Trends in annualized relapse rates in relapsing–remitting multiple sclerosis and consequences for clinical trial design

Abstract

Our investigations confirmed previously reported trends in ARR. In this context adaptive strategies such as BSSR designs are recommended for consideration in the planning of future trials in RRMS.

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

“…According to our meta-regression the temporal trend observed by Inusah et al [5] and Nicholas et al [6] becomes relatively insignificant and other changes explain about 60% of the variation in the trial ARR. Similar analyses, aiming at modelling the pre-trial ARR, or excluding the pre-trial ARR from the set of predictors, yield comparable R² values using different sets of explanatory variables with age, number of eligibility criteria and number of patients being among the influential variables in addition.…”

“…This trend is unexplained but has implications for inter-trial comparability of ARRs [6]. This is particularly important as more therapies are licensed in the absence of head-to-head data.…”

“…In these cases, pre-trial ARRs of the same groups calculated over different time periods were compared. When inclusion criteria appeared in a complex context, allowing 6 alternative options to qualify in one measure or mutually exclusive options of different measures, items were omitted.…”

“…The development of therapies that have successfully targeted relapses has meant that relapse focused outcome measures are common in RMS trials -of particular importance is the annualized relapse rate (ARR) [3,4]. Recently, a downward trend in trial ARRs of placebo patients has been identified in randomized controlled trials (RCTs) [5,6].…”

Evolving landscapes in multiple sclerosis research: adaptive designs and novel endpoints

“…Since this time, patients have developed an increasingly sophisticated and accurate understanding of MS [2]. Additionally, the increasing number of clinical trials has allowed investigators to observe changes in terms of characteristics and behaviors of clinical trial populations in RMS [3,4]. In particular, patient populations in recent studies are characterized by a lower clinical disease activity level at the time of entry into clinical trials in comparison to the past.…”