Randomised double blind placebo controlled study of interferonβ-1a in relapsing-remitting multiple sclerosis analysed by area underdisability/time curves

摘要

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 trialcompletion. Analyses were also carried out on subgroups with entry EDSSstratified above and below 3.5.
RESULTS—EDSSdata analysed by AUC normalised to baseline scores disclosed that bothdoses 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 morebeneficial than placebo using SNRS (p= 0.038) and AI data (p= 0.039).AUC analysis of SNRS scores also showed that for patients with baselineEDSS>3.5, the 44 µg (but not the 22 µg) dose was more advantageousthan placebo (p=0.028).
CONCLUSIONS—Summarymeasure analysis using the AUC of serial disability/time plots,confirms and extends the results of conventional end point analysis ofdisability from the PRISMS Study data. AUC evaluations show that highdose INFβ-1a (44 µg three times weekly) was beneficial on all ofthe clinical rating scale scores used in this study. This methodprovides a statistically powerful and clinically meaningful assessmentof treatment effects on in trial disability in patients with multiplesclerosis with fluctuating and highly heterogeneous disease courses.