Introduction
Pathogenesis of brain atrophy
The time trajectory of brain atrophy
Pathogenesis of acute demyelination and axonal injury
Mechanisms of late axonal loss (Fig. 1)
Ion overload
Mitochondria dysfunction
Iron dysregulation
Glutamate excitotoxicity
Clinical correlates of brain atrophy
Effect of disease modifying treatments (Tables 1, 2 and 3)
Approved DMTs and brain volume outcomes
References | DMT and trial design | Clinical trial | Baseline/MRI cohorts | Type of MS | Main effect on brain atrophy |
---|---|---|---|---|---|
IFN β-1a i.m. 30 mcg weekly vs placebo | Phase III MS.C.RG 2 years | 140 IFN β-1a n = 68, placebo n = 72 | RRMS | Percent change inbrain parenchymal fraction was lower in IFN β-1a treated patients compared to placebo, during the second year of treatment (p = 0.03) but not the first (p = 0.71) | |
Fisher et al. [104] | IFN β-1a i.m. 30 mcg weekly vs placebo | Retrospective analysis of Phase III MS.C.RG 2 years | 131 IFN β-1a n = 62, placebo n = 69 | RRMS | IFN β-1a significantly preserved GM [4] atrophy (p = 0.03) and whole brain atrophy (p = 0.04) during the second year of treatment, but not WM atrophy (at any point) |
Fillipi et al. [106] | IFN β-1a s.c. 22 μg weekly vs placebo | Phase III ETOMS 2 years | 262 IFN β-1a n = 131, placebo n = 132 | CIS | Significant reductions in PBVC the IFN β-1a treated arm (p = 0.0031) compared to placebo, from baseline to second year |
De Stefano et al. [173] | IFN β-1a s.c. 44mcg TIW vs placebo | double-blind and rater-blind phase IMROVE 40 weeks | 180 (double-blind phase) IFN β-1a n = 120, placebo n = 60 | RRMS | Non-significant differences in mean [102] PBVC between treatment groups (placebo: − 0.24% [0.48%]; IFN β-1a: − 0.22% [0.54%]; p = 0.76) at week 16 (end of double-blind phase) |
De Stefano et al. [105] | IFN β-1a s.c. 44 mg TIW vs once a week vs placebo | Phase III REFLEX 2 years | 517 IFN β-1a TIW n = 171, IFN β-1a, once a week n = 175, placebo n = 171 | CIS | No differences in BVL (from baseline to 2 years) in patients receiving once or three times a week IFNβ-1a vs placebo. The greatest loss was in the TIW IFN β-1a group compared with the once a week IFN β-1a and placebo groups |
Kappos et al. [108] | IFN β-1a s.c. 44 or 22 mcg TIW vs placebo (2 years); then open label (4 years); long term follow up (2 years) | Phase III PRISMS ~ 8 years | 382 44 mcg sc TIW n = 136, 22 mcg sc TIW n = 123, placebo n = 123 | RRMS | Non-significant differences in median BPV (from baseline to long term follow-up and each study period therein) for all treatment arms |
Hardmeier et al. [174] | IFN β-1a i.m. 30 μg or 60 μg | Retrospective of The European IFNb-1a Dose- Comparison Study 3 years | annual MRI cohort n = 386, frequent MRI cohort n = 138 | RRMS | The greatest BVL took place during the first 4 months of therapy in frequent MRI cohort (from baseline to month 4, p < 0.05). Non-significant reduction in the brain atrophy in the 2nd and 3rd year of treatment |
Molyneux et al. [175] | INF β-1b s.c. 8 MIU every other day vs placebo | Phase III 3 years | 92 INF β-1b n = 48, placebo n = 44 | SPMS | Not significant effect of treatment with INF β-1b on cerebral volume loss (p = 0.343, from baseline to 3 years) compared with placebo. |
INF β-1βs.c. 250 μg every other day (early vs delayed treatment) | Extension study of the Phase III BENEFIT trial (3 and 5 years follow up) | Follow-up phase n = 418 early treatment n = 261, delayed treatment n = 157 5-year completers n = 358 early treatment n = 235, delayed treatment n = 123 | CIS | Marginal, non-significant differences between early and delayed treatment (p = 0.15, from baseline to 3 years, p = 0.121 from baseline to 5 years) | |
