Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial.
BACKGROUND
The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression.


METHODS
Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211.


RESULTS
235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b.


CONCLUSIONS
Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes.


BACKGROUND
Bayer Schering Pharma.
Kappos
Ludwig
L
University Hospital, Basel, Switzerland. lkappos@uhbs.ch
Freedman
Mark S
MS
Polman
Chris H
CH
Edan
Gilles
G
Hartung
Hans-Peter
HP
Miller
David H
DH
Montalbán
Xavier
X
Barkhof
Frederik
F
Radü
Ernst-Wilhelm
EW
Metzig
Carola
C
Bauer
Lars
L
Lanius
Vivian
V
Sandbrink
Rupert
R
Pohl
Christoph
C
D000328:Adult; D003627:Data Interpretation, Statistical; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy*; D016016:Proportional Hazards Models; D018570:Risk Assessment; D011795:Surveys and Questionnaires; D055815:Young Adult
D000068576:Interferon beta-1b; D016899:Interferon-beta