← Back
NeuroTrials.ai
Neurology Clinical Trial Database

EARLIMS

Comparison of first-line and second-line use of fingolimod in relapsing MS: The open-label EARLIMS study

Share Share Copied! Compare

Year of Publication: 2020

Authors: Oscar Fernández, Guillermo Izquierdo, Eduardo Aguera, ..., Michael Barnett; on behalf of the EARLIMS investigators

Journal: Multiple Sclerosis Journal-Experimental, Translational and Clinical

Citation: Mult Scler J Exp Transl Clin. 2020 Jul-Sep;6(3):2055217320957358

Link: https://doi.org/10.1177/2055217320957358

Clinical Question

Is fingolimod as first-line therapy superior to fingolimod as second-line therapy (after injectable DMT treatment) in patients with early relapsing-remitting multiple sclerosis?

Bottom Line

Fingolimod reduced annualized relapse rate to similar levels whether used first-line in treatment-naïve patients (ARR 0.21) or second-line after injectable DMT (ARR 0.30; p=0.17). However, the study was underpowered due to recruitment difficulties. Longitudinal analysis showed both groups achieved substantial ARR reductions, with treatment-naïve patients showing greater proportional reduction (88.7% vs 76.8%, p=0.04). Patients previously treated with multiple iDMTs had worse outcomes. The findings suggest fingolimod is equally effective as first- or second-line therapy, with a trend toward better outcomes in treatment-naïve patients.

Major Points

  • Study was underpowered (347 enrolled vs 432 planned; only 28% power to detect primary endpoint difference)
  • Both treatment-naïve and previously treated patients achieved substantial ARR reductions on fingolimod compared to pre-study rates
  • No significant difference in on-study ARR between treatment-naïve (0.21) and previously treated (0.30) groups (p=0.17)
  • Treatment-naïve patients had significantly greater longitudinal ARR reduction (88.7% vs 76.8%, p=0.04)
  • Patients previously treated with multiple iDMTs (multi-iDMT subgroup) had significantly worse outcomes: highest ARR (0.57, p=0.02), lowest ARR reduction (53.3%), and shortest time to first relapse (6.1 months)
  • No difference between single-iDMT subgroup and treatment-naïve patients for any outcome
  • Treatment-naïve patients had more severe disease at baseline (more frequent/severe relapses, higher pre-study ARR) but shorter disease duration
  • Approximately 80% of patients remained relapse-free at 48 weeks in both groups
  • No new safety signals; AE profile consistent with phase 3 fingolimod trials
  • Mean brain volume loss was -0.53% overall with no between-group differences

Design

Study Type: Multicenter, open-label, non-randomized, parallel-group, phase 3b/4 study

Randomization:

Blinding: Open-label. No blinding of patients, investigators, or outcome assessors. MRI analyses were performed centrally at Sydney Neuroimaging Analysis Centre.

Enrollment Period: December 21, 2011 to December 23, 2015

Follow-up Duration: 48 weeks (336 days)

Centers: 51

Countries: Spain, Australia

Sample Size: 347

Analysis: Intention-to-treat (ITT) population: all patients who received ≥1 dose with ≥1 visit data. Per-protocol (PP) population: ITT without major protocol deviations. Primary endpoint: Mann-Whitney-Wilcoxon test. Time to relapse: Kaplan-Meier with χ² or Fisher exact test. PBVC: ANCOVA adjusted for baseline brain volume. EDSS change: ANCOVA adjusted for day 0 score. Two-sided tests at α=0.05. No imputation for missing values.

Inclusion Criteria

  • Age 18-50 years
  • Diagnosis of relapsing-remitting MS for at least 1 year and no more than 5 years
  • Treatment-naïve OR continuously treated with first-line injectable DMT (glatiramer acetate, interferon beta-1a or -1b) for at least 1 year
  • At least 9 brain lesions on T2-weighted MRI
  • EDSS score <4.0
  • Spain only: At least 2 relapses in the preceding 2 years
  • Australia only: Eligible for Pharmaceutical Benefits Scheme

Exclusion Criteria

  • History of chronic immune disease
  • History of malignant disease (except localized basal-cell carcinoma of the skin)
  • Diabetes mellitus
  • Severe hepatic impairment
  • Prior treatment with fingolimod
  • Cardiac risk factors
  • Suspected macular oedema
  • Active infection
  • Seronegative for varicella-zoster, rubella, or measles at screening
  • Women of child-bearing age not using effective contraception

