EARLY IFNB-1a and Simvastatin Combination Therapy in Clinically Isolated Syndrome Suggestive of Multiple Sclerosis
The purpose of this study is to determine the safety, tolerability and efficacy of a combination therapy interferon beta-1a(Avonex) plus simvastatin (Zocor) vs. interferon beta-1a plus placebo in patients with clinically isolated syndrome suggestive of Multiple Sclerosis.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
|Official Title:||Phase IV Double-Blind Randomized Study to Evaluate Safety and Efficacy of Interferon Beta-1a (Avonex) Plus Simvastatin (Zocor) Combination Therapy in Clinically Isolated Syndrome Suggestive of Multiple Sclerosis Over a One Year Period|
- The primary objective of this study is to determine whether combination therapy with IFNb-1a plus simvastatin, when compared to IFNb-1a plus placebo decreases or delays additional clinical or MRI activity.
- We will use the following outcome measures:
- Relapse rates, Time to first relapse,Number of new T2 lesions, Number of new Gd-enhancing lesions
|Study Start Date:||September 2004|
|Study Completion Date:||December 2007|
|Primary Completion Date:||December 2007 (Final data collection date for primary outcome measure)|
Interferon beta-1a (IFNB-1a), a FDA approved therapy for relapsing-remitting (RR) MS has several mechanisms of action. It lowers proinflammatory cytokine production and inhibits antigen presentation by class II major histocompatibility complex (MHC) molecule. It also reduces metalloproteinase activity, which all lead to decreased migration of T-lymphocytes into the central nervous system (CNS), and subsequent inhibition of inflammatory lesion formation. We propose that combination therapy during early stages of the disease with second immunomodulatory agent that targets different steps in the pathogenesis of the disease may add to the effectiveness of IFNB-1a. IFNB-1a administered intramuscularly at 30 mg per week is particularly suitable for combination therapy due to its proven efficacy in Clinically Isolated Syndrome (CIS),favorable safety profile and low frequency of neutralizing antibodies (NABs) against IFNB-1a in comparison to other forms of IFNB-1a. Recent studies have reported a significant anti-inflammatory and neuroprotective effects of statins, cholesterol-lowering agents. Statins disrupt cellular membrane lipid rafts, which inhibit the clustering of T-cell receptor (TCR), co-stimulatory, and adhesion molecules, required for optimal T-cell activation. Along with inhibiting T-cell activation, statins decrease IFNB inducible MHC class II expression, suppressing an effective antigen presentation. They block migration of activated mononuclear cells from peripheral circulation into the CNS by blocking LFA-1 adhesion molecule and by reducing metalloproteinase type 9 secretion. While their anti-inflammatory effects at tolerable oral doses may not justify their use as monotherapy for RR MS, their pleiotropic mechanisms of action showed synergistic effects with IFNB-1a in studies in vitro. We propose that simvastatin may enhance the immunomodulatory effects of INFB-1a in patients with CIS suggestive of MS and that this combination may even more effectively prevent further disease activity if administered early in the course of the disease.
|United States, North Carolina|
|University of North Carolina-Chapel Hill MS clinic within the Neuroscience Hospital|
|Chapel Hill, North Carolina, United States, 27599|
|Principal Investigator:||Silva Markovic-Plese||University of North Carolina, Chapel Hill|