Systematic literature review and network meta-analysis in highly active relapsing–remitting multiple sclerosis and rapidly evolving severe multiple sclerosis

Abstract

ObjectiveMultiple sclerosis (MS) is a chronic, neurodegenerative autoimmune disorder affecting the central nervous system. Relapsing–remitting MS (RRMS) is the most common clinical form of MS and affects ∼85% of cases at onset. Highly active (HA) and rapidly evolving severe (RES) RRMS are 2 forms of RRMS amenable to disease-modifying therapies (DMT). This study explored the efficacy of fingolimod relative to other DMTs for the treatment of HA and RES RRMS.MethodsA systematic literature review (SLR) was conducted to identify published randomised controlled trials in HA and RES RRMS. Identified evidence was vetted, and a Bayesian network meta-analysis (NMA) was performed to evaluate the relative efficacy of fingolimod versus dimethyl fumarate (DMF) in HA RRMS and versus natalizumab in RES RRMS.ResultsFor HA RRMS, the SLR identified 2 studies with relevant patient subgroup data: 1 comparing fingolimod with placebo and the other comparing DMF with placebo. 3 studies were found for RES RRMS: 1 comparing fingolimod with placebo and 2 studies comparing natalizumab with placebo. NMA results in the HA population showed a favourable numerical trend of fingolimod versus DMF assessed for annualised relapse rate (ARR) and 3-month confirmed disability progression. For the RES population, the results identified an increase of ARR and 3-month confirmed disability progression for fingolimod versus natalizumab (not statistically significant). Sparse study data and the consequently high uncertainty around the estimates restricted our ability to demonstrate statistical significance in the studied subgroups.ConclusionsData limitations are apparent when conducting an informative indirect comparison for the HA and RES RRMS subgroups as the subgroups analyses were retrospective analyses of studies powered to indicate differences across entire study populations. Comparisons across treatments in HA or RES RRMS will be associated with high levels of uncertainty until new data are collected for these subgroups.

Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis

“…Several NMAs have been performed to compare the treatment effects of DMTs in MS (Fogarty et al, 2016;Huisman et al, 2017;Institute for Clinical and Economic Review, 2017;Tolley et al, 2015;Tramacere et al, 2015;Tsivgoulis et al, 2015;Siddiqui et al, 2017;Melendez-Torres et al, 2017). Most recently in November 2017, Siddiqui et al compared efficacy across five outcomes: ARR, 12-week CDP, 24-week CDP, proportion relapse-free, no evidence of disease activity (NEDA) and a single combined safety outcome (any AEs) (Siddiqui et al, 2017).…”

“…In the absence of such a trial, network meta-analyses (NMAs) can be used to compare treatments using both direct comparisons of interventions within clinical trials and indirect comparisons based on a common comparator, often placebo (Li et al, 2011). Several such NMAs have compared the different DMTs for RMS (Fogarty et al, 2016;Huisman et al, 2017;Institute for Clinical and Economic Review, 2017;Tolley et al, 2015;Tramacere et al, 2015;Tsivgoulis et al, 2015;Siddiqui et al, 2017;Melendez-Torres et al, 2017). However, these NMAs have used differing methodologies, have not used all available data by combining hazard ratio and count data, (Watkins, 2018) and did not consider the trade-off between efficacy and safety with surface under the cumulative ranking curve (SUCRA) values.…”

Overview of Differences and Similarities of Published Mixed Treatment Comparisons on Pharmaceutical Interventions for Multiple Sclerosis

“…These six studies did not provide subgroup analyses of patients with RRMS only. Two MTCs [23,24] focused on RES and highly active RRMS, while two [25,26] focused on RRMS, with the stipulation that the population in the included trials must be at least 80% patients with RRMS. The CADTH 2013 [27] study also focused on trials in patients with RRMS but specified that the population should be more than 50% RRMS.…”

Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing–remitting multiple sclerosis

“…Whilst these studies provide valuable insight into the use of DMTs in RRMS, alone they fail to address the question of the relative efficacy and safety of different DMTs. With the lack of head-to-head trials between DMTs, indirect comparisons and network meta-analyses (NMAs) have been performed to bridge this evidence gap and help inform clinical decision making [4][5][6][7] . Over time, these analyses require updating as new evidence emerges, new treatment options gain approval and new outcome measures gain relevance.…”

“…The trials also differed in terms of study characteristics (diagnostic criteria, study phase and blinding), the patient populations recruited (mean relapses in prior year, disease duration, treatment historypreviously treated versus treatment naïve) and definitions of outcomes. The NMA for patients with HRA þ DAT is also limited by variations in the definition of HRA þ DAT across studies, a lack of subgroup-specific baseline characteristic data to assess potential for effect modifiers and uncertainty surrounding effect sizes, as highlighted in Huisman et al 7 .…”