Effect of Peginterferon Beta-1a on MRI Measures in RRMS
Effect of Peginterferon Beta-1a on MRI Measures in RRMS
A total of 1516 patients underwent randomization, of whom 1512 received at least one dose of study drug and were included in the ITT population (placebo n = 500; peginterferon beta-1a every 2 weeks n = 512; peginterferon beta-1a every 4 weeks n = 500). Patient demographics and baseline disease characteristics in the overall study population were generally well balanced across the treatment groups; data are summarized in Table 1. Patients included in ADVANCE had mean baseline EDSS scores of 2.44−2.48; 17% had been treated with any MS medication prior to study entry, including 7% who used beta interferons or glatiramer acetate. Compared with the placebo and peginterferon beta-1a every 4 week groups, slightly more subjects in the peginterferon beta-1a every 2 week group had no Gd+ lesions at baseline (59%, 59%, and 65%, respectively; Table 1) and mean number of Gd+ lesions at baseline was also lower in this treatment group (Table 1); as mentioned above, analyses of Gd+ lesion number were adjusted for baseline Gd+ number of lesions. The overall study completion rate for Year 1 was 88% (a complete overview of ADVANCE Year 1 patient disposition has been published previously).
Peginterferon beta-1a every 2 weeks significantly reduced the number of new or newly-enlarging T2 lesions, new T1 hypointense lesions, Gd+ lesions, and new active lesions at Weeks 24 and 48, compared with placebo and peginterferon beta-1a every 4 weeks (all p < 0.0001; Figure 1). Peginterferon beta-1a every 4 weeks significantly reduced the number of new or newly-enlarging T2 lesions (Figure 1) and new active lesions at Weeks 24 and 48, compared with placebo (Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional), and numerically reduced the number of new T1 hypointense lesions and Gd+ lesions, although reductions did not reach statistical significance (Figure 1).
(Enlarge Image)
Figure 1.
Lesion numbers at Weeks 24 and 48. A) New or newly-enlarging T2 lesions Based on negative binomial regression analysis, adjusted baseline T2 lesion number. The data for 48 weeks has been published previously [10]. CI = confidence interval. B) New T1 hypointense lesions compared to baseline Based on mean number of new lesions only and p value based on multiple logit regression, adjusted for baseline number of T1 lesions. The data for 48 weeks has been published previously [10]. SE = standard error. C) Gd+ lesions Based on mean number of lesions only and p value based on multiple logit regression, adjusted for baseline number of Gd+ lesions. Gd+ = gadolinium-enhancing; SE = standard error.
Peginterferon beta-1a every 2 weeks significantly reduced the volume of T2 and T1 hypointense lesions at Weeks 24 and 48, compared with placebo and peginterferon beta-1a every 4 weeks (Table 2). Peginterferon beta-1a every 4 weeks significantly reduced the volume of T2 lesions at Weeks 24 and 48, compared with placebo (Table 2); no significant reduction in the volume of T1 hypointense lesions was seen versus placebo at Weeks 24 or 48 for every 4 week dosing (Table 2).
Significantly higher proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had NEDA during each assessment period, compared with placebo (baseline to Week 48 ORs: 2.89 [p < 0.0001] and 1.55 [p = 0.0103], respectively; baseline to Week 24 ORs: 2.47 [p < 0.0001] and 1.58 [p = 0.0022], respectively; Weeks 24–48 ORs: 3.71 [p < 0.001] and 1.42 [p = 0.0127], respectively; Figure 2). Significantly more patients had NEDA on every 2 week versus every 4 week dosing (baseline to Week 48: OR 1.87 [p < 0.0001]; baseline to Week 24: OR 1.57 [p = 0.0011]; Weeks 24–48: OR 2.62 [p < 0.001]; Figure 2). Less measured disease activity was observed in Weeks 24–48 than in the first 24 weeks for the every 2 week dosing group.
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Figure 2.
NEDA proportions. A) Baseline to Week 48. B). Baseline to Week 24. C). Weeks 24–48. ORs are shown with 95% confidence intervals in parentheses. Defined as absence of both clinical (no relapses and no onset of 12-week confirmed disability progression over the interval) and MRI (no gadolinium-enhancing lesions and no new or newly-enlarging T2 hyperintense lesions) disease activity; data from patients with complete MRI results during the time interval were used for analysis of MRI disease activity. NEDA = No evidence of disease activity; MRI = magnetic resonance imaging; OR = odds ratio.
