Multiple Sclerosis
Conditions
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.
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.
Interventions
DRUGAvonex (Interferon beta 1a)
DRUGRiluzole
DRUGPlacebo
Sponsors
National Multiple Sclerosis Society
Oregon Health and Science University
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRI Parameter- Percent Brain Volume Change for 2 Years | 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
| Measure | Time frame | Description |
|---|---|---|
| Changes in Normalized White Matter Volumes (nWMV) | 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 |
| Changes in MS Functional Composite (MSFC) | 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. |
| Changes in Peripapillary Retinal Nerve Fiber Layer Thickness (RNFL) | 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). |
| Changes in Symbol Digit Modality Test (SDMT) | 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). |
| Changes in Normalized Grey Matter Volume | 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 |
Countries
United States
Participant flow
Recruitment details
Patients with diagnosis of early Relapsing Remitting MS were invited to participate in the study at 2 US sites- UCSF and OHSU during the period between Dec 2007 and May 2010
Participants by arm
| Arm | Count |
|---|---|
| Riluzole Riluzole
Riluzole 50 mg BID added to weekly injection of Interferon beta 1a | 22 |
| Placebo placebo
1 tab of Placebo BID added to weekly injection of Interferon beta 1a | 21 |
| Total | 43 |
Baseline characteristics
| Characteristic | Riluzole | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 9.84 | 32.4 years STANDARD_DEVIATION 7.85 | 36 years STANDARD_DEVIATION 9.32 |
| Region of Enrollment United States | 22 participants | 21 participants | 43 participants |
| Sex: Female, Male Female | 17 Participants | 14 Participants | 31 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 22 | 15 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 |
Outcome results
Primary
MRI Parameter- Percent Brain Volume Change for 2 Years
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)
Time frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24
Population: Multivariate regression model was used as the statistical method of analysis for the study. So data from patients who have not completed the study are also used for statistical analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | MRI Parameter- Percent Brain Volume Change for 2 Years | -0.862 percent change per year |
| Placebo | MRI Parameter- Percent Brain Volume Change for 2 Years | -0.49 percent change per year |
Secondary
Changes in MS Functional Composite (MSFC)
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.
Time frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | Changes in MS Functional Composite (MSFC) | 0.041 percent change per year |
| Placebo | Changes in MS Functional Composite (MSFC) | 0.052 percent change per year |
Secondary
Changes in Normalized Grey Matter Volume
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
Time frame: Baseline, Month-3, Month-6, Month-12 and Month-24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | Changes in Normalized Grey Matter Volume | -14.369 percent change per year |
| Placebo | Changes in Normalized Grey Matter Volume | -18.444 percent change per year |
Secondary
Changes in Normalized White Matter Volumes (nWMV)
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
Time frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | Changes in Normalized White Matter Volumes (nWMV) | -1.75 percent change per year |
| Placebo | Changes in Normalized White Matter Volumes (nWMV) | -9.69 percent change per year |
Secondary
Changes in Peripapillary Retinal Nerve Fiber Layer Thickness (RNFL)
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).
Time frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | Changes in Peripapillary Retinal Nerve Fiber Layer Thickness (RNFL) | -4.670 percent change per year |
| Placebo | Changes in Peripapillary Retinal Nerve Fiber Layer Thickness (RNFL) | -1.839 percent change per year |
Secondary
Changes in Symbol Digit Modality Test (SDMT)
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).
Time frame: Baseline, Month-3, Month-6, Month-12, Month-18 and Month-24
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Riluzole | Changes in Symbol Digit Modality Test (SDMT) | 0.342 percent change per year |
| Placebo | Changes in Symbol Digit Modality Test (SDMT) | 0.417 percent change per year |