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

Abstract

The increasing amount of highly effective treatment options in relapsing forms of multiple sclerosis (MS) requires innovative clinical trial design strategies. These strategies may encompass the application of adaptive designs as well as the adoption of innovative primary outcome measurements. The offered advantages would include, among others, shorter study follow-up periods and reduction in the number of patients either on placebo or on non-suitable dosages of the small molecules or biological products under examination. Changing the primary endpoint during the study conduct additionally represents an option, when the primary endpoint originally is either a composite endpoint of Magnetic Resonance Imaging (MRI) and clinical variables or a unitary endpoint of clinical variables. The new outcome measurement of no-evidence-of-disease activity (NEDA) -the former disease activity free (DAF) status, might represent an attractive approach and NEDA may become a new standard for clinical trials in relapsing MS (RMS), particularly for pivotal Phase III trials, though also earlier phase trials and exploratory clinical research might benefit from this endpoint. Future studies in RMS could incorporate NEDA as a primary endpoint and utilize the adaptive design methodology in order to reduce the sample size and the duration of new therapeutic agents' clinical development.

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a

“…[10][11][12][13] NEDA may provide a more sensitive and comprehensive measure of capturing overall treatment benefit and has been proposed as a primary endpoint in future pivotal Phase III clinical studies. 14,15 NEDA is increasingly recognized as an important treatment goal for patients with RMS 16 and has been shown to be informative in the prediction of long-term disability progression both independent of DMT type 17 (cohort study) and in the core and extension periods of clinical trial patient populations. 18 As a binary outcome, NEDA status and its failure are often driven by MRI components of the measure and hence are particularly influenced by the frequency of MRI assessments.…”