Significantly higher proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had MRI-NEDA during each assessment period, compared with placebo (baseline to Week 48 ORs: 2.94 [p < 0.0001] and 1.41 [p = 0.0318], respectively; baseline to Week 24 ORs: 2.44 [p < 0.0001] and 1.46 [p = 0.0078], respectively; Weeks 24–48 ORs: 4.11 [p < 0.0001] and 1.44 [p = 0.0080], respectively; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). Significantly more patients had MRI-NEDA on every 2 week versus every 4 week dosing (baseline to Week 48: OR 2.09 [p < 0.0001]; baseline to Week 24: OR 1.67 [p = 0.0002]; Weeks 24–48 OR: 2.86 [p < 0.0001]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional).
Significantly greater proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had clinical-NEDA from baseline to Week 48 and from baseline to Week 24, compared with placebo (baseline to Week 48 ORs: 1.77 [p < 0.0001] and 1.48 [p = 0.0060], respectively; baseline to Week 24 ORs: 1.57 [p = 0.0088] and 1.61 [p = 0.0063], respectively; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). From Weeks 24 to 48, significantly greater proportions of patients receiving peginterferon beta-1a every 2 weeks had clinical-NEDA, compared with placebo (OR: 1.75 [p = 0.0070]; every 4 weeks vs. placebo OR: 1.22 [p = 0.3058]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). No significant difference was seen between every 2 week and every 4 week dosing for proportions of clinical-NEDA patients (baseline to Week 48: OR 1.20 [p = 0.2367]; baseline to Week 24: OR 0.98 [p = 0.8947]; Weeks 24–48 OR: 1.44 [p = 0.0898]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional).
Results from disease activity sensitivity analyses involving an allowance for missing MRI scan data, or defined as no clinical activity with allowances for minimal MRI activity, were consistent with the primary NEDA analyses, with higher ORs for peginterferon beta-1a every 2 weeks, favoring this dosing regimen over every 4 weeks and placebo (Table 3).
Results
Patient Disposition and Baseline Characteristics
A total of 1516 patients underwent randomization, of whom 1512 received at least one dose of study drug and were included in the ITT population (placebo n = 500; peginterferon beta-1a every 2 weeks n = 512; peginterferon beta-1a every 4 weeks n = 500). Patient demographics and baseline disease characteristics in the overall study population were generally well balanced across the treatment groups; data are summarized in Table 1. Patients included in ADVANCE had mean baseline EDSS scores of 2.44−2.48; 17% had been treated with any MS medication prior to study entry, including 7% who used beta interferons or glatiramer acetate. Compared with the placebo and peginterferon beta-1a every 4 week groups, slightly more subjects in the peginterferon beta-1a every 2 week group had no Gd+ lesions at baseline (59%, 59%, and 65%, respectively; Table 1) and mean number of Gd+ lesions at baseline was also lower in this treatment group (Table 1); as mentioned above, analyses of Gd+ lesion number were adjusted for baseline Gd+ number of lesions. The overall study completion rate for Year 1 was 88% (a complete overview of ADVANCE Year 1 patient disposition has been published previously).
MRI Outcomes
Peginterferon beta-1a every 2 weeks significantly reduced the number of new or newly-enlarging T2 lesions, new T1 hypointense lesions, Gd+ lesions, and new active lesions at Weeks 24 and 48, compared with placebo and peginterferon beta-1a every 4 weeks (all p < 0.0001; Figure 1). Peginterferon beta-1a every 4 weeks significantly reduced the number of new or newly-enlarging T2 lesions (Figure 1) and new active lesions at Weeks 24 and 48, compared with placebo (Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional), and numerically reduced the number of new T1 hypointense lesions and Gd+ lesions, although reductions did not reach statistical significance (Figure 1).
(Enlarge Image)
Figure 1.
Lesion numbers at Weeks 24 and 48. A) New or newly-enlarging T2 lesions Based on negative binomial regression analysis, adjusted baseline T2 lesion number. The data for 48 weeks has been published previously [10]. CI = confidence interval. B) New T1 hypointense lesions compared to baseline Based on mean number of new lesions only and p value based on multiple logit regression, adjusted for baseline number of T1 lesions. The data for 48 weeks has been published previously [10]. SE = standard error. C) Gd+ lesions Based on mean number of lesions only and p value based on multiple logit regression, adjusted for baseline number of Gd+ lesions. Gd+ = gadolinium-enhancing; SE = standard error.
