Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonß-1a versus subcutaneous interferonß-1b: results of the randomized, multicenter, Phase IIIb REFORMS study.

BACKGROUND: In patients with relapsing-remitting multiple sclerosis (RRMS), subcutaneous (sc) interferon (IFN)ß-1a and IFNß-1b have been shown to reduce relapse rates. A formulation of IFNß-1a has been produced without fetal bovine serum and without human serum albumin as an excipient (not currently approved for use in the US). The objectives of this study were to evaluate tolerability, injection-site redness, subject-reported satisfaction with therapy, and clinical safety and efficacy of the serum-free formulation of IFNß-1a versus IFNß-1b in IFNß-treatment-naïve patients with RRMS. The objectives of the extension phase were to evaluate long-term safety and tolerability of IFNß-1a. METHODS: This randomized, parallel-group, open-label study was conducted at 27 clinical sites in the US. Eligible patients aged 18-60 years were randomized to receive either IFNß-1a, titrated to 44 µg sc three times weekly (tiw) (n = 65), or IFNß-1b, titrated to 250 µg sc every other day (n = 64) over 12 weeks. Following this, all patients received IFNß-1a 44 µg tiw for 82-112 weeks. Primary endpoint was mean change in patient-reported pain, as assessed by visual analog scale (VAS) diary pain score (from 0 mm [no pain] to 100 mm [worst possible pain]) at the injection site, from pre-injection to 30 min post-injection over the first 21 full-dose injections. Secondary assessments included proportion of patients pain-free as recorded by VAS diary and the Short-Form McGill Pain questionnaire VAS. RESULTS: A total of 129 patients were included in the intent-to-treat analysis. Mean (standard deviation) change in VAS diary pain score was not significantly different between groups, although numerically lower with IFNß-1a versus IFNß-1b from pre-injection to immediately post-injection (1.46 [2.93] vs. 4.63 [10.57] mm), 10 min post-injection (0.70 [1.89] vs. 1.89 [5.75] mm), and 30 min post-injection (0.67 [2.32] vs. 1.14 [4.94] mm). Proportion of patients pain-free at all time periods post-injection was also not significantly different between groups. Adverse events were consistent with the known safety profiles of these treatments. CONCLUSIONS: In IFNß-treatment-naïve patients with RRMS, both the serum-free formulation of IFNß-1a and IFNß-1b treatments were generally accompanied by low-level injection-site pain and were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00428584.

Adherence to recommended dosing and monitoring for mitoxantrone in patients with multiple sclerosis: a healthcare claims database study supplemented with medical records--the RETRO study.

PURPOSE: Mitoxantrone was approved for treatment of multiple sclerosis (MS) in October 2000. Monitoring and dosing guidelines in the product labeling accompanying this indication include blood counts, liver function, and pregnancy tests at each administration. Due to potential cardiotoxicity, left ventricular ejection fraction (LVEF) testing prior to initial infusion and all infusions at a cumulative dose >or=100 mg/m(2) was recommended until April 2005 when LVEF testing before all infusions was recommended in the approved labeling. We sought to estimate provider adherence to dosing and monitoring guidelines and the effect of changes in LVEF monitoring guidelines. METHODS: MS patients who received mitoxantrone between October 2000 and June 2006 were selected from the claims of a large US health insurer. Claims for infusions and for specified tests prior to an infusion determined adherence to guidelines, with medical records providing additional information for a subset. RESULTS: There were 1827 mitoxantrone infusions to 548 eligible patients; medical records were obtained for 261 patients (1096 infusions). Most mitoxantrone recipients were 30-59 years of age and 73% were female. Adherence to recommended dosing was higher than for recommended monitoring. Blood counts were conducted for most infusions (78-83%), while liver function tests (LFT) were performed less often (47-54% of infusions). Pregnancy tests were performed for 10% or fewer of the infusions administered to reproductive age women. Adherence with LVEF testing guidelines improved following labeling changes. CONCLUSIONS: Adherence to recommended monitoring was incomplete, but amenable to change. Automated assessment through insurance claims supplemented with medical record data provides a balanced means for studying adherence to recommendations.

Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta-1a: modelling the clinical and economic implications.

