Assessment Study of Steroid Effect in Relapsing Multiple Sclerosis Subjects Treated With Glatiramer Acetate

A Multi-Centered, Randomized, Double-Blind, Placebo Controlled Study Assessing the Add-on Effect of Oral Steroids in Relapsing Remitting Multiple Sclerosis Subjects Treated With Glatiramer Acetate (GA)

This is a study evaluating the effect on brain volume of daily glatiramer acetate (GA) and add-on pulse steroids.

One interim analysis was planned for possible early termination due to proven efficacy when 75% of the preplanned 500 (approx. 375 patients) recruited patients completed the entire study duration or early discontinued.

In addition to the stopping rule already given for proven efficacy, the sponsor was also interested in examining the data for futility (i.e., absence of the desired treatment effect) with the view to terminating the trial if an "insufficient" effect of the treatment is seen. The reasons why the need for futility arose were:

1. Recruitment difficulties
2. Increasing dropout rate
3. Budgetary constraints

The primary efficacy measure is defined as the percent change from baseline to termination (Month 36 or Early Termination) in normalized brain volume (Brain Atrophy) measured according to the SIENA (Structural Imaging Evaluation using Normalization of Atrophy) method. However, since not many patients had completed the entire study at the time of futility analysis, it was the sponsor's decision that the futility analysis be performed on patients with MRI scans at months 24 or 36 or at early termination visits - the latest available.

Based on the recalculation of study power (probability is unconditioned on the interim result and provide the real power of the study if designed anew), conditional power (based on the interim results) and risk assessment of a false negative, the Data Monitoring Committee agreed that the study should be terminated early.

Inclusion Criteria:

1. Clinically definite multiple sclerosis (CDMS) according to Poser (Ann. Neurol. 1983) or McDonald (Ann. Neurol. 2001)
2. Subjects eligible for GA treatment based on the investigator's clinical assessment and according to the current indication.
3. Subjects must have a relapsing remitting disease course.
4. Subjects must have had at least 1 documented relapse within the last year prior to study entry.
5. Subjects may be male or female. Women of childbearing potential must practice an acceptable method of birth control. Acceptable methods include oral contraceptive, contraceptive patch, long-acting injectable contraceptive, double-barrier method (condom or intrauterine device [IUD] with spermicide), or partner's vasectomy.
6. Subjects must be between the ages of 18 and 55 years inclusive.
7. Subjects must be ambulatory, with a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0 inclusive.
8. Subjects must be willing and able to give written informed consent prior to entering the study.

Exclusion Criteria:

1. Long-term glatiramer acetate users who have been on therapy within 6 months of the baseline magnetic resonance imaging (MRI). New glatiramer acetate users who have initiated therapy for more than 6 weeks prior to the baseline MRI.
2. Previous use of cladribine.
3. Previous use of mitoxantrone.
4. Use of digitalis at study entry.
5. Previous use of immunosuppressive agents (such as azathioprine, cyclophosphamide or mycophenolate mofetil) in the last 6 months prior to screening.
6. Use of experimental or investigational drugs, including intravenous (IV) immunoglobulin within 6 months prior to screening.
7. Use of interferon agents within 1 month prior to the baseline MRI.
8. Use of corticosteroids (IV, intramuscular [IM] and/or by mouth [PO]) within 30 days prior to the baseline MRI.
9. Chronic corticosteroid (IV, IM and/or PO) treatment (more than 30 consecutive days) in the 6 months prior to the screening visit.
10. Subjects with diabetes.
11. Previous total body irradiation or total lymphoid irradiation.
12. Pregnancy or breast feeding.
13. Significant medical or psychiatric condition that affects the subject's ability to give informed consent, or to complete the study, or any condition which the investigator feels may interfere with participation in the study (e.g. alcohol or drug abuse).
14. Other diseases that can cause brain atrophy (ex. neurodegenerative disorder, cerebrovascular disease, history of alcohol abuse).
15. Bone density less than -2.5 standard deviations (SD) (osteoporosis).
16. A known history of sensitivity to mannitol.
17. Contraindication to, or known history of, sensitivity or severe reaction to steroids.
18. A known history of sensitivity to gadolinium.
19. Inability to successfully undergo MRI scanning.
20. Previous use of natalizumab.