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 (p < 0.0001). | 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 (p = 0.01). |
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|
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 (p = 0.01). | wk 96 (y2) | 42% risk reduction of 6-month CDA (p = 0.0084) 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 (p = 0.02). |
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|
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% (p = 0.004). | 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) (p < 0.001). 6-month CDP 7.6% in ocrelizumab-treated group vs. 12% % in INF-β-1a group (95% CI, 0.43–0.84) (p = 0.003). 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) (p = 0.004). |
|
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% (p = 0.09) was not significant. | ||
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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% (p < 0.05) 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% (p = 0.016) and IFN 1-a Q2w-treated group 71.3% (p = 0.0001) vs. delayed treatment. |
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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 (p < 0.001) vs. in fingolimod 0.5 mg -0.84 (p < 0.001) 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 83.4% ± 1.9 in fingolimod 1.25 mg group (p = 0.01) and 82.3% ± 1.9 in 0.5 mg fingolimod group (p = 0.03) and 75.9% ± 2.2 in placebo group. Absence of 6-month CDP was 88.5% (p = 0.004) in fingolimod 1.25 mg group (p = 0.01), and 87.5% in 0.5 mg fingolimod group (p = 0.01) vs. 81.0% in placebo group. Significant improvement of MSFC Z-score was observed in 1.25 mg fingolimod group 0.01 ± 0.40 (p = 0.02) and in 0.5 mg fingolimod group 0.03 ± 0.39 (p = 0.01) vs. placebo group with MSFC worsening −0.06 ± 0.57. |
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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% (p < 0.0001), in fingolimod 0.5 mg was -0.41% (p = 0.0002) | 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. |
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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 (p = 0.0019) and 30.6% in teriflunomide 14 mg group (p = 0.0001) | BL-wk 96 | Teriflunomide 14 mg group displayed significant reduction in 3-month confirmed disability worsening (p = 0.004) and 6-month confirmed clinical worsening (p = 0.006) measured from baseline to wk 96. |
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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 (p = 0.02) in cladribine 3.5 mg/kg group and −0.77 (p = 0.02) 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) (p = 0.015) and 36% risk reduction of 3-month sustained EDSS change in 5.25 mg cladribine group vs. placebo CI: (0.553-0.977) (p = 0.033). |
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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% (p < 0.05) | Ø | Not evaluated |
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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 |
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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 (p = 0.0002) and in 1 mg ozanimod group (p < 0.0001) vs. IFN 1-a. Significant reduction in cortical gray matter volume loss in 0.5 mg ozanimod group (p < 0.0001) and in 1 mg ozanimod group (p < 0.0001) vs. IFN beta-1a. Significant reduction in thalamic volume loss in 0.5 mg ozanimod group (p < 0.0133) and in 1 mg ozanimod group (p < 0.0004) 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 EDSS ≥ 1.0 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.