The EVIDENCE trial concluded that administering high-dose/high-frequency subcutaneous (SC) interferon-beta-1a (IFNb1a) was more effective in preventing relapses among patients with relapsing multiple sclerosis (MS) than low-dose weekly intramuscular (IM) IFNb1a after 64 weeks. This analysis utilized discrete-event simulation (DES) to model the potential longer-term clinical and economic implications of this trial. A DES predicting the course of relapsing MS and incorporating the effect of IFNb1a therapy was developed. The model began by randomly reading in actual patient data from the trial to create 1000 patients. Each simulated patient was replicated - one was assigned to receive SC IFNb1a three times a week and the other to receive IM IFNb1a once a week. During the simulation, patients may (i) experience relapses, with associated short- and long-term impacts on costs and disability; (ii) develop new T2 lesions detected by a magnetic resonance imaging scan; (iii) discontinue treatment because of adverse events or lack of response; (iv) advance to secondary progressive MS; or (v) die. Model inputs were mainly obtained from the EVIDENCE trial, but were taken from published literature if they could not be obtained from the trial. Direct medical costs ($US, year 2006 values) to the US payers were primarily obtained by updating a published cost analysis. Costs and benefits were discounted at 3% per annum. Extensive sensitivity analyses were conducted to test the robustness of the model results. Based on 100 replications of 1000 patient pairs over 4 years, SC IFNb1a was predicted to enable more patients to avoid relapse (216 vs 147). Total mean costs per patient (discounted) were $US79 890 with SC IFNb1a versus $US74 485 with IM administration, a net increase of $US5405 per patient. However, SC IFNb1a was estimated to prevent 0.50 relapses and save 23 relapse-free days per patient, yielding incremental cost-effectiveness ratios of $US10 755 per relapse prevented and $US232 per relapse-free day gained. Sensitivity analyses revealed that the result was most sensitive to the treatment efficacy, model time horizon and cost of IFNb1a treatment. Based on the results observed in the EVIDENCE trial, the model predicted that SC IFNb1a would yield greater health benefits over 4 years than IM IFNb1a, at a cost that would seem to be a reasonable trade-off.

Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison.

The treatment of relapsing-remitting multiple sclerosis (RRMS) has become more effective over the last decade with the advent of the currently available disease-modifying therapies (DMTs). Pivotal clinical studies differ in many characteristics, such that cross-comparisons of relative risk reductions are of limited value and can be misleading. Our objective was to compare the clinical efficacy of currently approved first-line DMTs in patients with RRMS, applying an evidence-based medicine approach. We reviewed all phase III pivotal trials of DMTs. Six clinical trials of Avonex, Betaseron, Copaxone, Rebif and Tysabri in patients with RRMS were identified for analysis. Only randomized, placebo-controlled, double-blind studies were included. The clinical efficacy endpoints compared were: proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months. Based on these analyses, Betaseron, Rebif, and Tysabri show comparable effects, whereas for several endpoints Avonex or Copaxone did not significantly differ from placebo. In the absence of head-to-head studies for all products used to treat RRMS, it still may be possible to compare treatment effects by applying evidence-based medicine principles.

Response to interferon beta-1a treatment in African American multiple sclerosis patients.

BACKGROUND: African Americans (AAs) with multiple sclerosis (MS) seem to have a more severe disease course than white Americans (WAs). To our knowledge, it is not known to what extent treatment with interferon beta-1a will effect the MS disease course within the AA population. OBJECTIVE: To compare the response to treatment with interferon beta-1a between AA and WA MS patients. DESIGN: This is an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study. SETTING: The EVIDENCE study is a randomized controlled trial that compared the efficacy of once weekly, intramuscular, 30-microg interferon beta-1a treatment with thrice weekly, subcutaneous, 44-microg interferon beta-1a therapy in treatment-naïve MS subjects. PARTICIPANTS: Thirty-six AA subjects were compared with 616 WA subjects. MAIN OUTCOME MEASURES: The number of MS exacerbations, the proportion of exacerbation-free subjects, and the number of new MS lesions present on brain magnetic resonance imaging were compared between AA and WA subjects at 24 and 48 weeks after initiating treatment with interferon beta-1a. RESULTS: The AA subjects experienced more exacerbations and were less likely to remain exacerbation free (statistical trends). The AA subjects developed more new MS lesions on T2-weighted brain magnetic resonance imaging at 48 weeks (P = .04). CONCLUSIONS: Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients.