Of the 372 RRMS patients randomized, 72 (19%) failed to complete two full years on their assigned treatments.

Over the two-year period, there were 25 MS-related hospitalizations in the 0.25 mg Betaseron-treated group compared to 48 hospitalizations in the placebo group. In comparison, non-MS hospitalizations were evenly distributed among the groups, with 16 in the 0.25 mg Betaseron group and 15 in the placebo group. The average number of days of MS-related steroid use was 41 days in the 0.25 mg Betaseron group and 55 days in the placebo group (p=0.004).

MRI data were also analyzed for patients in this study. A frequency distribution of the observed percent changes in MRI area at the end of two years was obtained by grouping the percentages in successive intervals of equal width. Figure 1 displays a histogram of the proportions of patients, which fell into each of these intervals. The median percent change in MRI area for the 0.25 mg group was -1.1%, which was significantly smaller than the 16.5% observed for the placebo group (p=0.0001).

Figure 1 : Distribution of Change in MRI Area

In an evaluation of frequent MRI scans (every six weeks) on 52 patients at one site, the percent of scans with new or expanding lesions was 29% in the placebo group and 6% in the 0.25 mg treatment group (p=0.006).

The exact relationship between MRI findings and clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in this study has not been evaluated.

Studies 2 and 3 were multicenter, randomized, double-blind, placebo controlled trials conducted to assess the effect of Betaseron in patients with SPMS. Study 2was conducted in Europe and Study 3 was conducted in North America. Both studies enrolled patients with clinically definite or laboratory-supported MS in the secondary progressive phase, and who had evidence of disability progression (both Study 2 and 3) or two relapses (Study 2 only) within the previous two years. Baseline Kurtzke expanded disability status scale (EDSS) scores ranged from 3.0 to 6.5². Patients in Study 2 were randomized to receive Betaseron 0.25 mg (n=360) or placebo (n=358). Patients in Study 3 were randomized to Betaseron 0.25 mg (n=317), Betaseron 0.16 mg/m²of body surface area (n=314, mean assigned dose 0.30 mg), or placebo (n=308). Test agents were administered subcutaneously, every other day for three years.

The primary outcome measure was progression of disability, defined as a 1.0 point increase in the EDSS score, or a 0.5 point increase for patients with baseline EDSS ≥ 6.0. In Study 2, time to progression in EDSS was longer in the Betaseron treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Betaseron and placebo groups, respectively. In Study 3, the rates of progression did not differ significantly between treatment groups, with estimated annualized rates of progression of 12%, 14%, and 12% in the Betaseron fixed dose, surface area-adjusted dose, and placebo groups, respectively.

Multiple analyses, including covariate and subset analyses based on sex, age, disease duration, clinical disease activity prior to study enrollment, MRI measures at baseline and early changes in MRI following treatment were evaluated in order to interpret the discordant study results. No demographic or disease-related factors enabled identification of a patient subset where Betaseron treatment was predictably associated with delayed progression of disability.

In Studies 2 and 3, like Study 1, a statistically significant decrease in the incidence of relapses associated with Betaseron treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Betaseron and placebo groups, respectively (p < 0.001). In Study 3, the mean annual relapse rates were 0.16, 0.20, and 0.28, for the fixed dose, surface area-adjusted dose, and placebo groups, respectively (p < 0.02).

MRI endpoints in both Study 2 and Study 3 showed lesser increases in T2 MRI lesion area and decreased number of active MRI lesions in patients in the Betaseron groups. The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in MRI findings often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies is not known.

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