Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: A multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon β-1a for relapsing multiple sclerosis
Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited.
This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study.
The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase.
A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001).
The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.
"Injected every other day (EOD) subcutaneously (SC), IFN beta-1b (Betaseron® in the USA, Betaferon® in Europe; Bayer) was joined in 1996 by IFN beta-1a (Avonex®; Biogen Idec), which requires intramuscular (IM) injection weekly. A second IFN beta-1a (Rebif®; Merck Serono), which is injected three times a week SC, gained approval in 2002, only after head-to-head comparison with Avonex in the Evidence of Interferon Dose–Response-European North American Comparative Efficacy (EVIDENCE; ClincalTrials.gov #NCT00292266) trial . Extavia® (Novartis), launched in 2009, uses the same biological ingredient (IFN beta-1b) and administration route as Betaseron. "
[Show abstract][Hide abstract] ABSTRACT: Interferon (IFN) beta-1b was the first disease-modifying therapy to be approved for the treatment of multiple sclerosis (MS), and over 21 years of follow-up data demonstrate its efficacy and long-term safety profile. Following recent regulatory approvals in the USA and European Union, IFN beta-1b is now one of the seven disease-modifying therapies [intramuscular IFN beta-1a; subcutaneous (SC) IFN beta-1a; IFN beta-1b SC; glatiramer acetate SC; oral dimethyl fumarate; oral teriflunomide; and intravenous alemtuzumab] indicated for first-line use in relapsing–remitting MS. Here we review the clinical trial and follow-up data for IFN beta-1b and discuss factors that clinicians may consider when selecting this treatment, both at first line in early MS, and later in the disease course.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0149-1) contains supplementary material, which is available to authorized users.
Advances in Therapy 09/2014; 31(9). DOI:10.1007/s12325-014-0149-1 · 2.27 Impact Factor
"According to results from clinical trials, IFN-β treatment reduces relapse rates by about 30%, decreases the formation of inflammatory lesions in the CNS and extends remission periods (Schwid and Panitch, 2007). However, a major problem is that a high proportion of about 20% of the patients do not or only poorly respond to IFN-β treatment. "
[Show abstract][Hide abstract] ABSTRACT: Type I interferons (IFNs) were originally identified as antiviral effector molecules that exert pleiotropic physiological processes ranging from immune modulation, control of proliferation, apoptosis to antitumor activity. However, type I IFNs were recently also shown to apply both beneficial and detrimental effects to the central nervous system (CNS) and a tightly balanced equilibrium between cellular activation and inhibition seems to be essential to maintain homeostasis within the CNS. In inflammatory pathologies affecting the CNS, type I IFNs are in the center of attention not only because interferon beta (IFN-β) is used as a standard therapeutic in the treatment of relapsing-remitting multiple sclerosis (MS), but also as type I IFN expression is associated with distinct pathologies. Despite the great efficiency of IFN-β in reducing MS relapses and attenuation of novel inflammatory lesions is well documented, underlying molecular mechanisms and cellular target specificities are just beginning to emerge. In contrast to the curative effects, aberrant activation of the type I IFN response were also recently shown to be associated with detrimental effects exemplified by the Aicardi-Goutières syndrome (AGS), a severe disabling autoimmune inflammatory encephalopathy. This review will highlight the dual role of type I interferons during chronic CNS inflammation. Recently uncovered molecular and cellular mechanisms in the etiology of AGS and experimental autoimmune encephalomyelitis (EAE), the murine model of MS will be highlighted.
Frontiers in Immunology 04/2012; 3:67. DOI:10.3389/fimmu.2012.00067
[Show abstract][Hide abstract] ABSTRACT: It is well known that if the frequency used for a sinewave test of an analog to digital converter or waveform recorder is strategically chosen, it is guaranteed that the phases of the samples will be uniformly distributed between 0 and 2π. The requirement is that the record contain an integer number, J, of cycles and that J is relatively prime to the record length, M. We analyze how the sample uniformity is affected by small changes in J from its integer value. It is shown that the behavior depends on the value of K, the multiplicative inverse of J Mod M, and that the behavior can be drastically different for positive and negative errors in J. We provide tables of particularly good values for J for both positive and negative errors. We provide a strategy for selecting the values of M and J and for controlling the sign of the frequency error.
IEEE Transactions on Instrumentation and Measurement 01/2005; 54:73-78. DOI:10.1109/IMTC.2002.1006838 · 1.79 Impact Factor
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