Abstract

OBJECTIVES The commonly employed outcome measures on disability and relapse rates in treatment trials of relapsing-remitting multiple sclerosis have well demonstrated sensitivity to treatment effects, but their clinical interpretation is problematic. An alternative method of analysis, which is more clinically meaningful and statistically appropriate to a condition with a fluctuating disease course, uses the summary measure statistic “area under the disability/time curve (AUC)”, to estimate each patient’s total in trial morbidity experience.

METHODS The AUC technique was applied in an intention to treat analysis of serial disability data derived from the expanded disability status scale (EDSS), the Scripps neurologic rating scale (SNRS), and the ambulation index (AI), collected during a double blind, randomised, placebo controlled, phase III trial of subcutaneous interferon β-1a (INFβ-1a) in relapsing-remitting multiple sclerosis (PRISMS Study). The results were compared with the often quoted “conventional” end point of mean change in rating scores from baseline to trial completion. Analyses were also carried out on subgroups with entry EDSS stratified above and below 3.5.

RESULTS EDSS data analysed by AUC normalised to baseline scores disclosed that both doses of IFNβ-1a (22 or 44 μg) were superior to placebo (p= 0.008 and 0.013, respectively). In addition, the high dose (44 μg) was more beneficial than placebo using SNRS (p= 0.038) and AI data (p= 0.039). AUC analysis of SNRS scores also showed that for patients with baseline EDSS>3.5, the 44 μg (but not the 22 μg) dose was more advantageous than placebo (p=0.028).

CONCLUSIONS Summary measure analysis using the AUC of serial disability/time plots, confirms and extends the results of conventional end point analysis of disability from the PRISMS Study data. AUC evaluations show that high dose INFβ-1a (44 μg three times weekly) was beneficial on all of the clinical rating scale scores used in this study. This method provides a statistically powerful and clinically meaningful assessment of treatment effects on in trial disability in patients with multiple sclerosis with fluctuating and highly heterogeneous disease courses.