The behavior of the control groups can substantially affect the power and outcome of a clinical trial. We report a meta-analysis of the control groups of four large, double-blind, placebo-controlled clinical trials of immuno-suppressive treatment of progressive MS to address the sensitivity of five hypothetical definitions of treatment failure (TF). The rate of TF in the aggregate control groups (n = 427) was 31% when a confirmed increase of 1.0 expanded disability status scale (EDSS) point was required at the end of the trial; it was 51% when confirmation was not required and TF was allowed at the first point where the criteria for TF were met. The rate of confirmed TF was 45% when the TF criteria were indexed to baseline EDSS, accounting for the observed differences in staying times at different EDSS levels. We developed models predicting TF in progressive MS. In addition to baseline EDSS, the pyramidal functional score and, for one definition, brainstem functional score were associated with probability of TF.