Calabresi et al. [111] | Peginterferon b-1a s.c. 125 μg Q2 W vs Q4 W vs placebo | Phase III ADVANCE 1 year, then open label | 1512 PEG-IFN β-1a 125 μg Q2 W n = 512, PEG-IFN β-1a 125 μg Q4 W n = 500, placebo n = 500 | RRMS | Core study: During the first 6 months of treatment there was a significant “pseudoatrophy” effect (PEG-IFN β-1a 125 μg Q2 W vs placebo, p = 0.0170) Baseline to year 1: Νo significant differences on whole brain volume between groups (Q2Wvs placebo p = 0.0841; Q4 W vs placebo p = 0.3747) |
Arnold et al. (F2069, 1rst EAN Congress 2015) [112] | Peginterferon b-1a s.c. 125 μg Q2 W vs Q4 W | Extension study of Phase III ADVANCE 2 years | At week 96/569 PEG-IFN β-1a 125 μg Q2 W n = 384, PEG-IFN β-1a 125 μg Q4 W n = 185 (delayed treatment) | RRMS | From week 24 to week 96, the delayed treatment PEG-IFN β-1a 125 μg Q4 W n = 185 demonstrated a significantly greater decrease in whole brain volume compared with the Q2 W group (p = 0.0034) |
Sorensen et al. [110] | INF β-1a s.c. 44 μg plus Methylprednisolone orally 200 mg or placeboorally | Phase III NORMI.M.S 2 years | 110 INF β-1a and oral methylprednisolone n = 54, IFN β-1a and placebo n = 56 | RRMS | Mean changes in normalized brain parenchymal volume favored pulsed treatment with oral methylprednisolone combined with INF β-1a vs INFβ-1a monotherapy, but the benefit was not significant (p = 0.25) between baseline and week 96 |
Ravnborg et al. [109] | INF β-1a i.m. 30 μg once weekly plus Methylprednisoloneorally 500 mg daily (3 consecutive days per month for 3–4 years) or placebo | Phase III MECOMBIN 3 years | 338 INF β-1a plus placebo n = 167, INF β-1a plus methylprednisolone n = 171 | RRMS | The study showed no effect on brain parenchymal volume (p = 0.58) or change in normalized brain volume (p = 0.52) |
Comi et al. [114] | GAs.c. 20 mg daily vs Placebo | Phase III PreCISe 2 years | 481 GA n = 243, Placebo n = 238 | CIS | No significant difference in percentage change from baseline to last observed value in brain volume between the treatment groups (− 0.33% in GA vs − 0.38% in placebo) |
Comi et al. [115] | GAs.c. 20 mgdailyvs placebo | open-label, extension phase of Phase III PreCISe 2 years | 409 early-treatment group n = 198, placebo (delayed-treatment) n = 211 | CIS | Significant reduction of BVL in early versus delayed treatment onset (28% reduction, p = 0.0209) |
Ge et al. [116] | GAs.c. 20 mg daily vs placebo | Phase III The US GA study 2 years | 27 GA treated n = 14, placebo n = 13 | RRMS | GA significantly reduced the rate of BVL (77% reduction) in the 2-year treatment period (p = 0.007) compared with placebo |
Rovaris et al. [119] | GA s.c. 20 mg daily vs placebo for 9 months, then GA open-label | Phase III European/ Canadian GA trial 18 months | 227 GA n = 113, placebo n = 114 | RRMS | During the double-blind, placebo-controlled phase of the study, GA treatment did not have any measurable impact on the absolute or percentage change of BV (from baseline to 9 months, p = 0.88) In the subsequent open-label phase, early GA treatment showed a 40% reduction in the rate of brain atrophy (from 9th to 18th month) |
