Validity of area-under-the-curve analysis to summarize effect in rheumatoid arthritis clinical trials

There is a continuing interest in increasing the statistical efficiency of the analysis of clinically meaningful endpoints in rheumatology. One issue that is attracting increasing attention is whether the conventional practic e of only reporting the outcome at the end of the study (EOS) might be repl aced or complemented by a longitudinal summary that better reflects the cli nical course of the disease. The area under the curve (AUC) is a summary me asure that integrates serial assessments of a patient's endpoint over the d uration of the study. We evaluated the utility of AUC as a summary measure for the analysis and reporting of two RA trials: (i) methotrexate combined with cyclosporine versus methotrexate and placebo in partial methotrexate r esponders in relatively late disease, and (ii) prednisone plus methotrexate plus sulfasalazine versus sulfasalazine alone in relatively early disease. We replicated the published results of each trial first using the conventi onal EOS and then AUC summaries. For each patient, the changes from baselin e over time were transformed into a summary measure by calculating AUC usin g the trapezium rule and then standardizing it by the study duration. Using an approach similar to the index of responsiveness to change, we scaled tr eatment differences derived from EOS and AUC summary measures by their stan dard deviation of the control group. This signal-versus-noise ratio capture s the treatment discrimination ability of each summary measure. Compared to EOS and within each treatment group, the AUC summary reported smaller effe cts (i.e., change from baseline) with reduced errors in the estimates. AUC measures preserved discriminant validity in treatment comparisons and repor ted smaller but more precise treatment effect estimates. In the COBRA trial with rapidly-acting medications, AUC seemed to be more sensitive than EOS to detect treatment difference. With slow acting medications and in relativ ely late disease patients as in the cyclosporine trial, EOS was more sensit ive to detect treatment difference than mas AUG. In this setting, AUG, howe ver, still seemed to be more sensitive than EOS for the two responsive-to-c hange endpoints: tender joint counts and pain by visual analog scale. AUC i ntegrates repeated assessments during the trial duration into summary measu res. Compared to EOS, the report of RA trial results using AUC summary prov ides smaller estimates of treatment effects but with better precision. AUC summary is likely to preserve treatment group discrimination taking into ac count the appropriate onset and offset of the drug action. Trial reports us ing AUC summary have smaller effect sizes. Far trials with long acting medi cations and short duration similar to the cyclosporine trial, AUC still pre serves treatment discrimination but may not be as sensitive as EOS. The cal culations of AUC require some additional work in the analysis of each endpo int.