain Parenchymal Fraction | Measured based on MRI scan on a 3T Phillips scanner. This is a measure of brain atrophy (i.e., brain volume loss) with lower values indicating greater atrophy (possible range 0-1). | Baseline, 48 weeks, 96 weeks | 
| Change Over Time in Normalized Thalamic Volume | Measured on MRI scan | Baseline, 48 weeks, 96 weeks | 
| Change Over Time in Normalized Hippocampal Volume | Measured on MRI scan | Baseline, 48 weeks, 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, OCT, Tysabri, Multiple Sclerosis, cognition