Safety Study of Natalizumab to Treat Multiple Sclerosis (MS)

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

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 Overview

• Status: Completed
• Conditions: Relapsing-Remitting Multiple Sclerosis; Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: natalizumab; Other: standard of care

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Research Site
    • Scottsdale, Arizona, United States, 85259
      • Research Site
  • California
    • Berkeley, California, United States, 94705
      • Research Site
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Research Site
  • Florida
    • Maitland, Florida, United States, 32751
      • Research Site
    • Vero Beach, Florida, United States, 32960
      • Research Site
  • Illinois
    • Peoria, Illinois, United States, 61637
      • Research Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Research Site
  • New York
    • Buffalo, New York, United States, 14203
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75214
      • Research Site
    • Round Rock, Texas, United States, 78681
      • Research Site
  • Virginia
    • Vienna, Virginia, United States, 22182
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Natalizumab IV (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab; natalizumab; Other Names: BG00002; Tysabri ®
EXPERIMENTAL: 2; Natalizumab IM (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab; natalizumab; Other Names: BG00002; Tysabri ®
EXPERIMENTAL: 3; Natalizumab SC (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab; natalizumab; Other Names: BG00002; Tysabri ®
OTHER: 4; Standard of care as determined by the Investigator and Treating Neurologist (Participants with secondary progressive multiple sclerosis)	Other: standard of care; standard of care as determined by the Investigator and Treating Neurologist
EXPERIMENTAL: 5; Natalizumab SC (Participants with relapsing forms of multiple sclerosis)	Drug: natalizumab; natalizumab; Other Names: BG00002; Tysabri ®
EXPERIMENTAL: 6; Natalizumab IV (Participants with relapsing forms of multiple sclerosis)	Drug: natalizumab; natalizumab; Other Names: BG00002; Tysabri ®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Biogen
• Collaborators: Elan Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (ACTUAL): November 1, 2011
• Study Completion (ACTUAL): November 1, 2011

Study Registration Dates

• First Submitted: November 7, 2007
• First Submitted That Met QC Criteria: November 14, 2007
• First Posted (ESTIMATE): November 16, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2014
• Last Update Submitted That Met QC Criteria: September 5, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: multiple sclerosis; natalizumab; Tysabri ®
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Immunologic Factors; Natalizumab
• Other Study ID Numbers: 101MS102