Arms

FieldControlTreatment-Naïve
InterventionPatients previously treated with first-line injectable DMT (glatiramer acetate, interferon beta-1a or -1b) for at least 1 year, then switched to fingolimod 0.5 mg orally daily for 48 weeks. Subgroups: single-iDMT (n=97) and multi-iDMT (n=28).Treatment-naïve patients (no prior DMT) receiving fingolimod 0.5 mg orally daily for 48 weeks as first-line therapy
Duration48 weeks48 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Annualized relapse rate (ARR) - the number of relapses in 12 months, comparing treatment-naïve with previously treated patients. Relapse confirmed by neurologist if accompanied by EDSS increase of ≥0.5 points, or 1.0-point increase in two functional systems, or 2.0-point increase in one functional system (unless sphincter- or cognition-related).Primary0.30 (95% CI 0.20-0.41) [n=128]0.21 (95% CI 0.14-0.29) [n=173]0.1668
ARR reduction from year before enrollment (longitudinal)Secondary-76.8% (95% CI -85.7% to -67.8%) [n=114]-88.7% (95% CI -93.1% to -84.2%) [n=162]0.0408
ARR - Single-iDMT subgroupSecondary0.23 (95% CI 0.13-0.33) [n=97]0.21 (95% CI 0.14-0.29) [n=173]Not reported (NS)
ARR - Multi-iDMT subgroupSecondary0.57 (95% CI 0.25-0.90) [n=28]0.21 (95% CI 0.14-0.29) [n=173]0.0212 (3-group comparison)
Time to first relapse (months), mean (SE)Secondary10.2 (0.32)9.8 (0.22)0.3217
Time to first relapse - Multi-iDMT subgroup (months)Secondary6.19.80.0429 (vs single-iDMT 10.5 months)
Patients with no relapses at week 48Secondary104/135 (77.0%)152/185 (82.2%)0.2577
Total duration of relapses (days), mean (95% CI)Secondary42.4 (17.9-66.9) [n=31]63.8 (27.3-100.3) [n=33]0.4973
Patients with relapses requiring hospitalization (among relapsing patients)Secondary2/31 (6.5%)3/33 (9.1%)1.0000
Change in EDSS score from baseline, mean (95% CI)Secondary-0.05 (-0.20 to 0.09) [n=131]-0.06 (-0.18 to 0.05) [n=179]NR
EDSS categorical change - ImprovedSecondary23 (17.6%)30 (16.8%)0.7567 (overall)
EDSS categorical change - StableSecondary94 (71.8%)134 (74.9%)
EDSS categorical change - WorseningSecondary14 (10.7%)15 (8.4%)
Active T2 lesions at week 48, mean (95% CI)Secondary1.6 (1.0-2.1) [n=106]2.0 (1.5-2.5) [n=163]0.1091
Percentage brain volume change (PBVC) from baseline (%)Secondary-0.39 (95% CI -0.58 to -0.19) [n=43]-0.60 (95% CI -0.76 to -0.43) [n=92]0.2312
Free from clinical disease activitySecondary90/135 (66.7%)133/185 (71.9%)0.2166
No active T2 lesionsSecondary59/135 (43.7%)70/185 (37.8%)0.0414
Any AE during first 24 hoursAdverse17 (11.6%)19 (9.5%)0.5331
SAE during first 24 hoursAdverse2 (1.4%)4 (2.0%)0.6516
Any AE after first 24 hoursAdverse111 (75.5%)139 (69.5%)0.2177
SAE after first 24 hoursAdverse2 (1.4%)7 (3.5%)0.2154
Infections (total)Adverse50 (34.0%)75 (37.5%)
Urinary tract infectionAdverse14 (9.5%)15 (7.5%)
Upper respiratory tract infectionAdverse10 (6.8%)13 (6.5%)
NasopharyngitisAdverse8 (5.4%)15 (7.5%)
HeadacheAdverse14 (9.5%)15 (7.5%)
LymphopeniaAdverse7 (4.8%)9 (4.5%)
FatigueAdverse9 (6.1%)11 (5.5%)
Increased aminotransferase levelsAdverse10 (6.8%)2 (1.0%)
Macular oedemaAdverse01 (0.5%)
Bradycardia/sinus bradycardia (first 24h)Adverse2 (1.4%)3 (1.5%)
B-cell lymphomaAdverse01 case
Superficial spreading melanomaAdverse01 case
DeathsAdverse00

Subgroup Analysis

Patients were divided into treatment-naïve, single-iDMT (treated with one injectable DMT, n=97), and multi-iDMT (treated with >1 injectable DMT, n=28) subgroups. Multi-iDMT patients had significantly worse outcomes: highest on-study ARR (0.57 vs 0.23 [single-iDMT] vs 0.21 [treatment-naïve]; p=0.02), lowest longitudinal ARR reduction (53.3% vs 82.4% [single-iDMT] vs 88.7% [treatment-naïve]; p=0.004), and shortest time to first relapse (6.1 vs 10.5 months [single-iDMT]; p=0.04). No significant differences were found between treatment-naïve and single-iDMT groups for any outcome, suggesting that patients who have failed only one iDMT respond similarly to treatment-naïve patients when switched to fingolimod.

Criticisms

  • Study was significantly underpowered: only 347 of planned 432 patients enrolled, resulting in only 28% power to detect primary endpoint difference
  • Open-label design with no randomization introduces potential bias in treatment allocation and outcome assessment
  • Non-randomized design means baseline differences between groups (disease duration, pre-study ARR, relapse severity) could confound results
  • Different eligibility criteria between Spain (≥2 relapses required) and Australia (PBS eligibility) may affect generalizability
  • Small multi-iDMT subgroup (n=28) limits reliability of subgroup conclusions
  • Missing MRI data for substantial proportion of patients (11.9% treatment-naïve, 21.5% previously treated) limits MRI outcome interpretation
  • No imputation for missing values may bias results
  • Study duration of 48 weeks is relatively short to assess long-term outcomes or rare adverse events (e.g., PML, cryptococcal infections)
  • PRIMUS patient-reported outcomes showed no change from baseline in any group, possibly due to ceiling effects or insensitivity
  • Recruitment difficulties related to timing of fingolimod's second-line approval in Europe

Funding

Novartis Pharma AG

Based on: EARLIMS (Multiple Sclerosis Journal-Experimental, Translational and Clinical, 2020)

Authors: Oscar Fernández, Guillermo Izquierdo, Eduardo Aguera, ..., Michael Barnett; on behalf of the EARLIMS investigators

Citation: Mult Scler J Exp Transl Clin. 2020 Jul-Sep;6(3):2055217320957358

Content summarized and formatted by NeuroTrials.ai.