Brain Volume Change By Quartile and Disability Progression in Multiple Sclerosis: A 4-Year Analysis of the Phase 3 Freedoms Trial and Its Extension

Background: Brain volume loss (BVL) is a feature of multiple sclerosis (MS), reflecting diffuse and focal neurological damage. Studies have shown significant correlations between BVL and disability progression in MS.

Objectives: To investigate whether the extent of BVL at month 24 associates with, and is prognostic of, disability progression over 48 months in the phase 3 FREEDOMS trial and its extension.

Methods: Patients (n = 1029) were categorized post hoc from baseline (BL) to month 24 (M24) by quartile of total percentage BV change (PBVC), assessed using 'Structural Image Evaluation, using Normalization, of Atrophy' (SIENA), and mean annualized PBVC from BL to M24 was determined in each quartile. Patient characteristics at BL were also determined in each quartile, as were the proportions of patients at M24 and at M48 with: Expanded Disability Status Scale (EDSS) score ≥ 4.0 or ≥ 6.0 at any time and disability progression (an increase in EDSS score of ≥ 1.0 if BL EDSS ≤ 5.0, or of 0.5 if BL EDSS ≥ 5.5) confirmed over 3 months (CDP3) or over 6 months (CDP6). Mean change in EDSS score was also calculated from BL to either M24 or M48.

Results: Quartile ranges of PBVC at M24 were: Q1 (n = 256), −13.5% to −1.7%; Q2 (n = 254), −1.7% to −0.8%; Q3 (n = 257), −0.8% to −0.2%; and Q4 (n = 262), −0.2% to 3.0%. Respective mean (standard deviation [SD]) annualized PBVC (BL-M24) was −1.5% (0.7%), −0.6% (0.1%), −0.2% (0.1%) and 0.2% (0.3%). Comparing Q1 and Q4 at BL, there were proportionately more women (74.6% vs 68.7%), mean (SD) EDSS was greater (2.7 [1.3] vs 2.1 [1.2]), as were T2 lesion volume (11.3 [10.2] cm³ vs 3.3 [4.4] cm³), T1 hypointense lesion volume (3.6 [4.2] cm³ vs 1.0 [1.9] cm³) and number of Gd+ lesions (3.1 [5.6] vs 0.6 [1.3]). The respective proportions of patients in Q1 and Q4: with EDSS ≥ 4.0 were (M24) 30.3% and 11.4%, and (M48) 35.8% and 13.8%; with EDSS ≥ 6.0 were (M24) 14.8% and 1.1%, and (M48) 19.2% and 3.1%; with CDP3 were (M24) 22.7% and 13.4%, and (M48) 28.8% and 17.9%; and with CDP6 were (M24) 19.1% and 10.7%, and (M48) 24.2% and 15.4%. Respective mean (SD) changes in EDSS scores in Q1 and Q4 were 0.1 (1.1) and −0.1 (0.8) for BL-M24, and 0.2 (1.2) and 0.0 (0.9) for BL-M48.

Conclusions: The quartile of patients with greatest BVL at 24 months (Q1) had the greatest disease activity and severity at BL, and the most disability progression at both 24 and 48 months. This suggests that 24-month BVL is associated with long-term disability evolution.