Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts

Abstract

Objectives-Recent phase III clinical trials of immunomodulatory therapies in relapsing-remitting multiple sclerosis have shown significant benefits of active treatment on relapse related end points, but eVects on disability outcomes have been inconsistent. These apparent discrepancies could be due to diVerences in the clinical end points employed, the behaviour of placebo cohorts, or both. Methods-Disability data from the placebo cohorts of two large phase III studies, the United States glatiramer acetate trial (Copolymer 1 Multiple Sclerosis Study Group) and the multinational interferon -1a trial (PRISMS Study Group) were combined and masked (n=313). Two groups of disability outcome measures were assessed. Firstly, measures of disability change (2 year EDSS diVerence and area under the EDSS/time curve, AUC) were calculated. Secondly, conventional disease progression end points ("confirmed progression" and "worsening to EDSS 6.0") were evaluated by using Kaplan-Meier analysis and compared with a categorical classification based on EDSS trends. Results-The average increase in disability for the entire cohort as assessed by mean 2 year EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was small. For the "confirmed progression" end points, increasing the stringency of the definition lowered their incidence (from 32% with 1.0 point at 3 months, to 9% with 2.0 points at 6 months), but did not improve the positive predictive accuracy for "sustained progression" maintained to the end of the study. The error rate for this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable end point, but had even lower sensitivity (incidence <10%). EDSS trend analysis showed markedly heterogeneous disease courses, which were then categorised into "stable" (26%), "relapsing-remitting" (59%), and "progressive" (15%) courses. Patients with the last course had deteriorated considerably by the end of 2 years (mean worsening of 2.0 EDSS points). Conclusion-In relapsing-remitting multiple sclerosis treatment trials, the conventional measure of mean EDSS change has low sensitivity, whereas the widely applied confirmed progression end points have high error rates regardless of their definition stringency. Alternative methods with better data utilisation include AUC summary measures and categorical disease trend analysis. The heterogeneity of disability outcomes in short trials, combined with unreliable clinical end points, diminishes the credibility of therapeutic claims aimed at reducing irreversible neurological deficits. The behaviour of patients treated with placebo should be carefully analysed before conclusions are drawn on the eYcacy of putative treatments. (J Neurol Neurosurg Psychiatry 2000;68:450-457)

Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis

“…The focus of research studies is often sustained progression on the EDSS, which is defined as a one point increase sustained for at least three or six months. Unfortunately, this outcome is imperfect within the lower range of the scale because patients can experience sustained progression according to this definition and still improve at later time points due to natural fluctuations or relapse-related disability [9,10]. An alternative approach is to model the EDSS scores directly, either using a proportional odds model for the EDSS scores or treating the EDSS scores as a continuous variable, which was recently employed in Brown et al [11] to determine the effect of DMT on the change in the EDSS over time.…”

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation

“…71,77 A study examining placebo groups from two large Phase III trials also noted that half of the patients satisfying criteria for 'confirmed progression' (definitions ranging from a 1.0-point EDSS increase confirmed at 3 months to a 2.0-point EDSS increase confirmed at 6 months) were erroneously diagnosed, as their EDSS scores did not sustain progression, even through the end of the trial. 78 Thus, in short-term studies, EDSS scores measured months after relapse may still be reflecting changes in active, not progressive, disease. These longer timescales for recovery from relapse may need greater recognition.…”

Outcome of beta-interferon treatment in relapsing-remitting multiple sclerosis: a Bayesian analysis

“…A significant but unavoidable problem relates to the different EDSS assessors between the IFNβ and historical control groups. This study is also limited in that it is a retrospective assessment of data collected over a period of two years; however, while retrospective assessment under-estimates relapse rates [23], it is more reliable than prospective assessment when diagnosing fixed disability [24,25]. The exclusion of patients who stopped IFNβ during the first two years of treatment introduces a selection bias.…”