Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx

This is a multicenter, double blind, randomized trial examining combination therapy versus single agent therapy with three-year follow-up on the last patient randomized. All patients will remain on therapy until the last patient completes the study. All patients will then be transitioned, based on the findings, to open label of combination with continued follow-up or some recommendation about single agent therapy. While the study design benefits from having two arms of single agent therapy to examine the important question of whether there are differences between the single agents, the primary interest is in combination therapy. Therefore, a two-group combination versus single agent concept was used - splitting the population into single agent and combination therapy equally. The single agent arm is divided into two groups, IFN and GA providing for 3 treatment arms: IFN intramuscularly (IM) and GA subcutaneously (SC) (50% of the patients), IFN IM and placebo SC (25% of the patients) and GA SC and placebo IM (25% of the patients).

Inclusion criteria

• Male and female subjects between the ages of 18 and 60 years, inclusive.
• Diagnosis of relapsing-remitting MS by either the Poser or McDonald criteria.
• Expanded Disability Status Scale (EDSS) score between 0 and 5.5, inclusive.
• At least 2 exacerbations in the prior three years; one exacerbation may utilize the McDonald MRI criteria for dissemination in time (a new gadolinium [Gd]-enhancing lesion demonstrated on a scan done at least 3 months following onset of a clinical attack or a new T2 lesion or Gd-enhancing lesion on a follow-up scan after an additional 3 months).
• Give written informed consent prior to any testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care.

Exclusion criteria

• Any prior use of interferon beta or glatiramer acetate.
• Acute exacerbation within 30 days of screening.
• Steroids for acute exacerbations (>100 mg/day) within 30 days of study entrance or chronic systemic steroid use.
• Evidence of progressive MS.
• Use IVIg, azathioprine, methotrexate, cyclosporine, mitoxantrone, cyclophosphamide, mycophenolate (CellCept) or plasma exchange in the twelve weeks prior to study drug dosing.
• Any previous treatment with natalizumab (Tysabri, Antegren), cladribine, T cell vaccine, Campath, daclizumab, rituximab, altered peptide ligand or total lymphoid irradiation.
• Treatment with 4 aminopyridines in the four weeks prior to study drug dosing.
• Prior treatment with any other investigational drug, unless approved by the Clinical Coordinating Center (Dr. Lublin).
• Inability to perform the baseline MSFC (timed 25-foot walk, 9-hole peg test [9HPT], and Paced Auditory Serial Addition Test 3 [PASAT3]).
• Inability to undergo baseline MRI scan.
• History of any significant cardiac, hepatic, pulmonary, or renal disease, immune deficiency, or other medical conditions that would preclude therapy with interferon beta, glatiramer acetate, or participation in this study.
• Known history of sensitivity to gadopentetate dimeglumine or mannitol.
• History of a seizure within the 3 months prior to randomization.
• History of suicidal ideation or an episode of severe depression within the 3 months prior to randomization.
• Abnormal screening blood tests exceeding any of the limits defined below:

• Alanine transaminase (ALT) or aspartate transaminase (AST) greater than two times the upper limit of normal (i.e., >2 × ULN)
• Total white blood cell count <2,300/mm3
• Platelet count <80,000/mm3
• Creatinine >2 × ULN
• Participation in another experimental clinical trial, without formal approval.
• History of alcohol or drug abuse within the 2 years prior to randomization.
• Female subjects who are currently pregnant, breast-feeding, or plan to become pregnant.
• For female subjects, unless postmenopausal or surgically sterile, unwillingness to practice effective contraception, as defined by the investigator, during the study. The rhythm method is not to be used as the sole method of contraception.
• Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition that is likely to affect the subject's returning for scheduled follow-up visits on schedule (any physical, mental, or social condition).