United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates

Abstract

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2,433 +/- 59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

Unified Approach for Multiple Sclerosis Lesion Segmentation on Brain MRI

“…MRIdetermined lesion burden is used as a secondary outcome measure in a number of multicenter clinical trials on MS. 18 , 12 Accurate tissue segmentation is a prerequisite for robust estimation of lesion volumes. Independent of the segmentation technique used, various factors such as noise, intensity inhomogeneities, and partial volume effects introduce false tissue classifications.…”

The heritage of glatiramer acetate and its use in multiple sclerosis

“…Long-term and real-word data Even with all the limitations of long-term extension studies, due to potential selection bias, available data suggest that the efficacy of GA is maintained over time [63][64][65][66][67][68][69][70][71]. Moreover, there have been no reports of rebound effect or delayed disease reactivation after treatment discontinuation in extensions of clinical trials or postmarketing studies [63,70,72,73].…”

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double‐blind, placebo‐controlled trial

“…16,17 However, during patient enrollment, the image analysis program underwent an upgrade to incorporate several revisions in the image analysis strategy and segmentation algorithms. The results using the new segmentation program were strongly correlated with those of the original segmentation system, and all results reported here are from an analysis of the entire image data set with the advanced image analysis package.…”