Table 2.
Studies investigating the use of oral DMTs for the treatment of aggressive MS.a.
| Author | Study and DMT | Definition(s) of aggressive MS | Disease activity outcomes | Disability outcomes | NEDA as outcome |
|---|---|---|---|---|---|
| Bar-Or J et al.26 | DEFINE subgroup analysis, DMFb | a. ⩾ 2 relapses in the 12 months prior to study entry b. T2 lesion volume ⩾ median of the study population c. Gd+ lesions at baseline |
ARR at 2 years compared to placebo, RR (95% CI) a. 0.446 (0.296–0.673) b. 0.374 (0.226–0.619) c. 0.321 (0.175–0.589) |
CDP at 2 years, HR (95% CI)c: a. 0.67 (0.38–1.20) b. 0.58 (0.30–1.12) c. 0.56 (0.25–1.26) |
NA |
| Hutchinson et al.27 | CONFIRM subgroup analysis, DMFb | a. ⩾ 2 relapses in the 12 months prior to study entry b. T2 lesion volume ⩾ median of the study population c. Gd+ lesions at baseline |
ARR at 2 years compared to placebo, RR (95% CI) a. 0.664 (0.422–1.043) b. 0.497 (0.302–0.819) c. 0.490 (0.276–0.871) |
Not analysed (non-significant results in the ITT population of the CONFIRM trial) | NA |
| Devonshire et al.28 | FREEDOMS subgroup analysis, fingolimodd | Group E: treatment-naïve patients with rapidly evolving severe RRMS (⩾ 2 relapses within the year prior to study inclusion and ⩾ 1 Gd+ lesions at baseline) | ARR at 2 years compared to placebo, RR (95% CI): 0.33 (0.18–0.62), p = 0.0006 |
CDP at 2 years, HR (95% CI)e: 0.73 (0.25–2.07), p = 0.55 |
NA |
| Derfuss et al.29 | FREEDOMS and FREEDOMS II post hoc analysis, fingolimod | Disease activity despite previous DMTs: ⩾ 1 relapse in the previous year and either ⩾ 1 Gd+ lesion or ⩾ 9 T2 lesions at baseline, and/or as many or more relapses in the year before baseline as in the previous year |
ARR at 2 years compared to placebo, RR (95% CI): 0.52 (0.40–0.69), p < 0.001 |
CDP at 6 months, HR (95% CI): 0.5 (0.34–.90), p = 0.016 |
NA |
| Derfuss et al.30 | FREEDOMS, FREEDOMS II and TRANSFORMS pooled data, fingolimodd | a. ⩾ 3 relapses in the 2 years prior to study inclusion b. ⩾ 1 Gd+ lesions at baseline c. Baseline EDSS ⩾ 3.0 |
ARR at 2 years compared to placebo: relative reduction of 46%–59% across the three subgroups (p < 0.001 for all comparisons) ARR at 1 year compared to IM IFN-β1a: relative reduction of 39%–51% (p < 0.001 for b. and p < 0.01 for a. and c.) |
NA | NA |
| Prosperini et al.36 | Propensity score-matched cohort study comparing natalizumab, fingolimod and self-injectables | a. Non-responders to first-line DMTs: either ⩾ 2 relapses or 1 relapse associated with a residual EDSS score ⩾ 2.0 in the previous year while on DMTs b. HA, treatment-naïve patients: ⩾ 2 relapses in the previous year and ⩾ 1 Gd+ lesion on brain or spinal cord MRI |
NA | NA | NEDA-3f at 2 years: a. Natalizumab 67% versus fingolimod 42%, p = 0.034 b. Natalizumab 75% versus fingolimod 67%, p > 0.2 |
| Huisman et al.37 | Systematic review and meta-analysis, efficacy of fingolimod relative to DMF in a. and natalizumab in b. | a. HA RRMS: unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with ⩾ 1 DMT b. RES MS: ⩾ 2 disabling relapses in the past year, and ⩾ 1 Gd+ lesions on MRI or increase in the T2 lesion load compared with a previous MRI |