Peginterferon beta-1a every 2 weeks significantly reduced the volume of T2 and T1 hypointense lesions at Weeks 24 and 48, compared with placebo and peginterferon beta-1a every 4 weeks (Table 2). Peginterferon beta-1a every 4 weeks significantly reduced the volume of T2 lesions at Weeks 24 and 48, compared with placebo (Table 2); no significant reduction in the volume of T1 hypointense lesions was seen versus placebo at Weeks 24 or 48 for every 4 week dosing (Table 2).
Analyses of Achieving No Evidence of Disease Activity
Significantly higher proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had NEDA during each assessment period, compared with placebo (baseline to Week 48 ORs: 2.89 [p < 0.0001] and 1.55 [p = 0.0103], respectively; baseline to Week 24 ORs: 2.47 [p < 0.0001] and 1.58 [p = 0.0022], respectively; Weeks 24–48 ORs: 3.71 [p < 0.001] and 1.42 [p = 0.0127], respectively; Figure 2). Significantly more patients had NEDA on every 2 week versus every 4 week dosing (baseline to Week 48: OR 1.87 [p < 0.0001]; baseline to Week 24: OR 1.57 [p = 0.0011]; Weeks 24–48: OR 2.62 [p < 0.001]; Figure 2). Less measured disease activity was observed in Weeks 24–48 than in the first 24 weeks for the every 2 week dosing group.
(Enlarge Image)
Figure 2.
NEDA proportions. A) Baseline to Week 48. B). Baseline to Week 24. C). Weeks 24–48. ORs are shown with 95% confidence intervals in parentheses. Defined as absence of both clinical (no relapses and no onset of 12-week confirmed disability progression over the interval) and MRI (no gadolinium-enhancing lesions and no new or newly-enlarging T2 hyperintense lesions) disease activity; data from patients with complete MRI results during the time interval were used for analysis of MRI disease activity. NEDA = No evidence of disease activity; MRI = magnetic resonance imaging; OR = odds ratio.
Significantly higher proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had MRI-NEDA during each assessment period, compared with placebo (baseline to Week 48 ORs: 2.94 [p < 0.0001] and 1.41 [p = 0.0318], respectively; baseline to Week 24 ORs: 2.44 [p < 0.0001] and 1.46 [p = 0.0078], respectively; Weeks 24–48 ORs: 4.11 [p < 0.0001] and 1.44 [p = 0.0080], respectively; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). Significantly more patients had MRI-NEDA on every 2 week versus every 4 week dosing (baseline to Week 48: OR 2.09 [p < 0.0001]; baseline to Week 24: OR 1.67 [p = 0.0002]; Weeks 24–48 OR: 2.86 [p < 0.0001]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional).
Significantly greater proportions of patients receiving peginterferon beta-1a every 2 and every 4 weeks had clinical-NEDA from baseline to Week 48 and from baseline to Week 24, compared with placebo (baseline to Week 48 ORs: 1.77 [p < 0.0001] and 1.48 [p = 0.0060], respectively; baseline to Week 24 ORs: 1.57 [p = 0.0088] and 1.61 [p = 0.0063], respectively; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). From Weeks 24 to 48, significantly greater proportions of patients receiving peginterferon beta-1a every 2 weeks had clinical-NEDA, compared with placebo (OR: 1.75 [p = 0.0070]; every 4 weeks vs. placebo OR: 1.22 [p = 0.3058]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional). No significant difference was seen between every 2 week and every 4 week dosing for proportions of clinical-NEDA patients (baseline to Week 48: OR 1.20 [p = 0.2367]; baseline to Week 24: OR 0.98 [p = 0.8947]; Weeks 24–48 OR: 1.44 [p = 0.0898]; Additional file 2 http://www.biomedcentral.com/1471-2377/14/240/additional).
Results from disease activity sensitivity analyses involving an allowance for missing MRI scan data, or defined as no clinical activity with allowances for minimal MRI activity, were consistent with the primary NEDA analyses, with higher ORs for peginterferon beta-1a every 2 weeks, favoring this dosing regimen over every 4 weeks and placebo (Table 3).
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