Safety Study of Natalizumab to Treat Multiple Sclerosis (MS)

Relapsing-Remitting Multiple Sclerosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00559702
• Other study ID #: 101MS102
• Status: Completed
• Phase: Phase 1
• First received: November 7, 2007
• Last updated: September 5, 2014
• Start date: October 2007
• Est. completion date: November 2011

Study information

• Verified date: September 2014
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: November 2011
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-Remitting Multiple Sclerosis
• Sclerosis
• Secondary Progressive Multiple Sclerosis

Intervention

Drug:
• natalizumab
natalizumab

Other:
• standard of care
standard of care as determined by the Investigator and Treating Neurologist

Locations

Country	Name	City	State
United States	Research Site	Berkeley	California
United States	Research Site	Buffalo	New York
United States	Research Site	Centennial	Colorado
United States	Research Site	Dallas	Texas
United States	Research Site	Farmington Hills	Michigan
United States	Research Site	Maitland	Florida
United States	Research Site	Peoria	Illinois
United States	Research Site	Phoenix	Arizona
United States	Research Site	Round Rock	Texas
United States	Research Site	Scottsdale	Arizona
United States	Research Site	Vero Beach	Florida
United States	Research Site	Vienna	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Biogen	Elan Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	Area under the curve extrapolated to infinity (AUC0-8) of natalizumab		Pre-dose, 4, 24, 48, 72 and 96 hours post-dose and Days 7, 14, 21, 28, 35, 42 and 56	No
Primary	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	No
Primary	a4-integrin saturation	PD activity will be assessed by measuring the degree of natalizumab saturation of the very late antigen-4 (also known as a4ß1 integrin) VLA-4 (a4ß1) 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	No
Secondary	Number of Participants with adverse events		13-19 months	Yes
Secondary	Number of participants with abnormalities in vital signs		13-19 months	Yes
Secondary	Number of participants with changes in the physical examination		13-19 months	Yes
Secondary	Number of participants with abnormal laboratory test results		13-19 months	Yes
Secondary	Number of participants with natalizumab antibodies		Days 28, 42, 56, Weeks 24 and 32	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Change from Baseline in visual function test		Baseline, Weeks 8, 20, and 32	No
Secondary	Number of new or newly enlarging T2 hyperintense lesions	Measured by magnetic resonance imaging (MRI).	Baseline and Week 32	No
Secondary	Number of new gadolinium-enhanced lesions	Measured by magnetic resonance imaging (MRI).	Baseline and Week 32	No
Secondary	Number of new T1 hypointense lesions	Measured by magnetic resonance imaging (MRI).	Baseline and Week 32	No
Secondary	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	No
Secondary	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	No
Secondary	Diffusion tensor imaging (DTI)		Baseline and Week 32	No
Secondary	Injection site pain assessment		Pre-dose, 5 and 15 minutes and 24 hours post-dose	No