Background and Introduction
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by focal T-cell and macrophage infiltrates that lead to demyelination and loss of neurologic function. The ultimate goal of immunotherapy in MS is to find immunologically specific, relatively nontoxic forms of therapy. Currently available immunomodulatory therapies have demonstrated the ability to modify disease outcome in patients with relapsing-remitting MS (RRMS), and although there is evidence that some of these treatments delay progression, no therapy is available to definitively arrest the disease.
Our understanding of MS implicates T-cell activation as an important step in the pathogenesis of this autoimmune disease. The CD28-B7 pathway of T-cell costimulation plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Treatment of animals with CTLA4-Ig, a fusion protein that binds and blocks B7 interaction with CD28, suppresses EAE. Our hypothesis is that treatment with CTLA4-Ig will arrest the disease if administered early in the course of MS and decrease accumulation of lesions on MRI. Thus, our primary objective is to evaluate in a phase II study the efficacy of CTLA4-Ig therapy in patients with RRMS.
The current trial comprises a core phase during which the primary endpoint will be assessed followed by an extension phase. The core phase is intended to address the central research aim of the trial, which is to evaluate the ability of abatacept to affect the accumulation of inflammatory MRI lesions in patients with RRMS. This will be assessed by a direct comparison of the treated versus placebo groups. In the extension phase, participants initially assigned to placebo will receive abatacept and those initially assigned to abatacept will receive placebo. This phase will allow additional important aims to be addressed.
In the extension phase, the placebo-to-abatacept group will provide the opportunity to observe an effect of abatacept on a well-established baseline rate of new lesion accumulation. If a substantial decrease is observed, this would support a clinical benefit for abatacept.
The abatacept-to-placebo group will allow us to see if the effect of abatacept is long-lasting. If the rate of lesion accumulation is initially lowered by abatacept and remains low when these participants receive placebo, this would support a tolerance-inducing effect for abatacept.