Safety Study of Natalizumab to Treat Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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The primary objective of this study is to compare the pharmacokinetic (PK) and pharmacodynamics (PD) of single subcutaneous (SC) and intramuscular (IM) doses of 300 mg natalizumab to intravenous (IV) administration of 300 mg natalizumab in multiple sclerosis (MS) participants. The secondary objectives are to investigate the safety, tolerability and PK of repeated natalizumab doses administered SC and IM, to investigate the immunogenicity of repeated natalizumab doses administered SC and IM, to explore proof of concept within the secondary progressive multiple sclerosis (SPMS) population using change from baseline in clinical measures including: expanded disability status scale (EDSS), multiple sclerosis functional composite scale (MSFC), symbol digit modalities test (SDMT), visual analogue scale (VAS), and visual function test; and brain magnetic resonance imaging (MRI) measures including: number of new or newly-enlarging T2 hyperintense lesions, number of new T1 hypointense lesions, number of new gadolinium-enhancing (Gd+) lesions, whole brain atrophy, magnetization transfer ratio (MTR), and diffusion tensor imaging (DTI) and to observe the effect of natalizumab administered IV and SC on brain MRI measures in participants with relapsing forms of MS.

Official Title
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A Randomized, Open-Label, Dose-Ranging Study to Evaluate the Pharmacokinetics and Initial Safety of Subcutaneous and Intramuscular Natalizumab in Subjects With Multiple Sclerosis

Conditions
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Relapsing-Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: natalizumab
* Other: standard of care


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: For arms 1,2,3 and 4: Diagnosis of Secondary Progressive Multiple Sclerosis (SPMS) For arms 5 and 6: Diagnosis of relapsing forms of Multiple Sclerosis (MS). No past history of receiving natalizumab. Key Exclusion Criteria: For arms 1,2,3 and 4 Diagnosis of primary progressive MS or relapsing-remitting MS. Form arms 5 and 6: Diagnosis of primary progressive MS or secondary progressive MS without the occurrence of relapses. 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Natalizumab IV (Participants with secondary progressive multiple sclerosis) | Drug: natalizumab<br>* natalizumab<br>* Other names: BG00002;|
| Experimental: 2<br>Natalizumab IM (Participants with secondary progressive multiple sclerosis) | Drug: natalizumab<br>* natalizumab<br>* Other names: BG00002;|
| Experimental: 3<br>Natalizumab SC (Participants with secondary progressive multiple sclerosis) | Drug: natalizumab<br>* natalizumab<br>* Other names: BG00002;|
| Other: 4<br>Standard of care as determined by the Investigator and Treating Neurologist (Participants with secondary progressive multiple sclerosis) | Other: standard of care<br>* standard of care as determined by the Investigator and Treating Neurologist<br>|
| Experimental: 5<br>Natalizumab SC (Participants with relapsing forms of multiple sclerosis) | Drug: natalizumab<br>* natalizumab<br>* Other names: BG00002;|
| Experimental: 6<br>Natalizumab IV (Participants with relapsing forms of multiple sclerosis) | Drug: natalizumab<br>* natalizumab<br>* Other names: BG00002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Time to maximum observed concentration (Tmax) of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Area under the curve to the last measurable concentration (AUC0-last) of natalizumab | Area under the curve to the last measurable concentration as measured by the trapezoidal rule. | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Apparent volume of distribution of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Half-life of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Area under the curve extrapolated to infinity (AUC0-∞) of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| Apparent Clearance of natalizumab |  | Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 
| α4-integrin saturation | PD activity will be assessed by measuring the degree of natalizumab saturation of the very late antigen-4 (also known as α4β1 integrin) VLA-4 (α4β1) receptor on peripheral blood lymphocyte/monocyte populations. | Pre-dose, 4, 24 and 72 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with adverse events |  | 13-19 months | 
| Number of participants with abnormalities in vital signs |  | 13-19 months | 
| Number of participants with changes in the physical examination |  | 13-19 months | 
| Number of participants with abnormal laboratory test results |  | 13-19 months | 
| Number of participants with natalizumab antibodies |  | Days 28, 42, 56, Weeks 24 and 32 | 
| Change from Baseline in expanded disability status scale (EDSS) | The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist. | Baseline, Weeks 8, 20, and 32 | 
| Change form Baseline in Multiple Sclerosis Functional Composite Scale (MFSC) | The MFSC consists of 3 tests: 1. Timed 25-Foot Walk, a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet; 2. 9-Hole Peg Test (9HPT), a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. 3. 3 Second Paced Auditory Serial Addition Test (PASAT 3). The MSFC is based on the concept that scores for these 3 dimensions - arm, leg, and cognitive function are combined to create a single score that can be used to detect change over time. A composite z-score is created, which represents the number of standard deviations (SDs) a participant's test result is higher (z > 0) or lower (z < 0) than the average test result (z = 0) of the reference population. | Baseline, Weeks 8, 20, and 32 | 
| Change from Baseline in Symbol Digit Modalities Test (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, Weeks 8, 20, and 32 | 
| Change from Baseline in visual analog scale (VAS) | The participant's global assessment of well-being as assessed using a visual analogue scale (VAS) is a quality of life measurement that will be evaluated for the specified time periods. Participants report how they feel on a scale of 0 to 100, where 0 indicates being poor and 100 being excellent. | Baseline, Weeks 8, 20, and 32 | 
| Change from Baseline in visual function test |  | Baseline, Weeks 8, 20, and 32 | 
| Number of new or newly enlarging T2 hyperintense lesions | Measured by magnetic resonance imaging (MRI). | Baseline and Week 32 | 
| Number of new gadolinium-enhanced lesions | Measured by magnetic resonance imaging (MRI). | Baseline and Week 32 | 
| Number of new T1 hypointense lesions | Measured by magnetic resonance imaging (MRI). | Baseline and Week 32 | 
| Whole brain atrophy | Atrophy will be measured as the percent brain volume change (PBVC) and will be assessed using the Structural Image Evaluation of Normalized Atrophy (SIENA). | Baseline and Week 32 | 
| Percent change in magnetization transfer ratio (MTR) | Remyelination will be measured using magnetization transfer ratio (MTR) in whole brain (WB) and normal-appearing brain tissue (NABT), | Baseline and Week 32 | 
| Diffusion tensor imaging (DTI) |  | Baseline and Week 32 | 
| Injection site pain assessment |  | Pre-dose, 5 and 15 minutes and 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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natalizumab, multiple sclerosis, Tysabri ®