Reduction in grey matter atrophy in patients with relapsing multiple sclerosis following treatment with cladribine tablets

Abstract

Background and purpose: Measures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study.

Methods: We analysed T1-weighted magnetic resonance sequences using SIENA-XL, from 0 to 6 months (cladribine, n = 267; placebo, n = 265) and 6 to 24 months (cladribine, n = 184; placebo, n = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed-effect model.

Results: More GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: -0.53 vs. placebo: -0.25 [p = 0.045]; PWMVC: cladribine: -0.49 vs. placebo: -0.34 [p = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: -0.90 vs. placebo: -1.27 [p = 0.026]). In this period, volume changes in WM were similar in the two treatment arms (p = 0.52).

Conclusions: After a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.

Keywords: brain atrophy; cladribine tablets; grey matter; multiple sclerosis; white matter.

FIGURE 1

Example of brain extracted three‐dimensional T1‐weighted images (top row) and the segmentation map (bottom row) of the grey matter (GM; green) and white matter (WM; blue) of a patient at each time point (0, 6,12 and 24 months). The figure shows an example of axial T1‐weighted image quality of a patient on placebo and the segmentation maps of the GM and WM at each time point.

FIGURE 2

Flow diagram describing patient selection for the MRI analysis. Number of patients and the percentage of the cohort available for the analysis in the previous time interval are shown. Abbreviations: CT, cladribine tablets; GM, grey matter; M, Month; WM, white matter

FIGURE 3

Pseudoatrophy analysis, 0–6 months, from 267 patients treated with cladribine 3.5 mg/kg and 265 patients treated with placebo. Pseudoatrophy was present both in grey matter (GM) and white matter (WM) during the first 6 months of therapy, with a significant difference in percentage volume change between cladribine and placebo for GM only. The ∆% change in the treated group and the standard errors are indicated in the figure. Abbreviations: CladT3.5, cladribine tablets 3.5 mg/kg; PVC, percentage volume change

FIGURE 4

Atrophy analysis, 6–24 months, from 184 patients treated with cladribine 3.5 mg/kg and 186 patients treated with placebo. Brain volume loss from 6 to 24 months was reduced in patients treated with cladribine tablets 3.5 mg/kg body weight, with a significant difference in percentage volume change between cladribine and placebo for grey matter (GM) only. The ∆% change in the treated group and the standard errors are indicated in the figure. Abbreviations: CladT3.5, cladribine tablets 3.5 mg/kg; PVC, percentage volume change; WM, white matter