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Treatment of Primary Progressive Multiple Sclerosis

Glatiramer acetate did not have a statistically significant benefit in a study with a high dropout rate.

Wolinsky and colleagues exhaustively assessed whether glatiramer acetate (GA) can delay progression in primary progressive multiple sclerosis (PPMS). This multicenter, international, and multifaceted double-blind trial was designed to last 3 years. Clinical, laboratory, and statistical assessments were extremely thorough. Patients were classified into two strata according to Expanded Disability Scale (EDSS) score, but all post-entry data are given for the EDSS-score strata combined. There were 627 patients randomized to receive GA and 316 to receive placebo (PBO).

The second planned interim analysis of the data safety monitoring board indicated both that disease progression was much slower than expected and that the groups did not differ in the primary outcome measure. At that time, only 35 GA and 18 PBO recipients had completed 3 years of treatment, and 188 GA and 98 PBO recipients had dropped out. For the remaining 404 GA and 200 PBO recipients, the study sponsor (the drug’s manufacturer) halted the study at that point and offered "natural history" follow-up.

The intention-to-treat hazard ratio for confirmed progression in the planned 3-year study was 0.87, suggesting a drug effect, but was not significant. A post hoc analysis showed a significant effect for males (HR, 0.71) but not females (HR, 1.08). Numbers contributing to the "survival curves" for time to confirmed disease progression were 465 GA and 239 PBO recipients at 12 months; 355 GA and 175 PBO recipients at 24 months; and 68 GA and 30 PBO recipients at 36 months.

Comment: Why did this study — conducted by the most knowledgeable and experienced MS investigators extant, with a protocol that was a model for emulation — fail to meet its goal? I was struck by the large proportions of dropouts, particularly in the third year. I wonder whether the only contact with these patients after their initial assessment was during their trimonthly trek to receive the new drug packets along with their reassessments. Who took care of them in the interim? Was their total illness managed by the study centers with physiotherapy, counseling, or other treatments on a regular, ongoing basis?

I have been told that lack of proof is not proof of lack; "truth" lies in more than P<0.05, and we still must treat our patients today as best we can. I think the authors do have evidence to suggest efficacy at the 2-year point. Statistical testing for the hazard ratio up to that point might have indicated significance because dropouts were not then numerous, but the study design precluded such testing. However, the authors could have performed a post hoc analysis of the 2-year data, just as they had analyzed effects by sex — though I would not limit use of glatiramer acetate by sex. Barring anything better, this seems to me a reasonable treatment for patients with worsening PPMS, but not (yet) for those with stable illness.

— John F. Kurtzke, MD, FACP, FAAN

Dr. Kurtzke is Professor Emeritus of Neurology, Georgetown University, Washington, DC.

Published in Journal Watch Neurology May 1, 2007

Citation(s):

Wolinsky JS et al. Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007 Jan; 61:14-24.

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