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Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients

Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, Cleveland, OH, USA, rudickr{at}ccf.org

G R Cutter

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

M Baier

Center for Research Methods and Biometry, Cooper Institute, Denver, CO, USA

B Weinstock-Guttman

Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA

M K Mass

Department of Neurology, Oregon Health Sciences University, Portland, OR, USA

E Fisher

Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, OH, USA

D M Miller

Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, Cleveland, OH, USA

A W Sandrock

Biogen Idec, Cambridge, MA, USA

Two methods were used to estimate the long-term impact of disease-modifying drug therapy (DMDT) in patients with relapsing multiple sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of interferon beta-1a (IFNß-1a). The study cohort consisted of patients with ambulatory relapsing MS who had previously participated in a placebo-controlled clinical trial for two years. At its end, patients were managed in an unstructured fashion by their neurologists and re-evaluated at an average of 6.1 years after the end of the trial. Follow-up evaluation was obtained for 93% of the 172 eligible patients. Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of 3.5 at entry, disability progression at follow-up was defined as EDSS6.0. Two methods were used to estimate the expected proportions that reached EDSS6.0 at follow-up. Estimates were compared with observed proportions. Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period. Method 2 used progression rates from a natural history comparison group of relapsing-remitting MS patients. At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFNß-1a patients reached an EDSS 6.0, an observed treatment effect of approximately 30%. Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFNß-1a patients should have reached an EDSS 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes. Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFNß-1a group. Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome. The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.

Key Words: disease-modifying drug therapy • interferon beta • multiple sclerosis

Multiple Sclerosis, Vol. 11, No. 6, 626-634 (2005)
DOI: 10.1191/1352458505ms1203oa


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