"Summary measure" statistic for assessing the outcome of treatment trials in relapsing-remitting multiple sclerosis

Abstract

Objectives-To review the outcome measures commonly used in phase III treatment trials of relapsing-remitting multiple sclerosis and to introduce a method of data analysis which is clinically appropriate for the often reversible disability in this type of multiple sclerosis. Methods-The conventional end point measures for disability change are inadequate and potentially misleading. Those using the disability diVerence between study entry and completion do not take into account serial data or disease fluctuations. Rigid definitions of "disease progression" based on two measurements of change in disability several months apart, do not assess worsening after the defined "end point", nor the significant proportion of erroneous "treatment failures" which result from subsequent recovery from relapses that outlast the end point. Assessing attacks merely by counting their frequency ignores the variation in magnitude and duration. These problems can be largely circumvented by integrating the area under a disability-time curve (AUC), a technique which utilises all serial measurements at scheduled visits and during relapses to summarise the total neurological dysfunction experienced by an individual patient on any particular clinical scale during a study period. Conclusions-The "summary measure" statistic AUC incorporates both transient and progressive disability into an overall estimate of the dysfunction that was experienced by a patient during a period of time. It is statistically more powerful and clinically more meaningful than conventional methods of assessing disability changes, particularly for trials which are too short to expect to disclose major treatment eVects on irreversible disability in patients with a fluctuating disease. (J Neurol Neurosurg Psychiatry 1998;64:726-729)

Randomised, double blind, placebo controlled study of interferon beta -1a in relapsing-remitting multiple sclerosis analysed by area under disability/time curves

“…Whereas it is generally agreed that the primary outcome in phase III immunomodulatory trials in relapsing-remitting multiple sclerosis must be clinical,17 commonly employed end points associated with both disability and relapse assessment can be difficult to define and interpret 816 Meaningful clinical milestones, such as the conversion to secondary progression,18 19 are not realistic end points for relapsing-remitting multiple sclerosis cohorts within relatively short study periods of 2 to 3 years.…”

“…One method of analysis that indexes all in trial morbidity changes is the area under the disability/time curve (AUC) 8. This technique is appropriate for the mainly transient disability experienced early in the disease course in relapsing-remitting multiple sclerosis and should be more responsive to change as it utilises all the collected serial data.…”

The Neurotoxic Effect of Cuprizone on Oligodendrocytes Depends on the Presence of Pro-inflammatory Cytokines Secreted by Microglia

“…In the CNS, microglia and astrocytes are the main producers of TNFa. Conflicting results have indicated either an exacerbating or an ameliorating role of TNFa during experimentally induced brain trauma [10] and in a murine model of multiple sclerosis [11,12].…”

Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis

“…3,7 Thus, four disease categories were identified to classify the cohort into approximate quartiles of increasingly preferred disease courses:…”