Rovaris et al. [118] | GA s.c. 20 mg daily | Extension of the Phase III European/ Canadian GA trial 5 years | 142 Early treatment n = 73 Delayed treatment n = 69 | RRMS | Baseline to 5 years: Non-significant differences in median PBVC in early vs delayed treatment groups. |
Comi et al. [113] | GA s.c. 20 mg vs 40 mg (dose comparison) | Phase III FORTE 1 year | 1155 GA 20 mg n = 586, GA 40 mg n = 569 | RRMS | PBVCs were similar in both groups (p = 0.423). Higher dose of GA did not have a clear-cut impact on brain volume loss. Slower atrophy rates, compared with the Eur/Canadian GA trial |
Khan et al. [178] | GA s.c. 40 mg TIW vs placebo | Phase III GALA 1 year | 1263 GA 40 mg TIW n = 840, placebo n = 423 | RRMS | The percentage change in brain volume (from baseline to 1 year) was not statistically different between treatment arms (− 0.706 with GA vs − 0.645 with placebo; p = 0.2058) |
Lublin et al. [179] | INF β-1a i.m. 30 mg weekly, GA s.c. 20 mg daily | Phase III CombiRx 3 years | 790 IFN + GA n = 388, IFN n = 187, GA n = 215 | RRMS | Combination treatment was not superior to either INF β-1a or GA agents alone (CSF volume change from baseline to month 36; IFN β-1a + GA vs IFN, p = 0.008, INF β-1a vs GA p = 0.48). Whole brain tissue loss was reflected by the change in normalized CSF from baseline |
O’Connor et al. [180] | INF β- 1b s.c. 250 μg or 500 μg, every other day or GA s.c. 20 mg daily | Phase III BEYOND 2 years | 2244 IFN β-1b 500 μg n = 899, IFN β-1b 250 μg n = 897, GA n = 448 | RRMS | Non-significant differences between treatment groups High dose INF β-1b was not superior to the standard dose (500 μg IFN β-1b vs 250 μg IFN β-1b p = 0.74). Both doses of IFN β-1b had similar measurable brain volume (BV) effect as compared with GA (500 μg IFN β-1b vs GA p = 0.33; 250 μg IFN β-1b vs GA p = 0.46). During year 1, patients under IFN β-1b had a significantly greater reduction in mean brain volume than did patients treated with GA (250 μg IFN β-1b vs GA p = 0.02; 500 μg IFN β-1b vs GA p = 0.007) |
Arnold et al. [136] | DMF orally 240 mg BID vs TID vs placebo | Phase III DEFINE 2 years | 540 DMF BID n = 176, DMF TID n = 184, Placebo n = 180 | RRMS | Significant results for the DMF BID versus placebo on brain atrophy, from either baseline or 6 months to second year (baseline to 2 years p = 0.0449, 6 months to 2 years p = 0.0214). Non-statistically results for the DMF TID dose group |
Miller et al. [137] | DMF orally 240 mg BID vs TID vs GA 20 mg once daily vs placebo | Phase III CONFIRM 2 years | 681 DMF BID n = 169, DMF TID n = 170, GA n = 175, placebo n = 167 | RRMS | At 2 years, PBVC favored DMF BID, but not TID or GA, compared to placebo (BID vs placebo; p = 0.0645; TID vs placebo; p = 0.2636; GA vs placebo p = 0.8802) |
Kappos et al. (P7.243, AAN) [181] | DMF orally 240 mg BID vs TID vs placebo | 8 year follow-up study of Phase III ENDORSE Ongoing | year 1/464 DMF BID n = 197, GA n = 88, placebo n = 179 | RRMS | There was no significant effect in brain volume loss for the placebo/DMF and the GA/DMF groups relative to the group treated continuously with DMF BID (BID/BID group) (median PVC, from baseline to 5 years, BID/BID vs placebo/DMF p = 0.1165, BID/BID vs GA/DMF p = 0.3436) |
Miller et al. [129] | Teriflunomide orally 7 or 14 mg once-daily vs placebo | Phase III TOPIC 4 years | 614 Teriflunomide 14 mg n = 214, Teriflunomide 7 mg n = 203, placebo n = 197 | CIS | No significant differences were recorded for brain atrophy (SIENA). (Mean change from baseline at week 108 vs placebo, 14 mg p = 0.4495; 7 mg p = 0.4462) |
