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BENEFIT 15-Years

Long-term clinical outcomes in patients with CIS treated with interferon beta-1b: results from the 15-year follow up of the BENEFIT trial

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Year of Publication: 2024

Authors: Ludwig Kappos, Gilles Edan, Mark S. Freedman, ..., for the BENEFIT and BENEFIT 15 Study Groups

Journal: Journal of Neurology

Citation: J Neurol (2024) 271:4599–4609

Link: https://clinicaltrials.gov/ct2/show/NCT03269175

Clinical Question

What are the 15-year long-term clinical outcomes of early versus delayed treatment with interferon beta-1b in patients presenting with clinically isolated syndrome (CIS)?

Bottom Line

Fifteen years after randomization, early treatment with IFNB-1b at CIS maintained a 30.5% lower risk of conversion to clinically definite MS compared to delayed treatment. Disability remained low in both groups (median EDSS 2.0), SPMS conversion was low (~10%), and cognitive function (PASAT-3) was significantly better with early treatment. These results support the long-term benefits of early treatment initiation with IFNB-1b in CIS patients.

Major Points

  • 55.8% of original BENEFIT cohort (261/468) enrolled in 15-year follow-up with balanced baseline characteristics
  • Early treatment reduced risk of CDMS conversion by 30.5% at 15 years (HR 0.695, p=0.0029)
  • Kaplan-Meier estimate for CDMS conversion: 67.6% early vs 73.5% delayed treatment
  • Only 9.6% converted to SPMS overall (9.9% early, 9.0% delayed) with no significant difference
  • Median time to first relapse: 1888 days (early) vs 931 days (delayed)
  • Disability remained low: median EDSS 2.0 at Year 15; 62% had EDSS ≤2.5; only 2.7% were wheelchair-dependent (EDSS ≥7)
  • Significant treatment effect on PASAT-3 cognitive scores over 15 years (p=0.0036)
  • 66.3% remained employed at Year 15 vs 74.7% at baseline; 59.4% reported no MS impact on working ability
  • No significant differences in MRI outcomes between groups at Year 15
  • Quality of life remained good with median EQ-5D of 0.80
  • Mean delay in treatment initiation for delayed group was 1.53 years

Design

Study Type: Prospective cross-sectional 15-year follow-up of randomized, placebo-controlled, parallel group trial

Randomization: 1

Blinding: Original trial: double-blind for 2 years, then rater-blinded for 5 years; BENEFIT 15: blinded as for initial randomization

Enrollment Period: BENEFIT 15: September 2017 to May 2018

Follow-up Duration: 15.2 years mean follow-up from original randomization

Centers: 69

Countries: Austria, Belgium, Canada, Czech Republic, Denmark, France, Finland, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Portugal, Slovenia, Spain, Sweden, Switzerland, UK

Sample Size: 261

Analysis: Kaplan-Meier methods, log-rank tests, proportional hazards regression, generalized linear regression for ARR, parametric longitudinal linear mixed model for PASAT-3; exploratory analyses with no primary endpoint defined

Inclusion Criteria

  • Patients with clinically isolated syndrome (CIS)
  • ≥2 brain MRI lesions suggestive of multiple sclerosis
  • Originally randomized in BENEFIT trial

Exclusion Criteria

  • Not specified for BENEFIT 15 follow-up (all originally randomized patients invited)

Arms

FieldEarly TreatmentControl
InterventionInterferon beta-1b (IFNB-1b) 250 µg subcutaneously every other day starting at or shortly after CISPlacebo for 2 years or until conversion to CDMS, then offered open-label IFNB-1b 250 µg SC every other day; mean delay to treatment initiation was 1.53 years
Duration15 years follow-up15 years follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time to conversion to clinically definite multiple sclerosis (CDMS) - exploratory, no formal primary endpointPrimary0.6950.0029
Risk of relapse over 15 yearsSecondary0.1008 (not significant)
Time to first relapse - medianSecondary
Mean annualized relapse rate over 15 yearsSecondary
Time to recurrent relapseSecondary0.842 (95% CI 0.671-1.056)Not significant
Conversion to SPMS at 15 years (KM estimate)Secondary0.9713
EDSS score at Year 15 - mean (SD)SecondaryNot significant
EDSS ≤2.5 at Year 15Secondary
EDSS ≥7 (wheelchair dependent) at Year 15Secondary
Confirmed and sustained 1-point EDSS worseningSecondary
Confirmed 2.5-point EDSS worseningSecondary
PASAT-3 score at Year 15 - mean (SD)Secondary
EQ-5D index score at Year 15 - median (Q1, Q3)Secondary
EQ-5D VAS at Year 15 - median (Q1, Q3)Secondary
Employment at Year 15Secondary
Working >20 hours/week at Year 15Secondary
MS having no impact on working abilitySecondary
No hospitalizations in past 12 monthsSecondary
Use of adaptations in past 6 months due to MSSecondary
New T2 lesions since Year 11 scanSecondaryNot significant
McDonald 2010 MS criteria met at Year 15Secondary
McDonald 2001 MS criteria met at Year 15Secondary
Currently receiving DMT at Year 15Secondary
Currently receiving IFNB at Year 15Secondary
Any adverse event during BENEFIT 15Adverse
DeathsAdverse
Serious adverse eventsAdverse
PregnanciesAdverse

Subgroup Analysis

SPMS occurrence was weakly associated with higher age (HR 1.056, p=0.0484). In delayed treatment group, KM estimate for SPMS was 4.0% for patients <30 years at study entry vs 14.3% for ≥30 years. In early treatment group, SPMS conversion was similar regardless of age at entry (10.5% for <30 years vs 9.9% for ≥30 years).

Criticisms

  • Only 55.8% of original cohort participated in 15-year follow-up, raising potential selection bias concerns
  • Open-label treatment after initial 2-year double-blind phase limits interpretation of long-term differences
  • 23.75% of BENEFIT 15 patients evaluated by telephone rather than in-person assessment
  • Mean delay to treatment in 'delayed' group was only 1.53 years - both groups effectively received early treatment
  • Exploratory study design with no formal primary endpoint limits statistical conclusions
  • Many patients switched to other DMTs over 15 years, confounding IFNB-1b-specific effects
  • No untreated control group for comparison of natural history
  • Potential survival bias - patients with more severe disease may have dropped out
  • MRI data available for only 64.4% of BENEFIT 15 participants

Funding

Bayer AG

Based on: BENEFIT 15-Years (Journal of Neurology, 2024)

Authors: Ludwig Kappos, Gilles Edan, Mark S. Freedman, ..., for the BENEFIT and BENEFIT 15 Study Groups

Citation: J Neurol (2024) 271:4599–4609

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