The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

Abstract

Objective: To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay.

Methods: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed.

Results: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task-3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups.

Conclusions: Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS.

Clinicaltrialsgov identifier: NCT01795872.

Classification of evidence: This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years.

Figure 1. Study profile for the entire BENEFIT Study

^aIncludes one patient randomized to receive interferon beta-1b but treated with placebo. ^bIncludes one patient randomized to receive placebo but treated with interferon beta-1b. ^cIncludes one patient entered into the BENEFIT follow-up study after premature discontinuation of the BENEFIT Study. ^dFour lost to follow-up, 2 missing data, 1 noncompliance, 1 treatment failure, 2 refused final visit. ^eThree lost to follow-up, 1 relocated away from site, 1 pregnancy, 1 unable to attend visit because of job. ^fTo be eligible for the 11-year follow-up, patients only needed to be randomized and treated in the original BENEFIT Study (i.e., they did not need to be included in the previous BENEFIT analyses). BENEFIT = Betaferon/Betaseron in Newly Emerging MS for Initial Treatment; CDMS = clinically definite multiple sclerosis; DMT = disease-modifying therapy.

Figure 2. Kaplan-Meier estimates of probability of CDMS (A), ARR (B), and EDSS scores (C) in the BENEFIT 11 population

^aOne patient in the early-treatment arm was excluded from this analysis because diagnosis of CDMS was unclear. Risk of conversion to CDMS was significantly lower for the early-treatment group compared with the delayed-treatment group. Overall ARR was significantly lower in the early-treatment group compared with the delayed-treatment group. As expected, EDSS scores increased from baseline to year 11, but they tended to remain relatively low for both groups. *p < 0.05; **p < 0.01. ARR = annualized relapse rate; BENEFIT = Betaferon/Betaseron in Newly Emerging MS for Initial Treatment; CDMS = clinically definite multiple sclerosis; CI = confidence interval; EDSS = Expanded Disability Status Scale; HR = hazard ratio; RR = risk ratio.

Figure 3. Mean PASAT-3 total score from baseline to year 11

Over the entire study period, the mean PASAT-3 total score was higher in the early- than the delayed-treatment group (p = 0.0070). PASAT-3 = Paced Auditory Serial Addition Task–3.