Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study.
BACKGROUND
Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS.


METHODS
In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 microg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211.


RESULTS
Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31).


CONCLUSIONS
Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.
Kappos
Ludwig
L
Neurology and Department of Research, 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
Bauer
Lars
L
Dahms
Susanne
S
Lanius
Vivian
V
Pohl
Christoph
C
Sandbrink
Rupert
R
D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016899:Interferon-beta / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009103:Multiple Sclerosis / Q000145:classification / Q000188:drug therapy*; D012720:Severity of Illness Index; D013997:Time Factors
D007155:Immunologic Factors; D016899:Interferon-beta