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Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

ABSTRACT: BACKGROUND:In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). METHODS:In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ?1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ? 1.0, or ?1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. RESULTS:Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ?1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. CONCLUSIONS:Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].

SUBMITTER: Newsome SD

PROVIDER: S-EPMC5400156 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

Newsome Scott D SD Kieseier Bernd C BC Liu Shifang S You Xiaojun X Kinter Elizabeth E Hung Serena S Sperling Bjoern B

Therapeutic advances in neurological disorders 20161116 1

<h4>Background</h4>In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL).<h4>Methods</h4>In tota ...[more]

PMID: 28450894

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Project description:Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years.Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd?+?and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p?<?0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p?<?0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p?<?0.0001).Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period.ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009.

Project description:Background and objectivesDisease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes. The goal of this study is to identify and assess patient characteristics in MS that predict disease activity and worsening.MethodsThe study population consisted of a prospective cohort of 1,008 participants with relapsing-remitting onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics, clinical history, MRI metrics, and treatment with outcomes of time to first new disease activity over up to 7 years of follow-up including relapse, MRI activity, and disease worsening.ResultsOne thousand eight participants were randomized, with 959 eligible for assessment of disease activity and worsening on follow-up. In multivariable models, the risk of relapse was higher in participants younger than 38 years at BL than in those older (HR range 1.36-1.43), with the presence of gadolinium (Gd)+ lesions at BL (HR 1.38, [95% confidence interval, CI 1.14, 1.67]) and with BL EDSS ≥3.5 vs <3.5 (HR range 1.63-1.67). The risk of new MRI activity was higher in younger participants (HR range 1.58-1.84), with higher preexisting lesion counts greater than the median lesion count with ≥71 T2 hyperintense lesions vs <71 (HR 1.50, [95% CI 1.27, 1.77]), with the presence of BL Gd+ lesions (HR 1.75, [95% CI 1.49, 2.06]), and higher BL T2 lesion volume (HR 1.02 for every unit increase in baseline volume, [95% CI 1.01, 1.03]). The risk of new MRI activity was lower in those receiving combination therapy compared with those that in those receiving either glatiramer acetate (HR range 0.67-0.68) or interferon beta-1a (HR range 0.68-0.70). The risk of disease worsening was higher for those with higher T2 volume (HR for 1 unit increase in volume 1.01, 95% CI 1.004, 1.03) and BL EDSS <2 (HR range 2.79-2.96). There were no associations between sex, race, and disease duration on relapse, MRI activity, or disease worsening in the multivariable analysis.DiscussionProspective data from a large clinical trial cohort show that younger MS patients with high BL relapses and MRI lesion burden have the highest risk of subsequent disease activity.Trial registration informationClinical trial registration number NCT00211887. CombiRx was registered at ClinicalTrials.gov (NCT00211887) on September 21, 2005. Study enrollment began in January 2005.

Project description:ImportanceMultiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown.ObjectiveTo understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS.Design, setting, and participantsIn this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014.Main outcomes and measuresVoxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores).ResultsAmong the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations.Conclusions and relevanceThese biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

Project description:Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.RRMS patients (18-65 years; Expanded Disability Status Scale score ?5) were randomized to double-blind placebo or peginterferon beta-1a 125 ?g every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.1512 patients were randomized and dosed (placebo n?=?500; peginterferon beta-1a every 2 [n?=?512] or 4 [n?=?500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p?<?0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p?<?0.0001), as well as the volume of T2 and T1 lesions (p?<?0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p?<?0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity.During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.ClinicalTrials.gov: NCT00906399.

Dataset Information

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

Publications

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

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