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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
76
natalizumab
standard of care as determined by the Investigator and Treating Neurologist
Research Site
Phoenix, Arizona, United States
Research Site
Scottsdale, Arizona, United States
Research Site
Berkeley, California, United States
Research Site
Centennial, Colorado, United States
Research Site
Maitland, Florida, United States
Research Site
Vero Beach, Florida, United States
Research Site
Peoria, Illinois, United States
Research Site
Farmington Hills, Michigan, United States
Research Site
Buffalo, New York, United States
Research Site
Dallas, Texas, United States
...and 2 more locations
Maximum observed concentration (Cmax) of natalizumab
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Pre-dose, 4, 24 and 72 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56
Number of Participants with adverse events
Time frame: 13-19 months
Number of participants with abnormalities in vital signs
Time frame: 13-19 months
Number of participants with changes in the physical examination
Time frame: 13-19 months
Number of participants with abnormal laboratory test results
Time frame: 13-19 months
Number of participants with natalizumab antibodies
Time frame: 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.
Time frame: 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.
Time frame: 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).
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Time frame: 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."
Time frame: Baseline, Weeks 8, 20, and 32
Change from Baseline in visual function test
Time frame: Baseline, Weeks 8, 20, and 32
Number of new or newly enlarging T2 hyperintense lesions
Measured by magnetic resonance imaging (MRI).
Time frame: Baseline and Week 32
Number of new gadolinium-enhanced lesions
Measured by magnetic resonance imaging (MRI).
Time frame: Baseline and Week 32
Number of new T1 hypointense lesions
Measured by magnetic resonance imaging (MRI).
Time frame: 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).
Time frame: 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),
Time frame: Baseline and Week 32
Diffusion tensor imaging (DTI)
Time frame: Baseline and Week 32
Injection site pain assessment
Time frame: Pre-dose, 5 and 15 minutes and 24 hours post-dose