ARR at 2 years, HR (CrIs)g,h: a. Fingolimod versus DMF: 0.91 (0.57–1.47); SUCRA 82.0% versus 67.9% b. Fingolimod versus natalizumab: 1.72 (0.84–3.53); SUCRA 53.4% versus 96.5% |
3-month CDP at 2 years, HR (CrIs)i: a. Fingolimod versus DMF: 0.55 (0.27–1.12); SUCRA 96.7% for fingolimod; DMF not available b. Fingolimod versus natalizumab: 1.62 (0.51–5.13); SUCRA 46.1% versus 89.0% |
— |
| Giovannoni et al.31 | CLARITY post hoc and subgroup analysis, cladribine | ⩾ 2 relapses in the previous year and either ⩾ 1 T1 Gd+ lesions or ⩾ 9 T2 lesions on baseline MRI | NA | NA | NEDAj at 96 weeks, cladribine (3.5 mg/kg) compared to placebo, OR (95% CI)k: 4.28 (3.05–6.02), p < 0.0001 |
| Giovannoni et al.32 | CLARITY post hoc and subgroup analysis, cladribine 3.5 mg/kg | Two overlapping, categorical subgroups: a. HRA: ⩾ 2 relapses during the year prior to study entry, whether on DMT or not b. HRA + DAT: ⩾ 2 relapses during the year prior to study entry, whether on DMT or not, and patients with ⩾ 1 relapse during the year prior to study entry while on therapy with other DMTs and ⩾ 1 Gd+ lesions or ⩾ 9 lesions |
ARR at 2 years compared to placebo, RR (95% CI): a. 0.32 (0.22–047) b. 0.33 (0.23–0.48) Cumulative new Gd+ lesions, RR (95% CI): 0.087 (0.052–0.144) 0.077 (0.046–0.128) |
6-month CDP, HR (95% CI): a. 0.18 (0.08–0.44) b. 0.18 (0.07–0.43) |
Proportion of patients achieving NEDAj, OR (95% CI): a. 8.02 (3.93–16.35) b. 7.82 (4.03–15.19) |
DMT: disease-modifying treatment; MS: multiple sclerosis; NEDA: no evidence of disease activity; DMF: dimethyl fumarate; Gd+: gadolinium-enhancing; ARR: annualized relapse rate; RR: risk ratios; 95% CI: 95% confidence intervals; CDP: confirmed disability progression; HR: hazard ratios; NA: not assessed; ITT: intention-to-treat analysis; RRMS: relapsing–remitting multiple sclerosis; EDSS: Expanded Disability Status Scale; IFN: interferon; IM: intramuscular; HA: highly active; MRI: magnetic resonance imaging; RES: rapidly evolving severe; SUCRA: surface under the cumulative ranking curve; OR: odds ratio; HRA: high relapse activity; DAT: disease activity on treatment.
p-values shown when available.
Results for DMF BID. Results for DMF TID were similar (data not shown).
⩾ 1.0-point increase in the EDSS in patients with a baseline score ⩾ 1.0, or a ⩾ 1.5-point increase in patients with a baseline score of 0, sustained for 12 weeks.
Results for fingolimod 0.5 mg. Results for fingolimod 1.25 mg were similar (data not shown).
Time to disability progression confirmed after 3 months: increase in 1-point on the EDSS from baseline, or 0.5 points if the EDSS score was ⩾ 5.5.
Absence of clinical relapses, disability worsening and radiological activity.
Credible intervals (CrIs) used instead of CIs. CrIs assume the true value of the point estimate is within 95% of the range, whereas CIs assume that, if the analysis was replicated 100 times, 95% of the CIs would include the true value of the parameter.
HRs < 1 favour fingolimod and > 1 favour the comparator.
6-month confirmed disability progression also available for subgroup b. comparison, with similar results to 3-month CDP.
No relapses, no 3-month sustained change in EDSS and no T1 Gd+ or active T2 lesions. Time to NEDA not specified.
Similar results at 24 and 48 weeks and with cladribine 5.25 mg/kg.