Brain Atrophy as an Outcome of Disease-Modifying Therapy for Remitting-Relapsing Multiple Sclerosis

Table 1

Brain atrophy outcome data.

Intervention clinical trial	BVL timeframe	Percentage change of brain volume	Disability effect timeframe	Effect on disability
CARE MS I [36]; Group 1, alemtuzumab; Group 2, IFN-β-1a s.c	At wk 48 (y1); At wk 96 (y2)	Significant reduction in median change in BPF -0.867 in the alemtuzumab group vs. -1.488 in the IFN-β-1a group ().	wk 96 (y2)	30% reduction of risk of 6-month CDA, the effect on sustained 6-month disability accumulation and change in EDSS was not significant. Significant improvement in MSFC score, mean change 0.15 in alemtuzumab group vs. 0.07 in IFN-β-1a ().
CARE MS II [34]; Group 1, alemtuzumab; Group 2, IFN-β-1a s.c	At wk 96 (y2)	Significant reduction in median change in BPF -0.615 in the alemtuzumab group vs. -0.810 in the interferon IFN-β-1a s.c group ().	wk 96 (y2)	42% risk reduction of 6-month CDA () in alemtuzumab compared to IFN-β-1a group. 28.2% alemtuzumab-treated patients vs. 12.93% IFN-β-treated patients (95% CI) with sustained reduction of disability for 6-month. Mean MSFC score improved from baseline by 0.08 in alemtuzumab-treated patients vs. worsened from baseline by -0.04% in IFN-β-1a-treated patients ().
OPERA I [32, 33]; Group 1, ocrelizumab; Group 2, INF-β-1a	wk 24-96 (y2)	Significant difference in mean percentage BVC -0.57 in the ocrelizumab group (95% CI) vs. −0.74 in the INF-β-1a group (95% CI), difference in rate 22.8% ().	wk 24-96 (y2)	3-month CDP 9.8% in ocrelizumab-treated group vs. 15.2% in INF-β-1a group (95% CI, 0.45–0.81) (). 6-month CDP 7.6% in ocrelizumab-treated group vs. 12% % in INF-β-1a group (95% CI, 0.43–0.84) ().; In OPERA I, MSFC score between ocrelizumab group and INF 1a group was not significant; In OPERA II MSFC score MSFC 0.28 in ocrelizumab-treated group vs. 0.17 in INF-β-1a-treated group. Difference (95% CI) 0.11 (0.03 to 0.18) ().
OPERA II [32, 33]; Group 1, ocrelizumab; Group 2, INF-β-1a	wk 24-96 (y2)	Mean percentage change in brain volume was -0.646 in ocrelizumab group (95% CI) vs. 0.75 in INF-β-1a group. Difference in rate 14.9% () was not significant.
ADVANCE [44]; Group 1, Peg-IFN-β-1a Q4w; Group 2, Peg-IFN-β-1a Q2w; Group 3, delayed treatment	wk 24-96 (y2)	Significant reduction in mean percent change in whole brain volume 0.88% () in IFN-β-1a Q4w group vs. -0.8% in the IFN-β-1a Q2w group (p <0.001) vs. delayed treatment group -1.01	BL-wk 96	Significant difference in percentage of patients with clinical NEDA in IFN 1-a Q4w-treated group 64.2% () and IFN 1-a Q2w-treated group 71.3% () vs. delayed treatment.
FREEDOMS I [31, 45]; Group 1, fingolimod 1,25 mg; Group 2, fingolimod 0.5 mg; Group 3, placebo	BL–wk 96 (y2)	Significant reduction in men BVC in 1.25 mg fingolimod group -0.89 () vs. in fingolimod 0.5 mg -0.84 () vs. placebo group -1.31	BL-wk 96	About 40% reduction of risk of 6-month CDP in both 1.25 mg and 0.5 mg fingolimod group. Fingolimod demonstrated significant effect on disability: absence of 3-month CDP was in fingolimod 1.25 mg group () and in 0.5 mg fingolimod group () and in placebo group.; Absence of 6-month CDP was 88.5% () in fingolimod 1.25 mg group (), and 87.5% in 0.5 mg fingolimod group () vs. 81.0% in placebo group.; Significant improvement of MSFC Z-score was observed in 1.25 mg fingolimod group () and in 0.5 mg fingolimod group () vs. placebo group with MSFC worsening .
