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
ABSTRACT 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.
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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 · 1.71 Impact Factor
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ABSTRACT: The study objective is to compare the annual total medical and indirect costs of newly treated and untreated employees with multiple sclerosis (MS). A retrospective database analysis of employer medical, drug, and disability claims database (Ingenix Employer database, 1999-2005; 17 large US companies) was conducted for employees 18-64 years of age with > or =1 MS diagnosis after January 1, 2002. Employees with > or =1 MS disease-modifying drug (DMD) claim comprised the newly treated group; employees with MS but no DMD at any time comprised the untreated, comparison group. Index date was the day after the most recent claim (treated, DMD claim; untreated, MS claim) meeting the following requirements: continuous health coverage for 3 months before (baseline period) and 12 months after the index date (study period) and actively employed during baseline. Total medical costs and indirect (work loss) costs over the 1-year study period (2006 $US) were compared for DMD-treated and untreated MS employees, adjusting for baseline characteristics, including comorbidities. During the baseline, MS employees who became treated (n = 258) were younger (40.9 vs. 44.4 years, p < 0.0001) and had a higher proportion of women (72 vs. 62%, p = 0.007) than the untreated group of MS employees who never received DMD treatment (n = 322). The 3-month baseline MS-related medical costs were higher among treated MS employees ($2520 vs. $1012, p < 0.0001). There was a nonsignificant trend toward higher baseline non-MS-related medical costs in untreated versus treated MS employees. Risk-adjusted total annual medical costs ($4393 vs. $6187, p < 0.0001) and indirect costs ($2252 vs. $3053, p < 0.0001) were significantly lower for treated MS employees than for untreated MS employees. Initiation of MS disease-modifying drugs was associated with substantial significant medical and indirect savings for employees with MS. Study findings should be considered in the context of the study limitations (e.g., analytic focus on employees with at least 12-month follow-up; lack of clinical detail on MS severity).Current Medical Research and Opinion 03/2009; 25(4):869-77. DOI:10.1185/03007990902743869 · 2.37 Impact Factor
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