Annualized relapse rate of first-line treatments for multiple sclerosis: A meta-analysis, including indirect comparisons versus fingolimod

RTI Health Solutions, Manchester, UK.
Current Medical Research and Opinion (Impact Factor: 2.65). 04/2012; 28(5):767-80. DOI: 10.1185/03007995.2012.681637
Source: PubMed


Previous systematic reviews and meta-analyses of treatments in relapsing-remitting multiple sclerosis (RRMS) derived their findings from either placebo-controlled studies only or separately from head-to-head and comparative studies. The purpose of this study is to compare annualized relapse rates (ARR) of fingolimod versus all of the commonly used first-line treatments in RRMS using evidence from both placebo-controlled and head-to-head studies. In absence of the head-to-head data between fingolimod and the other treatments, these comparisons were formed using meta-analysis techniques for indirect treatment comparisons.
A systematic literature review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library with no limitations applied on publication language or dates. Included studies were randomized controlled trials evaluating one or more of fingolimod, interferon beta-1a, interferon beta-1b, or glatiramer acetate in RRMS populations. Primary outcome was ARR. Data extraction included author, year, treatment, dosage, mean age, percentage females, duration of disease, Expanded Disability Status Scale (EDSS) score at baseline, relapses in 2 years prior to baseline, trial duration, relapse-related outcome, and definition of relapse. The indirect treatment comparisons were performed using a mixed-treatment comparison framework. ARR was analyzed as a Poisson outcome.
The relative ARRs, for each treatment versus fingolimod, estimated from our meta-analyses were 1.43 (glatiramer acetate 20 mg), 1.51 (interferon beta-1b 250 mcg), 1.55 (interferon beta-1a 44 mcg), 1.67 (interferon beta-1a 22 mcg), 1.93 (interferon beta-1a 30 mcg), and 2.32 (placebo). None of the 95% confidence intervals for these estimates overlapped unity, implying statistical significance of these findings.
The key limitations of this study are the persisting heterogeneity even after adjusting for covariates and the variability in outcome definition across the included trials.
Our study demonstrated that fingolimod significantly reduces relapse frequency in patients with RRMS compared with current first-line disease-modifying therapies.

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    • "In a head-to-head phase III study of oral daily fingolimod versus IFNβ-1a IM in patients with MS (TRANSFORMS; Table 3), there were significantly greater reductions in relapse rate (52 % relative reduction), lesion activity, and brain volume loss with fingolimod than with IFNβ after 1 year [115]. In addition, meta-analyses indicate that fingolimod is more efficacious in reducing relapses than all IFNβ formulations and GA [116, 117]. The MoA of fingolimod likely accounts for its significant efficacy profile. "
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    ABSTRACT: Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.
    Full-text · Article · Apr 2014 · CNS Drugs
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    • "Disease-modifying therapies reduce the rate of relapse of MS by about 30% per year, and also reduce the rate of development of sustained disability [33] [34] [35]. Also, some studies suggest that currently available disease-modifying therapies may delay secondary progression to progressive MS in patients with relapsing-remitting MS [36]. "
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    ABSTRACT: The prevalence of multiple sclerosis (MS) is now considered to be medium-to-high in the Middle East and is rising, particularly among women. While the characteristics of the disease and the response of patients to disease-modifying therapies are generally comparable between the Middle East and other areas, significant barriers to achieving optimal care for MS exist in these developing nations. A group of physicians involved in the management of MS in ten Middle Eastern countries met to consider the future of MS care in the region, using a structured process to reach a consensus. Six key priorities were identified: early diagnosis and management of MS, the provision of multidisciplinary MS centres, patient engagement and better communication with stakeholders, regulatory body education and reimbursement, a commitment to research, and more therapy options with better benefit-to-risk ratios. The experts distilled these priorities into a single vision statement: "Optimization of patient-centred multidisciplinary strategies to improve the quality of life of people with MS." These core principles will contribute to the development of a broader consensus on the future of care for MS in the Middle East.
    Full-text · Article · Jan 2014
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    • "Randomized clinical trials in MS traditionally evaluate treatment effects in terms of overall impact on relapse frequency. While the challenges of cross-study comparisons are exacerbated by the variable severity and sequelae of relapses and their tendency to decline in frequency over time, meta-analyses suggest that the current first-line injectable therapies [i.e., interferon β-1a/1b (IFNβ-1a/1b) and glatiramer acetate] provide significant but largely similar benefits on relapse frequency [14]. Given the substantial health and economic burdens associated with MS relapses, it is also informative to evaluate the effects of treatment on outcomes from relapse, particularly in terms of neurological sequelae and their impact on overall healthcare resource consumption. "
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    ABSTRACT: Multiple sclerosis (MS) relapses impose a substantial clinical and economic burden. Teriflunomide is a new oral disease-modifying therapy approved for the treatment of relapsing MS. We evaluated the effects of teriflunomide treatment on relapse-related neurological sequelae and healthcare resource use in a post hoc analysis of the Phase III TEMSO study. Confirmed relapses associated with neurological sequelae [defined by an increase in Expanded Disability Status Scale/Functional System (sequelae-EDSS/FS) ≥30 days post relapse or by the investigator (sequelae-investigator)] were analyzed in the modified intention-to-treat population (n = 1086). Relapses requiring hospitalization or intravenous (IV) corticosteroids, all hospitalizations, emergency medical facility visits (EMFV), and hospitalized nights for relapse were also assessed. Annualized rates were derived using a Poisson model with treatment, baseline EDSS strata, and region as covariates. Risks of sequelae and hospitalization per relapse were calculated as percentages and groups were compared with a χ2 test. Compared with placebo, teriflunomide reduced annualized rates of relapses with sequelae-EDSS/FS [7 mg by 32 % (p = 0.0019); 14 mg by 36 % (p = 0.0011)] and sequelae-investigator [25 % (p = 0.071); 53 % (p < 0.0001)], relapses leading to hospitalization [36 % (p = 0.015); 59 % (p < 0.0001)], and relapses requiring IV corticosteroids [29 % (p = 0.001); 34 % (p = 0.0003)]. Teriflunomide-treated patients spent fewer nights in hospital for relapse (p < 0.01). Teriflunomide 14 mg also decreased annualized rates of all hospitalizations (p = 0.01) and EMFV (p = 0.004). The impact of teriflunomide on relapse-related neurological sequelae and relapses requiring healthcare resources may translate into reduced healthcare costs. Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-6979-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2013 · Journal of Neurology
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