Regression to the Mean and Predictors of MRI Disease Activity in RRMS Placebo Cohorts - Is There a Place for Baseline-to-Treatment Studies in MS?

Abstract

Background Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials. Objectives To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts. Methods 21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression. Results The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95% CI: 0.87-1.51) and 2 years (1.19, 95% CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95% CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months. Conclusion Baseline GD-enhancing lesions predict evolution of Gd-and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+ lesions per scan within 6 months.