Table 1.
First line 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 |
|---|---|---|---|---|---|
| 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 |
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