We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.

Background and objectivesDiagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis.MethodsUsing available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.ResultsWe present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system.ConclusionsDifferential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.

In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

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Article abstract-We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 pg), intermediate (30 pg) dence that a viral infection, an immunoregulatory defect, or both, may be implicated in disease In a double-blind, placebo-controlled crossover trial of natural alpha IFN given systemically,* the number of acute exacerbations in patients with relapsing-remitting MS was reduced, but the study was complicated by the crossover design and a marked placebo effect. Natural beta IFN administered intrathecally to 10 patients5 appeared to prevent exacerbations; however, the study lacked a placebo-treated control group. Recently, a multicenter double-blind controlled trial of intrathecal beta IFN6 confirmed the favorable results of the earlier study. The first clinical trial of recombinant IFN in MS, in which 2 million units of alpha, IFN were given subcutaneously three times per week for 1 year, was recently ~ompleted.~ There was no therapeutic effect, possibly because the dose was too low. Other studies, using higher systemic doses of recombinant IFN, are in progress.Gamma or immune IFN has many of the antiviral and immunoregulatory properties of other interferonss; in addition, it can activate macrophages and induce class I1 histocompatibility antigens on monocytes,9 endothelial cells,1° and astrocytes." These are properties that could stimulate an autoimmune process. On the other hand, recent reports of deficient gamma IFN production in MS patients12J3 suggested the possibility of a therapeutic trial. We therefore performed a pilot study of recombinant gamma IFN to determine toxicity and dose, and to judge whether a larger, long-term clinical trial would be feasible. The results have been partially reported elsewhere as a preliminary comm~nication.'~ Methods. Patients and treatment protocol. Eighteen patients with clinically definite relapsing-remitting MS participated. There were 3 men and 15 women ranging in age from 19 to 42 years. All patients had had at least two exacerbations in the preceding 2 years, and were in remission at the time of entry. The study was approved by the University of Maryland Human Volunteers Research Committee. Recombinant gamma IFN (Immuneron, Biogen Research, Cambridge, MA) was given in doses of 1, 30, or 1,000 pg, corresponding approximately to 1.5 X lo4, 4.5 X lo5, and 1.5 X lo7 IU of IFN, respectively. Patients were selected at random to receive the low, intermediate, or high doses twice a week for 4 weeks. One half of each dose was administered as an intravenous bolus; the remainder was given as an intravenous infusion over 2 hours. At the beginning and end of the trial, patients were scored according to the