Explaining temporal trends in annualized relapse rates in placebo groups of randomized controlled trials in relapsing multiple sclerosis: systematic review and meta-regression

TL;DR

This systematic review and meta-regression analyze how baseline characteristics and trial design factors influence the observed decline in placebo group relapse rates in multiple sclerosis trials over time.

Contribution

It identifies key factors such as pre-trial ARR and patient demographics that explain the decreasing relapse rates in placebo groups across recent trials.

Findings

Pre-trial ARR decreased over time.

Patient age and MS duration increased over time.

Major factors explaining ARR variation include pre-trial ARR and study duration.

Abstract

Background: Recent studies have shown a decrease in annualised relapse rates (ARRs) in placebo groups of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS). Methods: We conducted a systematic literature search of RCTs in RMS. Data on eligibility criteria and baseline characteristics were extracted and tested for significant trends over time. A meta-regression was conducted to estimate their contribution to the decrease of trial ARRs over time. Results: We identified 56 studies. Patient age at baseline (p < 0.001), mean duration of multiple sclerosis (MS) at baseline (p = 0.048), size of treatment groups (p = 0.003), Oxford Quality Scale scores (p = 0.021), and the number of eligibility criteria (p<0.001) increased significantly, whereas pre-trial ARR (p = 0.001), the time span over which pre-trial ARR was calculated (p < 0.001), and the duration of placebo-controlled follow-up (p = 0.006) decreased significantly over time. In meta-regression of trial placebo ARR, the temporal trend was found to be insignificant, with major factors explaining the variation: pre-trial ARR, the number of years used to calculate pre-trial ARR and study duration. Conclusion: The observed decline in trial ARRs may result from decreasing pre-trial ARRs and a shorter time period over which pre-trial ARRs were calculated. Increasing patient age and duration of illness may also contribute.