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Table 1 First 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
Rudick et al. [83, 87] 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.
Kappos et al. [176, 177] 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
  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