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

Abstract

Objective: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. Methods: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1-(entry expanded disability status scale, 3.0 -5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. Results: There was a nonsignificant delay in time to sustained accumulated disability in GA-versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p ϭ 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p ϭ 0.0193). Interpretation:The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated.

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

“…Based on previous evidence that sex may influence the rate of progression in PPMS,2 an additional exploratory subgroup analysis of NEPAD by sex was also conducted. NEP and NEPAD data are presented using a Venn diagram surface‐proportional representation.…”

“…Preventing progression is an essential treatment goal in PPMS, a goal that drugs tested in previous clinical studies failed to achieve 2, 3, 4. Ascertaining the absence of progression in both clinical trials and clinical practice requires reliable and comprehensive measures of disease progression.…”

Interferon Beta and Glatiramer Acetate Therapy

“…To study the effects of GA on PPMS, the 3 year PROMISE trial was initiated [91]. This randomized, double-blind, placebo controlled study enrolled participants ages 30 to 65 with baseline EDSS scores of 3-6.5 inclusive.…”

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

“…Moreover, it may be the case that each of these categories is actually heterogeneous, with mild clinical or subclinical relapses not being adequately recognized. 1,[12][13][14] Despite these limitations, the Lublin-Reingold classification has facilitated patient selection for enrollment in clinical trials and determination of which patients may be most likely to respond to approved drugs.…”

“…34 Gray matter lesion conspicuity is increased with DIR techniques as well as with ultraMoreover, it is likely that an inflammatory component of disease is present either always or at some time in all stages of MS. [20][21][22][23][24] Indeed, Gd+ lesions, which indicate both an abnormality in blood-brain barrier (BBB) and central nervous system (CNS) inflammation, can occur not only in RRMS but in all Lublin-Reingold forms of MS, including in 14.1% to 42% of patients with PPMS. [12][13][14] Pathologically inflammatory CNS lesions have also been described in all forms of MS, with or without the presence of Gd+ lesions, although the distribution of inflammatory lesions can vary in location or intensity in different forms of the disease. [20][21][22][23][24] When sensitive and frequent MRI studies are performed, Gd+ and unequivocally new or enlarging T2 brain lesions (subclinical relapses) can occur much more commonly than clinical symptoms (relapses or progression).…”