Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis.
Topic: Immunotherapy

Interferons-beta (IFNs-beta) and glatiramer acetate (GA) were the first two disease-modifying therapies (DMTs) approved 20 years ago for the treatment of multiple sclerosis (MS). DMTs' prescription rates as first or switching therapies and their costs have both increased substantially over the past decade. As more DMTs become available, the choice of a specific DMT should reflect the risk/benefit profile, as well as the impact on quality of life. As MS cohorts enrolled in different studies can vary significantly, head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared. The purpose of this systematic review is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through the analysis of head-to-head trials.This is an update of the Cochrane review 'Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis' (first published in the Cochrane Library 2014, Issue 7).

PICO
Population: Patients with relapsing-remitting multiple sclerosis
Intervention: Interferons-beta (IFNs-beta)
Comparison: Glatiramer acetate (GA)
Outcomes: Comparative effectiveness on disease course

Included studies:
title: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group.
abstract: We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB). Clinical results are presented in the preceding companion paper. Baseline MRI characteristics were the same in all treatment groups. Fifty-two patients at one center formed a cohort for frequent MRIs (one every 6 weeks) for analysis of disease activity. The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans (median 80% reduction, p = 0.0082) and appearance of new lesions. In addition, there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups (mean group difference of 23%, p = 0.001). These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients.
title: A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis.
abstract: Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a β2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy.
title: Randomized study combining interferon and glatiramer acetate in multiple sclerosis.
abstract: A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis.
title: Impact of inflammation on brain volume in multiple sclerosis.
abstract: To study changes in brain volume measured monthly in patients treated for relapsing multiple sclerosis due to loss of tissue and the appearance of inflammation.
title: Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis.
abstract: To measure the effects of disease-modifying drugs (DMDs) on the development of cortical lesions (CL) and cortical atrophy in patients with relapsing-remitting multiple sclerosis (RRMS).
title: Efficacy and safety of interferon beta-1b sc in older RRMS patients--a posthoc analysis of the BEYOND study.
abstract: Evidence of a significant improvement of IFNB-1b in clinical severity in the older population with RRMS has not been established so far. The aim of this exploratory post hoc analysis of the 250 mcg IFNB-1b group of the BEYOND study is to compare the efficacy and safety of older versus younger patients using a cut-off at the age of 50 and at the age of 40, respectively. There was no difference between age groups in adjusted relapse risk (age 50 cut-off: P = 0.482, age 40 cut-off: P = 0.073) nor in adjusted time to confirmed EDSS progression (age 50 cut-off: P = 0.096, age 40 cut-off: P = 0.189). There were no significant differences between patients <50 and ≥ 50 years in the adjusted annualized relapse rate (P = 0.285), whereas relapse rate was higher in the <40 as compared to the ≥ 40 group (P = 0.024). The proportion of patients with confirmed disability progression was not significantly different for the 50 cutoff (P = 0.148), whereas significantly fewer <40 than ≥ 40 patients had disability progression (P = 0.047). Only minor differences in adverse event frequencies between the age groups for the two cut-offs were seen. These results indicate that IFNB-1b is as efficacious and safe in patients ≥ 50 years as <50 years of age.
title: Phase III dose-comparison study of glatiramer acetate for multiple sclerosis.
abstract: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40 mg compared to a 20mg dose.
title: Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina.
abstract: Switching treatment may be beneficial in patients with relapsing-remitting multiple sclerosis (RRMS) who respond inadequately to first-line immunomodulatory therapy. The objective of this study was to evaluate clinical outcomes after switching treatment in such patients. This prospective longitudinal observational study included 114 patients with RRMS who failed first-line monotherapy and were switched treatments after 3 years. Every 3 months, patients underwent a full neurological examination. Outcome was compared between the 3-year Before Switch and After Switch treatment periods. The primary outcome measure was the annualized relapse rate; secondary outcome measures were the proportion of relapse-free patients and the median change in Expanded Disability Status Scale (EDSS). Patients were switched either from low-dose to high-dose interferon-beta (IFNbeta; n = 31), from IFNbeta to glatiramer acetate (GA; n = 52) or mitoxantrone (n = 13), or from GA to IFNbeta (n = 16). In 3 years after switching, annualized relapse rates fell by 57-78% according to the group. The proportion of relapse-free patients varied from 56% to 81%. Least improved was observed in patients switching between INFbeta preparations. Median EDSS scores remained stable in all groups except the GA to IFNbeta switchers. In conclusion, patients who fail first-line immunomodulatory therapy generally benefit from switching to another class of immunomodulatory therapy.
title: Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.
abstract: Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS.
title: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
abstract: The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.
title: Interferon β-1b and glatiramer acetate effects on permanent black hole evolution.
abstract: To compare interferon β-1b (IFNβ-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)--a marker of irreversible tissue damage--in patients with relapsing-remitting multiple sclerosis (RRMS).
title: Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial.
abstract: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial.
title: A prospective, open-label treatment trial to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing--remitting multiple sclerosis: results after 18 months of therapy.
