Observational Study of Tysabri in Early Relapsing-Remitting Multiple Sclerosis in Anti-JC Virus Antibody Negative Participants

Study Overview
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Brief Summary
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The primary objective of the study is to determine which baseline and yearly response factors (clinical and para clinical) predict overall disease-free status at Month 12 and Month 24, and clinical disease-free status in subsequent Months 36 and 48. The secondary objectives are: To identify prognostic factors at Baseline that predict overall disease-free status at Month 12, and to assess if yearly overall disease-free response factors predict overall disease-free status at Month 24; To evaluate clinical disease-free status (relapse, Expanded Disability Status Scale [EDSS]) at each analysis time point of Months 12, 24, 36, and 48; To identify prognostic factors at Baseline that predict clinical disease-free status at Month 12, and to assess yearly clinical disease-free response factors that predict clinical disease-free status (relapse, EDSS) in subsequent years at Months 24, 36, and 48; To evaluate the impact of Tysabri at each analysis time point of Months 12, 24, 36, and 48 on the following: annualized relapse rate (ARR), sustained EDSS progression and improvement (24-week sustained); To evaluate the impact of Tysabri at each analysis time point of Months 12, 24, 36, and 48 on the following: magnetic resonance image (MRI) measures: T2, T1, T1 with Gadolinium (Gd), brain atrophy; To evaluate the impact of Tysabri at Month 24 and Month 48 on the following: optical coherence tomography (OCT), Low and High Contrast Visual Acuity Assessment; To evaluate the impact of Tysabri at each analysis time point of Months 12, 24, 36, and 48 on the following: cognitive impairment (Symbol Digit Modalities Test [SDMT]), capacity for work (Work Productivity and Activity Impairment Questionnaire [WPAI]), quality of life (QoL) (Multiple Sclerosis Impact Scale [MSIS-29])

Official Title
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A Multicenter, Observational, Open-Label, Single-Arm Study of Tysabri in Early Relapsing-Remitting Multiple Sclerosis in Anti-JCV Antibody Negative Patients

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Biological: natalizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented diagnosis of Relapsing Multiple Sclerosis (McDonald 2010 Criteria ). <3 year disease duration. Must have an Expanded Disability Status Scale (EDSS) score from 0 to 4.0, inclusive. Anti-JCV antibody negative test within 6 months of Screening Visit. Must satisfy the approved therapeutic indications for Tysabri. Must be treatment-naïve to disease-modifying therapy (DMT) or have been treated with DMT (including but not limited to Avonex, Betaseron, Rebif, Copaxone, Extavia, or Gilenya) for ≤36 months total prior to date of informed consent. Decision to treat with Tysabri must precede enrollment. Key Exclusion Criteria: Any prior treatment with Tysabri. Anti-JCV antibody positive at any timepoint prior to the Screening Visit. Contraindications to treatment with Tysabri as described in the US Prescribing Information. History of progressive multifocal leukoencephalopathy (PML) or other opportunistic infections, or an increased risk for such infections. History of diagnosis of Primary Progressive Multiple Sclerosis (PPM) and/or Secondary Progressive Multiple Sclerosis (SPMS). Receiving immunomodulatory or immunosuppressive therapy. Prior history of immunosuppressive use (mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab). Immunocompromised at the time of enrollment. Known active malignancies (subjects with cutaneous basal cell carcinoma that has been completely excised prior to study entry remain eligible). Women breastfeeding, pregnant, or planning to become pregnant; women who are not post-menopausal or surgically sterile who are unwilling to practice contraception. Inability to comply with study requirements. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: natalizumab|Natalizumab will not be provided as a part of this study. Participants will receive natalizumab as prescribed by their treating physician.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants who are overall disease activity-free at Months 12 and 24 | Overall disease activity-free is defined as no relapses, no disability progression (RRMS), and absence of MRI disease activity (no gadolinium [gd])+ lesions, no new or enlarging T2-hyperintense lesions). A clinical relapse is defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement. Sustained disability progression defined by at least a 1.0-point increase on the EDSS from a Baseline EDSS ≥1.0 that is sustained for 12 or 24 weeks, or at least a 1.5-point increase on the EDSS from a Baseline EDSS <1.0 that is sustained for 12 or 24 weeks. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10, with higher scores indicating more disability. | Baseline and Months 12 and 24 | 
| Proportion of participants who are clinical disease activity-free at Months 36 and 48 | Clinical disease activity-free is defined as no sustained EDSS progression and no relapses at Month 36 and 48. | Baseline and Months 36 and 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of baseline prognostic factors that predict overall disease-free status |  | Baseline and Month 12 | 
| Identification of yearly overall disease-free response factors that predict overall disease-free status |  | Month 12 and Month 24 | 
| Number of Participants with Clinical Disease-Free Status Measured by Relapses | A clinical relapse is a new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement. | Months 12, 24, 36, and 48 | 
| Identification of baseline prognostic factors that predict clinical disease-free status |  | Month 12 | 
| Identification of yearly clinical disease-free response factors that predict clinical disease-free status |  | Months 24, 36 and 48 | 
| Annualized Relapse Rate | A clinical relapse is defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement. The ARR will be calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of study, and the ratio then multiplied by 365. | Months 12, 24, 36, and 48 | 
| Percentage of participants with Sustained EDSS progression |  | Baseline and Months 12, 24, 36, and 48 | 
| Sustained EDSS improvement | Sustained improvement in disability is defined as participants with Baseline EDSS of at least 2.0 who experience a ≥1.0 decrease in EDSS that is sustained for 24 weeks. | Baseline and Months 12, 24, 36, and 48 | 
| Change form baseline in number of new or newly enlarging T2 hyperintense lesions as assessed by MRI |  | Baseline and Months 12, 24, 36, and 48 | 
| Change from baseline in number of new T1 hypointense lesions as assessed by MRI |  | Baseline and Months 12, 24, 36, and 48 | 
| Change form baseline in number of T1 lesions with Gd-enhancing lesions as assessed by MRI |  | Baseline and Months 12, 24, 36, and 48 | 
| MRI brain atrophy as assessed by MRI |  | Baseline and Months 12, 24, 36, and 48 | 
| Change from baseline in retinal nerve fiber layer (RNFL) thickness as assessed by OCT |  | Baseline and Month 24 and Month 48 | 
| Change from baseline in low contrast visual acuity | Low-contrast visual acuity testing captures the minimum size at which individuals can perceive letters of a particular contrast level (shade of gray on white background). Using the low-contrast Sloan letter charts at 2.5% and 1.25% low contrast levels, participants will be asked to read each of the 2 charts at a 2-meter distance using a standardized testing protocol. | Baseline and Month 24 and Month 48 | 
| Change from baseline in high contrast visual acuity | High contrast acuity testing is important to help determine the smallest letters a person can read on a standardized visual acuity chart or on a card held 14 - 20 feet away. A visual acuity test is a routine part of an eye examination. | Baseline and Month 24 and Month 48 | 
| Cognitive impairment as assessed by change from baseline in SDMT | SDMT is a screening test for cognitive impairment. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. Scores range from 0 to 110 (best). | Baseline and Months 12, 24, 36 and 48 | 
| Capacity for work as assessed by change from baseline in WPAI questionnaire | The Work Productivity and Activity Impairment (WPAI) questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (work time missed) 2. Presenteeism (impairment at work / reduced on-the-job effectiveness) 3. Work productivity loss (overall work impairment / absenteeism plus presenteeism) 4. Activity Impairment WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | Baseline and Months 12, 24, 36 and 48 | 
| Quality of Life as measured by MSIS-29 | The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health. | Baseline and Months 12, 24, 36 and 48 | 
| Number of Participants with Clinical Disease-Free Status Measured by EDSS | Expanded Disability Status Scale (EDSS) is a method of quantifying disability in 8 Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. The FSS include pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral (or mental), and other. Each of the FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6, with higher scores indicating more disability. These ratings are then used in conjunction with observations and information concerning gait and use of assistive devices to rate the EDSS. The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments. Each of the FSS and the EDSS are single-item scales and there is no composite or summed score. | Months 12, 24, 36 and 48 |