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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 years | Early Treatment: 15.7% lower risk; Delayed Treatment: ReferenceSecondary0.1008 (not significant)
Time to first relapse - median | Early Treatment: 1888 days; Delayed Treatment: 931 daysSecondary
Mean annualized relapse rate over 15 years | Overall: 0.2083Secondary
Time to recurrent relapseSecondary0.842 (95% CI 0.671-1.056)Not significant
Conversion to SPMS at 15 years (KM estimate) | Early Treatment: 16/161 (9.9%; KM: 10.2%); Delayed Treatment: 9/100 (9.0%; KM: 9.9%)Secondary0.9713
EDSS score at Year 15 - mean (SD) | Early Treatment: 2.55 (1.76); Delayed Treatment: 2.43 (1.76); Median (Q1, Q3): 2.0 (1.5, 3.5) for bothSecondaryNot significant
EDSS ≤2.5 at Year 15 | Overall: 62%Secondary
EDSS ≥7 (wheelchair dependent) at Year 15 | Overall: 2.7%Secondary
Confirmed and sustained 1-point EDSS worsening | Early Treatment: 91 (56.5%) confirmed; 47 (29.2%) sustained; Delayed Treatment: 49 (49%) confirmed; 34 (34%) sustainedSecondary
Confirmed 2.5-point EDSS worsening | Early Treatment: 32 (19.9%); Delayed Treatment: 18 (18%)Secondary
PASAT-3 score at Year 15 - mean (SD) | Early Treatment: 51.4 (10.7); Delayed Treatment: 51.1 (8.8); Treatment Effect Over 15 Years: p=0.0036 (favors early treatment)Secondary
EQ-5D index score at Year 15 - median (Q1, Q3) | Overall: 0.7960 (0.6910, 1.000); Change from baseline: 0.00 (-0.1880, 0.00)Secondary
EQ-5D VAS at Year 15 - median (Q1, Q3) | Overall: 80.00 (65.00, 90.00); Baseline: 85.50 (75.00, 93.00)Secondary
Employment at Year 15 | Overall: 173/261 (66.3%); Baseline: 195/261 (74.7%)Secondary
Working >20 hours/week at Year 15 | Overall: 143 (54.8%)Secondary
MS having no impact on working ability | Overall: 155 (59.4%)Secondary
No hospitalizations in past 12 months | Overall: 245/261 (93.9%)Secondary
Use of adaptations in past 6 months due to MS | Overall: 29 (11.1%); Walking aids: 17 (6.5%); Wheelchairs: 8 (3.1%)Secondary
New T2 lesions since Year 11 scan | Early Treatment: 52/110 (47.3%); Delayed Treatment: 30/58 (51.7%)SecondaryNot significant
McDonald 2010 MS criteria met at Year 15 | Early Treatment: 149/157 (94.9%); Delayed Treatment: 94/98 (95.9%)Secondary
McDonald 2001 MS criteria met at Year 15 | Early Treatment: 146/155 (94.2%); Delayed Treatment: 92/97 (94.8%)Secondary
Currently receiving DMT at Year 15 | Overall: 161 (61.7%); Early Treatment: 61.5%; Delayed Treatment: 62%Secondary
Currently receiving IFNB at Year 15 | Overall: 60 (37.3% of those on DMT); Early Treatment: 37.4%; Delayed Treatment: 37.1%Secondary
Any adverse event during BENEFIT 15AdverseOverall: 0 (no AEs reported during BENEFIT 15 study period)
DeathsAdverseOverall: 0
Serious adverse eventsAdverseOverall: 0
PregnanciesAdverseOverall: 0

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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