Neuroprotection With Riluzole Patients With Early Multiple Sclerosis

Study Description

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Brief Summary:

This is a double blind, randomized, parallel group design placebo-controlled mono-center study. Patients will be evaluated within twelve months of CIS onset. Patients with at least 2 silent ovoid T2 bright areas in the deep white matter on their clinic brain MRI scan will be offered participation in the study. Patients will be randomized to oral riluzole or placebo (1:1). Patient will take 50 mg of riluzole or placebo once a day for one month. If 50 mg once a day is well tolerated, patients will then go on 50 mg twice daily for the rest of the study. They will start Avonex (Interferon beta 1a) therapy 30 mcg IM once weekly 3 months after study drug (riluzole or placebo) is initiated if their liver function has remained normal.

Forty patients within twelve months of onset CIS onset will be enrolled at UCSF MS Center. Patients will be evaluated every month for the first 12 months and every three months thereafter for a total study duration of 24-month. Enrollment period will last six months.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Avonex (Interferon beta 1a); Drug: Riluzole; Drug: Placebo	Phase 2

Detailed Description:

To determine the effect of riluzole up to 50 mg bid on MRI parameters, including T1 lesions load, atrophy of gray and white matter, and 1H-MRSI; and to determine safety of riluzole when administered orally up to 50 mg bid for 2 years in double blinded clinical trial of patients with clinically isolated syndromes (CIS) and at least 2 silent T2-bright areas in the deep white matter. These patients have a high risk of conversion to MS within 2 years and faster rate of atrophy (Dalton 2004).

Specific aims:

1. To determine the effect of treatment compared to placebo on annual change in measures of normalized brain gray and white matter volume changes.
2. To determine the effect of riluzole compared to placebo on annual change in proton spectroscopic intensities of N-acetyl aspartate (NAA) and glutamate in normal appearing white matter (NAWM), in acute and chronic lesions.
3. To determine the safety of riluzole up to 50 mg bid in patients with CIS in association to Avonex (Interferon beta 1a) 30 mcg IM once a week.
4. To monitor changes on MS functional composite (MSFC) (Cutter 1999, Rudick 1998), optic coherence tomography (OCT), low contrast sensitivity and EDSS in these patients.
5. To monitor recovery from exacerbations.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	43 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Prevention
Official Title:	Neuroprotection With Riluzole in Patients With Early Multiple Sclerosis
Study Start Date :	July 2006
Actual Primary Completion Date :	October 2012
Actual Study Completion Date :	October 2012

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Riluzole; Riluzole + Avonex	Drug: Avonex (Interferon beta 1a) Drug: Riluzole
Placebo Comparator: Placebo; placebo + Avonex	Drug: Avonex (Interferon beta 1a) Drug: Placebo

Outcome Measures

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Primary Outcome Measures :

1. MRI Parameter- Percent Brain Volume Change for 2 Years [ Time Frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24 ]
   Baseline MRI is compared to MRI images collected during subsequent timepoints. The percent brain volume change is measured using SIENAX (Structural Image Evaluation using Normalization of Atrophy-X)

Secondary Outcome Measures :

1. Changes in Normalized White Matter Volumes (nWMV) [ Time Frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24 ]
   The baseline data of white matter volume obtained from the MRI images is compared to data obtained at time points using SIENA (Structural Image Evaluation using Normalization of Atrophy) and SIENAX
2. Changes in MS Functional Composite (MSFC) [ Time Frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24 ]
   Baseline MSFC data is compared to MSFC data collected during the timepoints. The MSFC is a three-part, standardized, quantitative, assessment instrument that measures the clinical dimensions of leg function, arm/hand function and cognitive function and the components include Timed 25-Foot walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test.
3. Changes in Peripapillary Retinal Nerve Fiber Layer Thickness (RNFL) [ Time Frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24 ]
   Baseline RNFL data is compared to the RNFL data collected during the timepoint, and the changes in RNFL is measured using optical coherence tomography (OCT).
4. Changes in Symbol Digit Modality Test (SDMT) [ Time Frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24 ]
   Baseline SDMT data were compared to SDMT data collected during the timepoints. A simple substitution task, the SDMT gives the examinee 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The total score is the total number of correctly completed boxes in the time allowed. The test score range is from 0(worst outcome) to 110 (best outcome).
5. Changes in Normalized Grey Matter Volume [ Time Frame: Baseline, Month-3, Month-6, Month-12 and Month-24 ]
   The baseline data of grey matter volume obtained from the MRI images is compared to data obtained at time points using SIENA (Structural Image Evaluation using Normalization of Atrophy) and SIENAX

