Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study.
ABSTRACT It is not known whether the currently available treatment regimen of interferon beta-1b (IFNbeta-1b) 250 microg provides the maximum benefit possible in the treatment of relapsing-remitting multiple sclerosis (RRMS), or whether higher doses of IFNbeta-1b will prove to be more beneficial.
The objective of the present study was to evaluate the tolerability and safety profile of IFNbeta-1b 500 microg compared with the currently approved 250-microg dose.
A multicenter, randomized, double-blind, parallel-group pilot study was carried out to compare IFNbeta-1b 250 microg with IFNbeta-1b 500 microg, both self-administered SC QOD for >or=12 weeks in patients with RRMS. Patients in both groups started with 25% (0.25 mL) of their final dose and were scheduled to increase the dose by 0.25 mL every 2 weeks, so that the full dose (1.0 mL, 250 microg or 500 microg) would be reached by week 7. The primary outcome measure was the percentage of patients experiencing each of the following adverse events (AEs): influenza-like symptoms (general term used to code the presence of >1 symptom typical of influenza), fever, myalgia, asthenia, headache, injection-site reactions, injection-site pain, or liver or hematologic abnormalities. All patients underwent a priori magnetic resonance imaging (MRI) with 0.1 mmol/kg gadolinium (Gd)-diethylenetriaminepentaacetic acid as contrast medium at screening and at week 12. MRI evaluation was included as a safety measure to monitor for excessive new disease not visible through clinical symptoms.
Seventy-seven patients were assessed for inclusion in the study. Of these, 6 patients were screening failures and the remaining 71 were randomized to treatment (38-250 and 33-500 microg IFNbeta-1b). The uneven numbers in the groups were a consequence of the randomization process. Two patients in the 250-microg group (withdrawal of consent) and 1 in the 500-microg group (not completing follow-up visit) prematurely discontinued medication. The demographic characteristics were not significantly different between the 250-microg (n=38; mean [SD] age, 37.9 [8.3] years; weight, 83.5 [19.0] kg; height, 168.4 [9.3] cm) and 500-microg (n=33; mean [SD] age, 37.8 [7.7] years; weight, 82.3 [19.5] kg; height, 169.9 [10.5] cm) treatment groups. The patients in both groups were mostly white (87% and 73%, respectively). Baseline Expanded Disability Status Scale scores also were not significantly different between the 2 groups (mean [SD] score, 2.8 [1.4] vs 2.0 [1.4], respectively). In the IFN(2)-1b 250-microg group, 97% of the patients titrated to the full dose at some point during the course of the study, compared with 91% of the 500-microg group (P=NS). A dose-response effect was observed in some of the more frequent AEs (no. [%]) that included influenza-like syndrome (250-microg group, 13  vs 500-microg group, 16 ), asthenia (13  vs 16 , respectively), headache (12  vs 12 ), myalgia (10  vs 13 ), hypesthesia (10  vs 11 ), nausea (6  vs 8 ), paresthesia (6  vs 8 ), myasthenia (4  vs 8 ), chills (3  vs 6 ), depression (3  vs 5 ), back pain (2  vs 5 ), increased liver enzymes (4  vs 6 ), lymphopenia (4  vs 3 ), fever (2  vs 4 ), and pain in extremities (1  vs 4 ). The between-group incidence of injection-site reactions was not significantly different. No new or unexpected AEs were recorded. Changes in MRI parameters between screening and 12 weeks were not significantly different between dose groups; these included median T2 lesion volume, median Gd-enhanced lesion volume, median Gd-enhanced lesion number, and mean number of newly active lesions.
IFNbeta-1b 500 microg administered SC QOD was generally well tolerated in these patients with RRMS. Large, randomized controlled studies are needed to determine if there are significant differences in MRI end points between the 250- and 500-microg doses.
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ABSTRACT: Quantitative evaluation of lesion load in multiple sclerosis (MS) from magnetic resonance imaging (MRI) scans is becoming important in understanding and monitoring the progression of the disease. Methods of MS lesion segmentation based on intensity thresholding offer one of the most robust and easily-implemented means of computing the total lesion volume. This study evaluated the effects of slight changes in the choice of intensity threshold on computed lesion volumes in 20 patients with MS using such a technique. After judging the optimum choice of threshold value, the threshold value was increased and decreased by 3% in 1% steps around this value; we observed a mean change of 15% in computed lesion volumes for 1% changes of threshold value. Larger changes in lesion volume were found when the threshold was changed by larger amounts. On the other hand, the amount of time required for manual review decreased, and the confidence with which manual review could be performed increased when using lower thresholds. This study shows that the choice of threshold is a crucial factor in measuring lesion volumes in MS when using intensity-based techniques. It also suggests that in multicenter and/or longitudinal studies, criteria for choosing the threshold should be developed whereby the threshold level should be set such that all MR visible lesions are above it, in order to minimise the human interaction and, consequently, the reproducibility of the results.Acta Neurologica Scandinavica 02/1996; 93(1):30-4. · 2.47 Impact Factor
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ABSTRACT: There have been considerable advances made recently in the treatment of multiple sclerosis (MS). In particular, interferon (IFN)beta has been demonstrated in several independent, multicentre clinical trials to lower unequivocally the biological activity of this illness. The results of these trials have been remarkably consistent, demonstrating a reduction in both disease activity and cumulative disability, using a combination of clinical and magnetic resonance imaging outcome measures. Nevertheless, the importance of the total weekly IFNbeta dose in the clinical management of individual patients has been controversial. However, there is considerable information available regarding the effect of IFNbeta dose on the various biochemical and clinical markers that are affected by IFNbeta, which is derived both from pre-clinical studies and multicentre clinical trials. On balance, convincing evidence is provided to support the notion that there is a clinically relevant dose-response in the use of IFNbeta to treat patients with relapsing/remitting MS. However, many of the clinical trials of IFNbeta in MS have confounded the potential effects of dose with the possible effects of frequency of IFNbeta administration. As a result, it is possible that the apparent dose-response observed in these clinical trials may be due, in part, to the more frequent dose administration schedule rather than the total weekly dose.Drugs 02/2001; 61(12):1693-703. · 4.63 Impact Factor
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ABSTRACT: The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including “monosymptomatic” disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as “clinically definite” and “probable MS” are no longer recommended. The outcome of a diagnostic evaluation is either MS, “possible MS” (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or “not MS.”Annals of Neurology 06/2001; 50(1):121 - 127. · 11.19 Impact Factor