IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event
Kinkel RP, Kollman C, O'Connor P, Murray TJ, Simon J, Arnold D, et al.;
Commented by , 28 Apr 2006
Background
Treatment of clinically isolated syndrome (CIS) with interferon beta-1a (IFNβ-1a) have shown that conversion to clinically definite multiple sclerosis (CDMS) can be delayed for up to 3 years using Avonex 30 mg/week (CHAMPS (ref. 1)) or Rebif 22 mg/week (ETOMS (ref. 2)). The long-term effect of IFNβ on CIS conversion is still poorly described and we do not know if the beneficial effect of early intervention lasts.
Aim
To determine if the beneficial effect of IFNβ-1a observed in CHAMPS are sustained for up to 5 years.
Methods
A subgroup of patients from CHAMPS participated in the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS) Study. The study design was open label and the patients were offered IFNβ-1a 30 IMμg/week for up to 5 years from CHAMPS randomization.
Patients receiving placebo in CHAMPS were categorized as the delayed treatment group (DT; n=103), and patients who received IFNβ-1a were the immediate treatment group (IT; n=100). Primary outcome measure was rate of CDMS development and a number of additional clinical outcomes were also measured.
Results
Median time to initiation of IFNβ-1a therapy was delayed 29 months in the DT group.
The IT group had a lower probability of developing CDMS compared with the DT group (5-year incidence 36 ± 9 vs. 49 ± 10%, unadjusted hazard ratio 0.65, 95% CI: 0.43 to 0.97, p = 0.03).
Treatment effect was stronger after adjusting for confounding effects such as age, onset symptom, MRI T2 lesion volume and number of Gd-enhancing lesions (0.57, 95% CI: 0.38 to 0.86, p=0.008).
Multivariate analysis showed that factors independently associated with an increased rate of developing CDMS were randomization to the DT group and younger age at onset of neurologic symptoms.
Annualized relapse rates did not differ between year 3 and 5, which was also true for MRI data. No severe safety concerns arose during the study.
Dr Blinkenberg's comments
The study shows that treatment with IFNβ-1a IM once weekly immediately following a first clinical demyelinating event, delay the rate of development of MS by 35% after 5 years compared to delayed initiation of therapy. The statistical evaluation furthermore shows that adjusting for potential confounding effects may increase this delay to 43%.
Secondary outcome measures, such as annualized relapse rates and MRI data, did not differ between the two treatment groups after initiation of therapy in the DT group. These results indicate that the effect of IFNβ-1a is sustained over time and that immediate intervention has modest beneficial effect compared with delayed treatment initiation.
The study design was open-label and therefore primarily providing information on drug safety. Long-term controlled, randomized trials in MS are obviously unethical, due to the well-documented effect of IFNβ. Another important problem in long-term placebo-controlled trials, is the increased dropout of patients who are doing poorly in the placebo-group.
For these main reasons we will probably never see class I evidence for long-term IFNβ efficacy, and clinical decisions must rely on studies of lower class evidence. The results of the current study corroborate conclusions of other studies showing benefit of early treatment intervention, but most importantly, it indicates that the effect of immediate treatment with IFNβ-1a seem to last.
References
1. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. New England Journal of Medicine 2000; 343 (13); 898-904 (Note: Free full text article)
2. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357 (9268); 1576-82