Safety Study of Natalizumab to Treat Multiple Sclerosis (MS)

Sponsor

Biogen (Industry)

Overall Status

Completed

CT.gov ID

NCT00559702

Collaborator

Elan Pharmaceuticals (Industry)

Enrollment

Locations

Arms

Duration (Months)

6.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsing-Remitting Multiple Sclerosis Secondary Progressive Multiple Sclerosis	Drug: natalizumab Other: standard of care	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

76 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2007

Actual Primary Completion Date :

Nov 1, 2011

Actual Study Completion Date :

Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Natalizumab IV (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab natalizumab Other Names: Tysabri ® BG00002
Experimental: 2 Natalizumab IM (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab natalizumab Other Names: Tysabri ® BG00002
Experimental: 3 Natalizumab SC (Participants with secondary progressive multiple sclerosis)	Drug: natalizumab natalizumab Other Names: Tysabri ® BG00002
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: Tysabri ® BG00002
Experimental: 6 Natalizumab IV (Participants with relapsing forms of multiple sclerosis)	Drug: natalizumab natalizumab Other Names: Tysabri ® BG00002

Outcome Measures

Primary Outcome Measures

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 [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 as measured by the trapezoidal rule.
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 [Pre-dose, 4, 24 and 72 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56]
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.

Secondary Outcome Measures

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) [Baseline, Weeks 8, 20, and 32]
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.
Change form Baseline in Multiple Sclerosis Functional Composite Scale (MFSC) [Baseline, Weeks 8, 20, and 32]
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.
Change from Baseline in Symbol Digit Modalities Test (SDMT) [Baseline, Weeks 8, 20, and 32]
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).
Change from Baseline in visual analog scale (VAS) [Baseline, Weeks 8, 20, and 32]
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."
Change from Baseline in visual function test [Baseline, Weeks 8, 20, and 32]
Number of new or newly enlarging T2 hyperintense lesions [Baseline and Week 32]
Measured by magnetic resonance imaging (MRI).
Number of new gadolinium-enhanced lesions [Baseline and Week 32]
Measured by magnetic resonance imaging (MRI).
Number of new T1 hypointense lesions [Baseline and Week 32]
Measured by magnetic resonance imaging (MRI).
Whole brain atrophy [Baseline and Week 32]
Atrophy will be measured as the percent brain volume change (PBVC) and will be assessed using the Structural Image Evaluation of Normalized Atrophy (SIENA).
Percent change in magnetization transfer ratio (MTR) [Baseline and Week 32]
Remyelination will be measured using magnetization transfer ratio (MTR) in whole brain (WB) and normal-appearing brain tissue (NABT),
Diffusion tensor imaging (DTI) [Baseline and Week 32]
Injection site pain assessment [Pre-dose, 5 and 15 minutes and 24 hours post-dose]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States	85006
2	Research Site	Scottsdale	Arizona	United States	85259
3	Research Site	Berkeley	California	United States	94705
4	Research Site	Centennial	Colorado	United States	80112
5	Research Site	Maitland	Florida	United States	32751
6	Research Site	Vero Beach	Florida	United States	32960
7	Research Site	Peoria	Illinois	United States	61637
8	Research Site	Farmington Hills	Michigan	United States	48334
9	Research Site	Buffalo	New York	United States	14203
10	Research Site	Dallas	Texas	United States	75214
11	Research Site	Round Rock	Texas	United States	78681
12	Research Site	Vienna	Virginia	United States	22182