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

• Published in: Multiple sclerosis Vol. 11; no. 6; pp. 626 - 634
• Main Authors: Rudick, R A, Cutter, G R, Baier, M, Weinstock-Guttman, B, Mass, M K, Fisher, E, Miller, D M, Sandrock, A W
• Format: Journal Article
• Language: English
• Published: Thousand Oaks, CA SAGE Publications 01-12-2005; Arnold; Sage Publications Ltd
• Subjects: Adjuvants, Immunologic - therapeutic use; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disability Evaluation; Disease Progression; Follow-Up Studies; Humans; Immunomodulators; Interferon beta-1a; Interferon-beta - therapeutic use; Medical sciences; Models, Statistical; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - physiopathology; Neurology; Pharmacology. Drug treatments; Randomized Controlled Trials as Topic - methods; interferon beta; disease-modifying drug therapy; multiple sclerosis; Phase III trial; Human; Evaluation; Multiple sclerosis; Nervous system diseases; Inclusion; Prognosis; Long term; Inflammatory disease; Disability; Treatment; Cohort study; Central nervous system disease; Size effect; Beta interferon; Placebo; Clinical trial; Degenerative disease; Control method; Ambulatory; Comparative study
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1191/1352458505ms1203oa

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 (IFNβ-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 EDSS≥6.0. Two methods were used to estimate the expected proportions that reached EDSS≥6.0 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 IFNβ-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 IFNβ-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 IFNβ-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.