O’Connor et al. [130] | Teriflunomide orally 7 or 14 mg once-daily vs placebo | Phase III TEMSO 2 years | 1086 Teriflunomide 14 mg n = 358, Teriflunomide 7 mg n = 365, placebo n = 363 | RRMS | No effect on relative BPF change among the study groups (from baseline to 2 years: Teriflunomide 7 mg vs. placebo p = 0.19; Teriflunomide 14 mg vs. placebo p = 0.35) |
Wolinsky et al. [131] | Teriflunomide orally 7 or 14 mg once-daily vs placebo | Post hoc analysis of Phase III TEMSO 108 weeks | 1088 Teriflunomide 14 mg n = 359, Teriflunomide 7 mg n = 366, placebo n = 363 | RRMS | There was a significant decrease in WM fraction (from baseline to108 weeks) for both doses of Teriflunomide (WMF change 14 mg vs placebo p = 0.0002; 7 mg vs placebo p = 0.0609) |
Radue et al. (P3-089 AAN 2016) [134] | Teriflunomide orally 7 or 14 mg once-daily vs placebo | Post hoc analysis of Phase III TEMSO and TOWER 9 years | 969 808 baseline and week 48, 709 baseline and week 108 | RRMS | Significant gain in brain volume loss, by using an alternative method (SIENA). Median PVC, from baseline to first year, Teriflunomide 14 mg vs placebo p = 0.0001; Teriflunomide 7 mg vs placebo p = 0.0011; from baseline to second year: Teriflunomide 14 mg vs placebo p = 0.0001; Teriflunomide 7 mg vs placebo p = 0.0019) |
Sprenger et al. P3.047 [132] | Teriflunomide orally 14 mg once-daily vs placebo | Post hoc analysis of Phase III TEMSO and TOWER 2 years | 969 808 first year, 709 s year | RRMS | Teriflunomide resulted in lower atrophy rate in patients with and without disability progression vs placebo. Without disability progression: Median PBVC, from baseline to first year, Teriflunomide 14 mg vs placebo (22%) p = 0.0128 and from baseline to second year (23%) p = 0.0129 With disability progression: Median PBVC, from baseline to first year, Teriflunomide 14 mg vs placebo (69%) p = 0.0037 and from baseline to second year (44%) p = 0.0043 |
Wuerfel et al. P3.052 [135] | Teriflunomide orally 14 mg once-daily vs placebo | Post hoc analysis of Phase III of TEMSO | Year one cohort. 0–2 in previous 2 year: Teriflunomide 14 mg n = 191, placebo n = 197 2–3 in previous 2 year Teriflunomide 14 mg n = 195, placebo n = 198 | RRMS | Significant impact on median PBVC regardless of the level of disease activity (prior relapse rate) Patients with few prior relapses (0–2 in previous 2 years): Baseline to year 1: Teriflunomide 14 mg vs placebo, relative change in percentage brain volume 40% p = 0.0001. Year 1to year 2: relative change 36%, p = 0.0001. This finding was confirmed in patients with a greater number of relapses (2–3 in previous 2 years): p = 0.0018 at year 1 and p = 0.0067 at year 2 |
Freedman et al. (P734 ETCRIMS 2016) [133] | Teriflunomide orally 7 or 14 mg once-daily vs placebo | Subgroup analysis of Phase III TEMSO | 971 treatment-naïve n = 704, 1 Prior DMT n = 208, ≥2 Prior DMTs n = 57 | RMS | Positive results on median PBVC regardless of treatment history. PVC change from baseline to year 1, Teriflunomide 14 mg No prior DMT vs placebo p = 0.0025; baseline to year 2: p = 0.0109; Teriflunomide 14 mg prior DMT vs placebo p = 0.0119, baseline to year 2: p = 0.0109. PVC change from baseline to year 1: Terilunomide 7 mg No prior DMT vs placebo p = 0.0002; baseline to year e: p = 0.0089. Teriflunomide 7 mg prior DMT vs placebo p = 0.0119, baseline to year 2: p = 0.0109 |
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) |
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) |