abstract: We previously reported results of a 12 month prospective, non-randomized, open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis (RRMS). We now report the results after 18 months of follow-up. Our primary objective was to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and Glatiramer Acetate (GA, Copaxone) to no treatment on the relapse rate in patients with RRMS. One hundred and fifty-six consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 18 months. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrollment Thirty-three of 156 elected no treatment at enrollment; 40 elected IFNbeta-1a, 41 IFNbeta-1b, and 42 chose GA. There were no statistically significant differences among the four groups at enrollment. After 18 months of treatment 122 patients remained in their original treatment group. Compared to the untreated group (1.02), mean annualized number of relapses was significantly reduced only in the GA (0.49, P>0.0001) and IFNbeta-1b groups (0.55, P=0.001) in contrast to the IFNbeta-1a treated patients (0.81, P=0.106) who did not show a significant reduction. Despite limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naive RRMS patients.
title: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. 1995.
title: Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
abstract: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis.
title: 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study.
abstract: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis.
title: European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging--measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group.
abstract: Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden.
title: Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study.
abstract: Immunomodulatory drugs (IDs) (interferon beta (IFNgamma) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNbeta and GA in MS patients treated before 16 years of age.
title: Disability progression in a clinical trial of relapsing-remitting multiple sclerosis: eight-year follow-up.
abstract: To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status.
title: Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis.
abstract: To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 3× weekly (tiw) compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS).
title: Comparative studies of glatiramer acetate and interferon beta.
abstract: Over the last decade and a half, several disease-modifying therapies (DMTs) have been approved for the treatment of multiple sclerosis (MS) including glatiramer actetate (GA; Copaxone), interferon beta (IFNB)-1a (Avonex, Rebif), IFNB-1b (Betaferon/Betaseron), mitoxantrone (Novantrone), and natalizumab (Tysabri). Randomized controlled trials (RCTs) of each of these DMTs have demonstrated that treatment has a favourable impact on at least one (often several) of the short-term outcome measures typically used to assess efficacy in MS clinical trials. These outcomes include clinical measures of disease activity such as the number or frequency of relapses, the time to first relapse, etc. They also include clinical measures of disease severity such as disease progression on the Expanded Disability Status Scale (EDSS) or the MS Functional Composite score (MSFC), determined either as a confirmed change over a 3 to 6 month interval or as a total change over the entire duration of the trial, in addition to various magnetic resonance imaging (MRI) measures such as the number and volume of T2 lesions, the number and volume of new or gadolinium (Gd)-enhancing lesions, or the number and volume of T1 dark lesions.
title: Beta blockade during and after myocardial infarction: an overview of the randomized trials.
abstract: Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value, and for many such patients mortality reductions of about 25% can be achieved. No important differences are clearly apparent among the benefits of different beta blockers, although some are more convenient than others (or have slightly fewer side effects), and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit. If monitored, the side effects of long-term therapy are not a major problem, as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment. By contrast, although very early IV short-term beta blockade can definitely limit infarct size, more reliable information about the effects of such treatment on mortality will not be available until a large trial (ISIS) reports later this year, with data on some thousands of patients entered within less than 4 hours of the onset of pain. Our aim has been not only to review the 65-odd randomized beta blocker trials but also to demonstrate that when many randomized trials have all applied one general approach to treatment, it is often not appropriate to base inference on individual trial results. Although there will usually be important differences from one trial to another (in eligibility, treatment, end-point assessment, and so on), physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related randomized trials and not just a few particular trial results. Although most trials are too small to be individually reliable, this defect of size may be rectified by an overview of many trials, as long as appropriate statistical methods are used. Fortunately, robust statistical methods exist--based on direct, unweighted summation of one O-E value from each trial--that are simple for physicians to use and understand yet provide full statistical sensitivity. These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another. (Moreover, they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust.) Their robustness, sensitivity, and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews.
title: Clinical consequences of MRI activity in treated multiple sclerosis.
abstract: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial.
title: New acute and chronic black holes in patients with multiple sclerosis randomised to interferon beta-1b or glatiramer acetate.
abstract: Hypointense lesions on T1 weighted MRI, referred to as black holes (BH), are a marker of demyelination/axonal loss in multiple sclerosis (MS). There is some evidence that glatiramer acetate (GA) may decrease the conversion of new brain lesions to BH.
title: The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics.
abstract: Interferon-β1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective.
title: Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study.
abstract: There are no published MRI studies comparing interferon beta 1b (IFNbeta-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS).