Table 3.

New or emerging therapies and their effect on brain volume loss (BVL)

References	DMT and trial design	Clinical trial	Baseline/MRI cohorts	Type of MS	Main effect on brain atrophy
Comi et al. [157]	Laquinimod orally 0.6 mg once daily vs placebo	Phase III ALLEGRO 2 years	1106 Laquinimod n = 550, placebo n = 556	RRMS	Laquinimod had a significant effect on reducing brain volume loss vs placebo (p < 0.001, from baseline to 2 years)
Vollmer et al. [158]	Laquinimod orally 0.6 mg once daily vs IFN β-1a i.m. 30 μg once weekly vs oral placebo	Phase III BRAVO 1 year	1331 Laquinimod n = 434, IFN β-1a i.m. n = 4 47, placebo n = 450	RRMS	Robust effects on reducing brain atrophy are replicated for Laquinimod (p < 0.001, from baseline to year 1), whereas IFN β-1a showed no benefit at all (non-significant. increased BVL 11% vs placebo, p = 0.14)
Cohen et al. [147]	Alemtuzumab i.v. 12 mg (once per day for 5 days at baseline and once per day for 3 days at 12 months) vs INF β-1a s.c. 44 μg TIW	Phase III CARE-MS I 2 years	563 Alemtuzumab n = 376, INF β-1a n = 187	RRMS	Median change in brain parenchymal fraction was less in Alemtuzumab (− 0.867%) was compared with INF β-1a (1.488%), p < 0.001)
Coles et al. [148]	Alemtuzumab i.v. 12 mg once per day vs 24 mg once per day (once per day for 5 days at baseline and for 3 days at 12 months) vs INF β-1a s.c. 44 μg TIW	Phase III CARE-MS II 2 years	628 Alemtuzumab 12 mg n = 426, INF β-1a n = 202	RRMS	Compared to 44 μgsc IFN β-1a (− 0.810%), alemtuzumab-treated (− 0.615%) patients showed less reduction in median parenchymal brain fraction during the first year of the trial (p = 0.01)
Traboulsee et al. P1181 ECTRI.M.S [6]	Alemtuzumab i.v. 12 mg once daily received 2 annual courses (on 5 consecutive days at baseline and on 3 consecutive days 12 months later). Patients could receive additional treatment with alemtuzumab (12 mg on 3 consecutive days ≥ 1 year after the most recent course) during the extension study	Extension of Phase III CARE-MS I, CARE-MS II 4 years	93% of CARE-MS I n = 325, 88% of CARE-MS II n = 393	RRMS	Durable MRI positive outcomes (i.e. sustained low brain atrophy rates, in the absence of continuous treatment with Alemtuzumab or other DMTs during the follow up period)
Coles et al. [150]	Alemtuzumab i.v.(12 mg on 3 consecutive days) Alemtuzumab-treated patients who completed CARE-MS II could enroll in the extension and receive, at the investigator’s discretion, additional alemtuzumab courses (12 mg on 3 consecutive days) ≥ weeks after the most recent course, if they had evidence of MS disease activity. Patients who received s.c. IFN-b-1a for 2 years in the core study could also enroll in the extension and switch to alemtuzumab treatment; results for these patients will be reported separately	CARE-MS II 5 years follow-up	Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment	RRMS	Median yearly BVL remained low in the extension (years 1–5: − 0.48%, − 0.22%, − 0.10%, − 0.19%, − 0.07%). Yearly BVL rate continued to decrease in year 3 compared with the core study, remaining low in years 4 and 5. Median BPF change from baseline to year 5 was − 0.855%
Arnold et al. (P558, ECTRI.M.S 2015) [151]	Daclizumab s.c 150 mg every 4 weeks vs INF β-1ai.m. 30mcg once weekly	Post hoc of Phase III DECIDE 2 years	1806 Daclizumab n = 899, INF β-1a n = 907	RRMS	Daclizumab showed a significant effect in limiting the rate of brain atrophy vs IFN β-1a, between baseline and week 96 (p < 0.0001), week 0 and week 24 (p = 0.0325) and between week 24 and week 96 (p < 0.0001)
Montalban et al. [155]	Ocrelizumab i.v. 600 mg (two 300 mg infusions 14 days apart) vs placebo	Phase III ORATORIO	732 Ocrelizumab 600 mg, n = 488, placebo n = 244	PPMS	Ocrelizumab reduced the rate of whole brain volume loss from week 24 to week 120 by 17.5%120 (p = 0.0206) compared with placebo
Arnold et al. [154]	Ocrelizumab i.v 600 mg.every 24 weeks vs INF β-1as.c. 44 mcg TIW	Phase III OPERA I 96 weeks	821 Ocrelizumab n = 410, IFN β-1a n = 411	RMS	Ocrelizumab reduced brain volume loss compared with INF β-1a. (p < 0.001 from baseline to 96th week and p = 0.0042 from 24th to 96th week)
Arnold et al. [154]	Ocrelizumab i.v 600 mg.every 24 weeks vs INF β-1as.c. 44 mcg TIW	Phase III OPERA II	835 Ocrelizumab n = 417, IFN β-1a n = 418	RMS	Ocrelizumab reduced brain volume loss compared with INF β-1a. [p = 0.001 from baseline to 96th week and p = 0.09 (non-significant) from 24th to 96th week]
De Stefano et al. [162]	Cladribine3.5 mg/kg or Cladribine5.25 mg/kgvs placebo	Phase III CLARITY	1025 Cladribine 3.5 mg/kg n = 336, Cladribine 5.25 mg/kg n = 351, placebo n = 338	RMS	Patients treated with cladribine had significantly less annualized brain atrophy over 2 years compared with patients receiving placebo. At 18 months, patients treated with cladribine had 20% reduction in brain atrophy compared with patients receiving placeboIn patients under cladribine tablets 3.5 mg/kg (− 0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (− 0.57% ± 0.72, p = 0.019), the annualized PBVC was reduced compared with placebo (− 0.70% ± 0.79)

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