CLINICAL STUDIES
The clinical effects of Interferon beta-1b were studied in four randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis.
The effectiveness of Interferon beta-1b in relapsing-remitting MS (Study 1) was evaluated in a double blind, multiclinic, randomized, parallel, placebo controlled clinical investigation of two years' duration. The study enrolled MS patients, aged 18 to 50, who were ambulatory (EDSS of ≤ 5.5), exhibited a relapsing-remitting clinical course, met Poser's criteria1 for clinically definite and/or laboratory supported definite MS and had experienced at least two exacerbations over two years preceding the trial without exacerbation in the preceding month. Patients who had received prior immunosuppressant therapy were excluded.
An exacerbation was defined as the appearance of a new clinical sign/symptom or the clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persisted for a minimum of 24 hours.
Patients selected for study were randomized to treatment with either placebo (N=123), 0.05 mg of Interferon beta-1b (N=125), or 0.25 mg of Interferon beta-1b (N=124) self-administered subcutaneously every other day. Outcome based on the 372 randomized patients was evaluated after two years.
Patients who required more than three 28-day courses of corticosteroids were removed from the study. Minor analgesics (acetaminophen, codeine), antidepressants, and oral baclofen were allowed ad libitum, but chronic nonsteroidal anti-inflammatory drug (NSAID) use was not allowed.
The primary protocol-defined outcome measures were 1) frequency of exacerbations per patient and 2) proportion of exacerbation free patients. A number of secondary clinical and magnetic resonance imaging (MRI) measures were also employed. All patients underwent annual T2 MRI imaging and a subset of 52 patients at one site had MRIs performed every six weeks for assessment of new or expanding lesions.
The study results are shown in Table 3.
Table 3. Two Year RRMS Study Results. Primary and Secondary Clinical Outcomes
Efficacy Parameters
|
Treatment Groups |
Statistical Comparisons p-value |
Primary End Points
|
Placebo N=123 |
0.05 mg N=125 |
0.25 mg N=124 |
Placebo vs 0.05 mg |
0.05 mg vs 0.25 mg |
Placebo vs 0.25 mg |
Annual exacerbation rate |
1.31 |
1.14 |
0.90 |
0.005 |
0.113 |
0.0001
|
Proportion of exacerbation-free patients' |
16% |
18% |
25% |
0.609 |
0.288 |
0.094
|
Exacerbation frequency per patient |
0†1 2 3 4 ≥5 |
20 32 20 15 15 21 |
22 31 28 15 7 16 |
29 39 17 14 9 8 |
0.151 |
0.077 |
0.001
|
Secondary Endpoints
† â€
|
Median number of months to first on-study exacerbation |
5 |
6 |
9 |
0.299 |
0.097 |
0.010
|
Rate of moderate or severe exacerbations per year |
0.47 |
0.29 |
0.23 |
0.020 |
0.257 |
0.001
|
Mean number of moderate or severe exacerbation days per patient |
44.1 |
33.2 |
19.5 |
0.229 |
0.064 |
0.001
|
Mean change in EDSS score‡ at endpoint |
0.21 |
0.21 |
-0.07 |
0.995 |
0.108 |
0.144
|
Mean change in Scripps score‡‡ at endpoint |
-0.53 |
-0.50 |
0.66 |
0.641 |
0.051 |
0.126
|
Median duration in days per exacerbation |
36 |
33 |
35.5 |
ND |
ND |
ND
|
% change in mean MRI lesion area at endpoint |
21.4% |
9.8% |
-0.9% |
0.015 |
0.019 |
0.0001
|
ND Not done †14 exacerbation free patients (0 from placebo, six from 0.05 mg, and eight from 0.25 mg) dropped out of the study before completing six months of therapy. These patients are excluded from this analysis. ††Sequelae and Functional Neurologic Status, both required by protocol, were not analyzed individually but are included as a function of the EDSS. ‡ EDSS scores range from 1-10, with higher scores reflecting greater disability ‡‡ Scripps neurologic rating scores range from 0-100, with smaller scores reflecting greater disability. |
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 Interferon beta-1b-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 Interferon beta-1b 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 Interferon beta-1b 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).
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 Interferon beta-1b in patients with SPMS. Study 2 was 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 6.5. 2 Patients in Study 2 were randomized to receive Interferon beta-1b 0.25 mg (n=360) or placebo (n=358). Patients in Study 3 were randomized to Interferon beta-1b 0.25 mg (n=317), Interferon beta-1b 0.16 mg/m2 of 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 Interferon beta-1b treatment group (p=0.005), with estimated annualized rates of progression of 16% and 19% in the Interferon beta-1b 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 Interferon beta-1b 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 Interferon beta-1b 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 Interferon beta-1b treatment was demonstrated. In Study 2, the mean annual relapse rates were 0.42 and 0.63 in the Interferon beta-1b 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 Interferon beta-1b 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.
In Study 4, 468 patients who had recently (within 60 days) experienced an isolated demyelinating event, and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either 0.25 mg Interferon beta-1b (n = 292) or placebo (n= 176) subcutaneously every other day (ratio 5:3). The primary outcome measure was time to development of a second exacerbation with involvement of at least two distinct anatomical regions. Secondary outcomes were brain MRI measures, including the cumulative number of newly active lesions, and the absolute change in T2 lesion volume. Patients were followed for up to two years or until they fulfilled the primary endpoint.
Eight percent of subjects on Interferon beta-1b and 6% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation. Time to development of a second exacerbation was significantly delayed in patients treated with Interferon beta-1b compared to placebo (p<0.0001). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 45% in the placebo group and 28% of the Interferon beta-1b group (Figure 2). The risk for developing a second exacerbation in the Interferon beta-1b group was 53% of the risk in the placebo group (Hazard ratio= 0.53; 95% confidence interval 0.39 to 0.73).
Figure 2 – Onset of Second Exacerbation by Time on Study (Kaplan-Meier Methodology)
Patients treated with Interferon beta-1b demonstrated a lower number of newly active lesions during the course of the study. A significant difference between Interferon beta-1b and placebo was not seen in the absolute change in T2 lesion volume during the course of the study.
Safety and efficacy of treatment with Interferon beta-1b beyond three years are not known.
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