FREEDOMS II [29]; Group 1, fingolimod 1,25 mg; Group 2, fingolimod 0.5 mg; Group 3, placebo	BL–wk 96 (y2)	Significant reduction in BVC in fingolimod 1.25 mg -0.595 vs. -0.858 in fingolimod 0.5 mg vs. -1.279 in placebo group. Treatment difference vs. placebo in fingolimod 1.25 mg was -0.63% (), in fingolimod 0.5 mg was -0.41% ()	BL-wk 96	Fingolimod 1.25 mg and 0.5 mg had no significant effect on 3- and 6-month confirmed disability progression and MSFC Z-score at 96 week (y2) comparing to placebo.
TEMSO [39]; Group 1, teriflunomide 7 mg; Group 2, teriflunomide 14 mg; Group 3, placebo	BL-wk 96 (y2)	Annualized median percentage BVC was -0.94 in teriflunomide 7 mg group, 0.9 in teriflunomide 14 mg group, and -1.29 in placebo group. Treatment difference vs. placebo 27.6% in teriflunomide 7 mg group () and 30.6% in teriflunomide 14 mg group ()	BL-wk 96	Teriflunomide 14 mg group displayed significant reduction in 3-month confirmed disability worsening () and 6-month confirmed clinical worsening () measured from baseline to wk 96.
CLARITY [30]; Group 1, cladribine 3.5 mg/kg; Group 2, cladribine 5.25 mg/kg; Group 3, placebo	wk 24-96 (y2)	Mean percentage of BVC −0.77 () in cladribine 3.5 mg/kg group and −0.77 () in cladribine 5.25 mg/kg group vs. −0.95 in placebo group	BL-wk 96	43% risk reduction of 3-month sustained EDSS change in 3.5 mg cladribine group vs. placebo CI: (0.518-0.934) () and 36% risk reduction of 3-month sustained EDSS change in 5.25 mg cladribine group vs. placebo CI: (0.553-0.977) ().
DEFINE [41]; Group 1, DMF BID; Group 2, DMF TID; Group 3, placebo	BL-wk 96 (y2)	Only dimethyl fumarate twice daily (DMF BID) showed significant reduction in median percentage change in whole brain volume at week 96, -0.64% in DMF BID group vs. -0.81 in placebo group, treatment difference vs. placebo 21% ()	Ø	Not evaluated
CONFIRM [46, 47]; Group 1, DMF BID; Group 2, DMF TID; Group 3, glatiramer acetate; Group 4, placebo	BL-wk 96 (y2)	No significant effect of treatment with dimethyl fumarate on median percentage change in whole brain volume	At wk 96	No significant correlation between brain parenchymal volume change and change in EDSS
RADIANCE [43]; Group 1, ozanimod 0.5 mg; Group 2, ozanimod 1 mg; Group 3, IFN beta-1a	BL-wk 96 (y2)	Significant reduction in percent of whole brain volume loss in 0.5 mg ozanimod group () and in 1 mg ozanimod group () vs. IFN 1-a. Significant reduction in cortical gray matter volume loss in 0.5 mg ozanimod group () and in 1 mg ozanimod group () vs. IFN beta-1a. Significant reduction in thalamic volume loss in 0.5 mg ozanimod group () and in 1 mg ozanimod group () vs. IFN beta-1a	At wk 96	No significant difference between group treated with 0.5 mg and 1 mg ozanimod and in IFN-β-1a in reduction of 3- and 6-month CDP or change of MSFC Z-scores.

Abbreviations: wk: week; y: year; Q4w: every 4 weeks; Q2w: very 2 weeks; BPF: brain parenchymal fraction; BVC: brain volume change; DMF BID: delayed-release dimethyl fumarate twice daily; DMF TID: delayed-release dimethyl fumarate three times daily; INF-β-1a: interferon beta-1a; BVL: brain volume loss; s.c: subcutaneous; DMT: disease-modifying therapies; EDSS: Expanded Disability Status Scale; BL: baseline; CDA: Confirmed Disability Accumulation; CDP: confirmed disability progression; MSFC: Multiple Sclerosis Functional Composite; Clinical-NEDA: no relapses and no onset of 12-week CDP—increase in the EDSS score of in patients with baseline score of ≥1.0, or an increase of 1.5 points in patients with a baseline score of 0, confirmed after 12 or 24 weeks.