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Table 2 Second line therapies and their effect on brain volume loss (BVL)

From: Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

References DMT and trial design Clinical trial Baseline/MRI cohorts Type of MS Main effect on brain atrophy
Kappos et al. [122] Fingolimod orally 0.5 mg or 1.25 mg once daily vs placebo for 2 years, then FTY open-label Phase III FREEDOMS 2 years 1272 Fingolimod 1.25 mg n = 429, Fingolimod 0.5 mg n = 425, placebo n = 418 RRMS Significant reductions in the rate of brain volume loss were detected as early as 6 months for the 12 mg Fingolimod treatment group (PBVC values from baseline to 6 months, 1.25 mg Fingolimodvs placebo p = 0.003; 0.5 mg Fingolimodvs placebo p = 0.006) and remained significant at 24 months (P < 0.001 in all comparisons)
Kappos et al. [124] Fingolimod orally 0.5 mg or 1.25 mg once daily (FTY open label) Extension of Phase III FREEDOMS 2 years 920 RRMS Significantly lower atrophy rates in the continuous Fingolimod groups relative to the combined switch group, over 4 years (Continuous Fingolimod 0.5 mg p = 0.0013; Continuous Fingolimod 1.25 mg p = 0.001)
Patients who switched to Fingolimod 0.5 mg during the extension study experienced significant improvements in rates of brain volume decline (Placebo—Fingolimod 0.5 mg p = 0.0084, months 24–48 vs months 0–24)
Cohen et al. [121] Fingolimod orally 1.25 or 0.5 mgonce daily vs INF β-1a i.m. 30 μg (1 year, then open-label) Phase III TRANSFORMS 1 year 1280 Fingolimod 1.25 mg n = 420, Fingolimod 0.5 mg n = 429, INF β-1a N = 431 RRMS Compared to i.m. INF β-1a, patients treated with Fingolimod presented less brain volume loss, over 1 year (all p < 0.001)
Khatri et al. [125] Fingolimod orally 1.25 or 0.5 mg once daily Extension of Phase III TRANSFORMS 2 years 799 INF β-1a to 0.5 mg Fingolimod n = 124, INF β-1a to 1.25 mg Fingolimod n = 130. Continuous 0.5 mg Fingolimod n = 290, Continuous 1.25 mg Fingolimod n = 255 RRMS Patients switching from INF β-1a to Fingolimod (either 1.25 or 0.5 mg) reduced their brain volume decrease (PBVC: months 13–24 vs months 0–12, p = 0.006 for the INF β-1a to 0.5 mg Fingolimod switch group p = 0·007 for the INF β-1a to 1.25 mg FTY720 switch group. No further gain in BVL for patients on continuous Fingolimod treatment (p values non-significant at months 13–24 vs months 0–12)
Calabresi et al. [120] Fingolimod orally 1.25 or 0.5 mg once daily vs placebo Phase III FREEDOMS II 1 year 1083 Fingolimod 1.25 mg n = 370, Fingolimod 0.5 mg n = 358, placebo n = 355 RRMS Patients given Fingolimod had decreased brain volume loss compared with those given placebo from baseline to months 6 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.012) 12 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.004) and 24 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.013). (Total treatment effect on PBVC vs placebo p < 0·0001 and p = 0·0002 respectively)
Cohen et al. [123] Fingolimod orally 1.25 or 0.5 mg once daily IFN β-1a i.m. 30 μg once a week Extension of Phase III TRANSFORMS 4.5 years Fingolimod 0.5 mg n = 356, IFN β-1a-switch Fingolimod 0.5 mg n = 167, Fingolimod 1.25 mg n = 330, IFN β-1a switch fingolimod 1.25 mg n = 174 RRMS Non-significant long term benefit on mean PBVC (from baseline to 4.5 years): continuous-fingolimodvs IFN β-1a-switch group −1.01% (−0.8) vs −0.96% (−0.8); p = 0.937. The PBVC from baseline to month 12 was reduced significantly by fingolimod compare to IFN β-1a (p < 0.0001) and the low rate was maintained through the study completion
Lublin et al. [126] Fingolimod orally 0.5 mg once daily vs placebo Phase III INFORMS 3 years 714 Fingolimod 0.5 mg n = 293, placebo n = 421 PPMS In patients with primary progressive MS, percentage change in brain volume did not differ between Fingolimod and placebo groups (p = 0.673)
Miller et al. [139] Natalizumab i.v. 300 mg every 4 weeks vs placebo Phase III AFFIRM 2 years 942 Natalizumab n = 627, placebo n = 315 RRMS Overall, not significant effect of treatment with Natalizumabvs placebo (mean percentage change in BPF, 0.80% vs 0.82%, p = 0.822, from baseline to 2 years). During the first year, natalizumab-treated patients presented greater BVL compared to placebo (0.56% vs 0.40%, p = 0.002) but the rate of brain atrophy was significantly less in natalizumab-treated patients over the second year of treatment (0.24% vs 0.43% p = 0.004)
Radue et al. [140] (IFN β-1a i.m.30 μg + Natalizumab i.v.300 mg every 4 weeks) vs IFN β-1a i.m. 30 μg + placebo once weekly Phase III SENTINEL 2 years 1171 IFN β-1a + natalizumab n = 589, IFN β-1a + placebo n = 582 RRMS From baseline to second year, no significant differences were reported between the 2 treatment arms regarding change in BPF (p = 0.926). During the first year, there was a significant reduction in BPF in the Natalizumab treated arm (p = 0.058), but lower rates during the 2nd year of treatment (– 0.31% versus – 0.40%; p = 0.020)
  1. mg: milligrams; mcg: micrograms; μg: micrograms; vs: versus; PBVC: percentage of brain volume change; BPF: brain parenchymal fraction; BPV: brain parenchymal volume; SIENA: structural imaging evaluation using normalization of atrophy; i.m.: intramuscular; s.c: subcutaneous; i.v.: intravenous; ΤΙW: three times weekly; SD: standard deviation;Q2W: once every 2 weeks; Q4W: once every 4 weeks; BID: twice daily; TID: thrice daily; DMT: disease modifying therapies; CSF: cerebrospinal fluid; PVC: percentage volume change