Brain volume loss in relapsing multiple sclerosis: indirect treatment comparisons of available disease-modifying therapies

Abstract

Background: Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials.

Methods: In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA).

Results: In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 - 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 - 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 - 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 - 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 - 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA.

Conclusions: Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL.

Keywords: Brain volume loss; Disease modifying therapy; Magnetic resonance imaging; Model-based meta-analysis; Multiple sclerosis; Network meta-analysis; Systematic literature review.

Fig. 1

Evidence network for ITCs of BVL^{a a}Treatment nodes are sized proportionally to sample sizes, and connections between treatment nodes are indicated with line thickness proportional to the number of trials informing the connection. All connections were incorporated in the MBMA analysis, whereas only the nodes and trials shown in boldface were included in the NMA (since DMT dosages that were not of interest were excluded from the NMA) Abbreviations: 24W = every 24 weeks, 2W = every two weeks, 4W = every four weeks, ALE = alemtuzumab, BID = twice daily, BVL = brain volume loss, CI = confidence interval, DMF = dimethyl fumarate, FIN = fingolimod, GA = glatiramer acetate, IFNβ = interferon β, NAT = natalizumab, OFA = ofatumumab, OZA = ozanimod, PBO = placebo, PEG = peginterferon β-1a, PON = ponesimod, Q2W = every two weeks, QD = once daily, QOD = every other day, QW = once weekly, TER = teriflunomide, TID = three times daily

Fig. 2

MBMA (A) and NMA (B) results for differences in brain volume loss at two years, versus placebo^{a a}MBMA and NMA used fixed effect models. Measurement timepoint and dosage were covariates in the MBMA. Round parentheses indicate the probability of being better than placebo. Peginterferon could not be incorporated in the NMA due to a lack of eligible BVL data reported at two years Abbreviations: 24W = every 24 weeks, 2W = every two weeks, 4W = every four weeks, ALE = alemtuzumab, BID = twice daily, BVL = brain volume loss, CI = confidence interval, DMF = dimethyl fumarate, FIN = fingolimod, GA = glatiramer acetate, IFNβ = interferon β, NAT = natalizumab, OFA = ofatumumab, OZA = ozanimod, PEG = peginterferon β-1a, PON = ponesimod, Q2W = every two weeks, QD = once daily, QOD = every other day, QW = once weekly, TER = teriflunomide