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 55 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Patient must give written informed consent;
2. Patients with a early MS or clinically isolated syndromes (CIS) in the past 12 months as defined by an acute or sub-acute episode suggestive of demyelination affecting the optic nerves, brain stem or spinal cord or other central nervous system location.
3. Entry age 18-55
4. Males and females
5. At least 2 silent T2 bright areas in the deep white matter on screening brain MRI.
6. No riluzole, interferon, copaxone, cyclophosphamide, mitoxantrone or other off-label immunosuppressive drugs for MS prior to study entry
7. No corticosteroid during the 4 weeks prior to baseline MRI exam
8. No prior exposure to total lymphoid irradiation
9. No history of substance abuse, including documented alcohol dependence within 6 months prior to screening or alcohol liver damage with AST , ALT > twice upper normal limits
10. No pregnant or nursing patients
11. No history of systemic illness or medical condition that would limit the likelihood of completing the gadolinium-enhanced MRI procedures. Automatic exclusionary conditions will include hypersensitivity reaction to riluzole or any of the tablets components, uncontrolled hypertension, epilepsy, and insulin dependent diabetes, asthma, known malignancy other than skin cancer, symptomatic cardiac disease or metallic objects on or inside the body.
12. Patients willing to use birth control during the study.
13. Patients willing to go on Avonex therapy 3 months after being randomized to study drug and no contra-indication to use of interferon therapy.

Exclusion Criteria:

1. A history of major depression or psychosis.
2. A clinically significant MS exacerbation within 30 days of the screening
3. Pregnancy
4. Abnormal screening liver function (AST or ALT > twice the upper normal limit).
5. Patients receiving hepatotoxic medications such as drugs interfering with CYP 1A2.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, California
UCSF MS Center , 675 Nelson Rising Lane, Suite 221
San Francisco, California, United States, 94158

Sponsors and Collaborators

University of California, San Francisco

National Multiple Sclerosis Society

Oregon Health and Science University

Investigators

Principal Investigator:	Emmanuelle Waubant, MD, PhD	UCSF , MS Center
Principal Investigator:	Emmanuelle Waubant, MD PhD	UCSF, MS Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kuhle J, Nourbakhsh B, Grant D, Morant S, Barro C, Yaldizli Ö, Pelletier D, Giovannoni G, Waubant E, Gnanapavan S. Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology. 2017 Feb 28;88(9):826-831. doi: 10.1212/WNL.0000000000003653. Epub 2017 Feb 1.

Maghzi AH, Graves J, Revirajan N, Spain R, Liu S, McCulloch CE, Pelletier D, Green AJ, Waubant E. Retinal axonal loss in very early stages of multiple sclerosis. Eur J Neurol. 2015 Jul;22(7):1138-41. doi: 10.1111/ene.12722. Epub 2015 Apr 29.

Responsible Party:	Emmanuelle Waubant, Associate Professor of Clinical Neurology, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT00501943 History of Changes
Other Study ID Numbers:	H9924-29155-05
First Posted:	July 16, 2007
Results First Posted:	April 9, 2014
Last Update Posted:	April 9, 2014
Last Verified:	March 2014

Additional relevant MeSH terms:

Riluzole; Sclerosis; Multiple Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Interferons; Interferon-beta; Interferon beta-1a	Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Anticonvulsants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neuroprotective Agents; Protective Agents