Time-patterns of annualized relapse rates in randomized placebo-controlled clinical trials in relapsing multiple sclerosis: A systematic review and meta-analysis

Background: Although it is known that the annualized relapse rate (ARR) in patients with multiple sclerosis (MS) changes as disease progresses, in the design and analysis of trials in relapsing multiple sclerosis (RMS) constant ARRs are assumed. Objectives: This paper aims to assess time-patterns of trial ARR by conducting a systematic review of randomized, placebo-controlled trials in RMS. Methods: A systematic literature search was conducted by searching PubMed for randomized, placebo-controlled trials in RMS. In meta-analyses the following comparisons of trial ARR were carried out for the placebo controls and active treatment arms: months 1-6 vs. months 7-12, and months 1-12 vs. months 13-24. Results: A total of 52 trials was identified. Out of these, information on the time-dependence of trial ARR could be extracted from 13 trials. The ARR was by 25% (p = 0.0005) and 40% (p < 0.0001) higher in months 1-12 compared with months 13-24 for placebo and active treatments, respectively. Consequently, the treatment effects were by 13% (p = 0.23) larger in the second year compared with the first year. Within the first year of follow-up the ARR was by 4% (p = 0.75) and 23% (p = 0.06) higher in months 1-6 compared with months 7-12 for placebo controls and active arms, respectively. Conclusions: Trial ARR decreases during a trial in RMS, which is in line with epidemiological findings and has implications for design and analysis of future trials. The observed decrease in trial ARR might be at least partially explained by regression to the mean. Individual patient data analyses are warranted.