Xiaojun You

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study

BackgroundInterferon beta (IFNβ) and glatiramer acetate (GA) are administered by subcutaneous (SC) or intramuscular (IM) injection. Patients with multiple sclerosis (MS) often report injection-site reactions (ISRs) as a reason for noncompliance or switching therapies. The aim of this study was to compare the proportion of patients on different formulations of IFNβ or GA who experienced ISRs and who switched or discontinued therapy because of ISRs.MethodsThe Swiss MS Skin Project was an observational multicenter study. Patients with MS or clinically isolated syndrome who were on the same therapy for at least 2 years were enrolled. A skin examination was conducted at the first study visit and 1 year later.ResultsThe 412 patients enrolled were on 1 of 4 disease-modifying therapies for at least 2 years: IM IFNβ-1a (n = 82), SC IFNβ-1b (n = 123), SC IFNβ-1a (n = 184), or SC GA (n = 23). At first evaluation, ISRs were reported by fewer patients on IM IFNβ-1a (13.4%) than on SC IFNβ-1b (57.7%; P < 0.0001), SC IFNβ-1a (67.9%; P < 0.0001), or SC GA (30.4%; P = not significant [NS]). No patient on IM IFNβ-1a missed a dose in the previous 4 weeks because of ISRs, compared with 5.7% of patients on SC IFNβ-1b (P = 0.044), 7.1% of patients on SC IFNβ-1a (P = 0.011), and 4.3% of patients on SC GA (P = NS). Primary reasons for discontinuing or switching therapy were ISRs or lack of efficacy. Similar patterns were observed at 1 year.ConclusionsPatients on IM IFNβ-1a had fewer ISRs and were less likely to switch therapies than patients on other therapies. This study may have implications in selecting initial therapy or, for patients considering switching or discontinuing therapy because of ISRs, selecting an alternative option.

Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis

BackgroundSubcutaneous 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.MethodsRRMS patients (18–65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125xa0μg every 2 or 4xa0weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.Results1512 patients were randomized and dosed (placebo nu2009=u2009500; peginterferon beta-1a every 2 [nu2009=u2009512] or 4 [nu2009=u2009500] weeks). Every 2xa0week dosing significantly reduced, versus placebo and every 4xa0week 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 pu2009<u20090.0001. Every 2xa0week 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 pu2009<u20090.0001), as well as the volume of T2 and T1 lesions (pu2009<u20090.05) at Weeks 24 and 48. Significantly more patients dosed every 2xa0weeks had NEDA versus placebo and every 4xa0weeks (all pu2009<u20090.01) 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.ConclusionDuring Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2xa0weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4xa0week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.Trial registrationClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT00906399

A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing-Remitting Multiple Sclerosis.

Subcutaneous pegylated interferon beta-1a (peginterferon beta-1a [PEG-IFN]) 125 μg every two or four weeks has been studied in relapsing-remitting multiple sclerosis (RRMS) patients in the pivotal Phase 3 ADVANCE trial. In the absence of direct comparative evidence, a network meta-analysis (NMA) was conducted to provide an indirect assessment of the relative efficacy, safety, and tolerability of PEG-IFN versus other injectable RRMS therapies. Systematic searches were conducted in MEDLINE, Embase, and the Cochrane Library, and conference proceedings from relevant annual symposia were hand-searched. Included studies were randomized controlled trials evaluating ≥1 first-line treatments including interferon beta-1a 30, 44, and 22 μg, interferon beta-1b, and glatiramer acetate in patients with RRMS. Studies were included based on a pre-specified protocol and extracted by a team of independent reviewers and information scientists, utilizing criteria from NICE and IQWiG. In line with ADVANCE findings, NMA results support that PEG-IFN every 2 weeks significantly reduced annualized relapse rate, and 3- and 6-month confirmed disability progression (CDP) versus placebo. There was numerical trend favoring PEG-IFN every 2 weeks versus other IFNs assessed for annualized relapse rate, and versus all other injectables for 3- and 6-month CDP (6-month CDP was significantly reduced versus IFN beta-1a 30 μg). The safety and tolerability profile of PEG-IFN beta-1a 125 μg every 2 weeks was consistent with that of other evaluated treatments. Study limitations for the NMA include variant definitions of relapse and other systematic differences across trials, assumptions that populations were sufficiently similar, and inability to perform NMA of adverse events. With similar efficacy compared to other RRMS treatments in terms of annualized relapse rate and 3- and 6-month CDP, a promising safety profile, and up to 93% reduction in number of injections (which may improve adherence), PEG-IFN every 2 weeks offers a valuable alternative treatment option for patients with RRMS.

Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM.

Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing−remitting multiple sclerosis, could impact ambulation performance was examined.

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

Background: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). Objectives: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. Methods: Patients (n=140) with relapsing−remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. Results: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. Conclusions: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Change in quality of life in patients with relapsing–remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon β-1a:

Background: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNβ-1a) in relapsing–remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). Objective: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. Methods: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. Results: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (pu2009=u20090.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNβ-1a significantly improved Physical SIP subscores. Conclusions: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNβ-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study.

Background: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). Objective: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150u2009mg subcutaneous versus intramuscular interferon beta-1a 30u2009µg for 96–144u2009weeks. Methods: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0–24, and weeks 24–96. Results: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592−2.661); pu2009<u20090.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357−2.007; pu2009<u20090.0001) and 2.051 (1.628−2.582; pu2009<u20090.0001), respectively. ORs in favor of daclizumab for weeks 24–96 were consistently higher than for weeks 0–24. Conclusion: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial

BackgroundSubcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2xa0years 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 1xa0year 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 2xa0years.MethodsPatients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4xa0weeks for 2xa0years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4xa0weeks 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 Gdu2009+u2009and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.ResultsPeginterferon beta-1a every 2xa0weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2xa0years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6xa0months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2xa0weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; pu2009<u20090.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; pu2009<u20090.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; pu2009<u20090.0001).ConclusionPeginterferon 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.Trial registrationClinicalTrials.gov: NCT00906399; Registered on: May 20, 2009.

Weekly IM interferon beta-1a in multiple sclerosis patients over 50 years of age

Background:u2002 Efficacy and safety data have not previously been compiled for intramuscular interferon beta‐1a (IM IFNβ‐1a) in patients with multiple sclerosis (MS) ≥u200350u2003years of age. We investigated the efficacy and safety of IM IFNβ‐1a in patients segregated by 50 and 40u2003years of age in separate meta‐analyses.