Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT

Abstract

Objective: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS).

Methods: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years.

Results: Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms.

Conclusions: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.

Keywords: INTERFERON; INTERVENTIONAL; MULTIPLE SCLEROSIS; RANDOMISED TRIALS.

Figure 1

Proportion of patients requiring escalation therapy pooled across total population. The majority of patients did not require escalation therapy during the study. The treatments used by the 6.6% who required escalation therapy are shown in the inset box. Escalation therapies included alemtuzumab, cyclosporine, cladribine, cyclophosphamide, daclizumab, fingolimod, fingolimod hydrochloride, methotrexate, methotrexate sodium, mitoxantrone, mitoxantrone hydrochloride, mycophenolate mofetil, mycophenolate sodium, natalizumab, rituximab, sirolimus, tacrolimus and temsirolimus. ^aWhen multiple therapies are listed, the order indicates the sequence of therapies. Inset box lists only the escalation therapies administered during the study. Escalation therapy was generally similar between groups, with the exception of natalizumab (early treatment, 10 patients (3.4%); delayed treatment, 9 patients (5.1%)).

Figure 2

Kaplan–Meier estimates for the probability of CDMS over 8 years. Probability of conversion to CDMS was significantly higher in the delayed treatment group. At the 50th percentile, conversion to CDMS was delayed by approximately 3.7 years in the early treatment group. ^aBy proportional hazards regression, adjusted for steroid use during the first clinical event, type of disease onset, and categorised number of T2 lesions on BENEFIT screening MRI. CDMS, clinically definite multiple sclerosis.

Figure 3

Annualised relapse rate (ARR) by year in the total number of patients observed overall and during each study year. ARR was significantly lower in the early treatment group than in the delayed treatment group over the entire study period as well as in years 1 and 8. ARR was lower among patients in the early treatment than the delayed treatment group for years 1 and 2 (0.233 (95% CI 0.195 to 0.277) vs 0.325 (95% CI 0.268 to 0.392), p=0.0073^a; RR=0.705, 95% CI 0.546 to 0.910) and from years 6 to 8 (0.146 (95% CI 0.115 to 0.184)) vs 0.212 (95% CI 0.164 to 0.270); p=0.032^a; RR=0.694, 95% CI 0.497 to 0.969). ^aWald-type χ² test. Generalised linear Poisson regression model.