Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 μg 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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- "In recommended doses IFN-β1b causes the following frequent adverse effects (frequency is given in parenthesis): injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions) (85%), insomnia (31%), influenza-like syndrome (34%), asthenia (34%), headache (32%), myalgia (26%), hypoesthesia (26%), nausea (16%), paresthesia (16%), myasthenia (11%), chills (8%), depression (8%), back pain (5%), increased liver enzymes (11%), lymphopenia (11%), fever (5%), and pain in extremities (3%).34,35 In pediatric populations, the most common adverse events recorded in clinical trials are influenza- like syndrome (35%), abnormal liver function tests (26%), and injection site reactions (21%).36 "
ABSTRACT: Multiple sclerosis (MS) is chronic inflammatory and demyelinating disease with either a progressive (10%-15%) or relapsing-remitting (85%-90%) course. The pathological hallmarks of MS are lesions of both white and grey matter in the central nervous system. The onset of the disease is usually around 30 years of age. The patients experience an acute focal neurologic dysfunction which is not characteristic, followed by partial or complete recovery. Acute episodes of neurologic dysfunction with diverse signs and symptoms will then recur throughout the life of a patient, with periods of partial or complete remission and clinical stability in between. Currently, there are several therapeutic options for MS with disease-modifying properties. Immunomodulatory therapy with interferon beta-1b (IFN-β1b) or -1a, glatiramer and natalizumab shows similar efficacy; in a resistant or intolerant patient, the most recently approved therapeutic option is mitoxantrone. IFN-β1b in patients with MS binds to specific receptors on surface of immune cells, changing the expression of several genes and leading to a decrease in quantity of cell-associated adhesion molecules, inhibition of major histocompatibility complex class II expression and reduction in inflammatory cells migration into the central nervous system. After 2 years of treatment, IFN-β1b reduces the risk of development of clinically defined MS from 45% (with placebo) to 28% (with IFN-β1b). It also reduces relapses for 34% (1.31 exacerbations annually with placebo and 0.9 with higher dose of IFN-β1b) and makes 31% more patients relapse-free. In secondary-progressive disease annual rate of progression is 3% lower with IFN-β1b. In recommended doses IFN-β1b causes the following frequent adverse effects: injection site reactions (redness, discoloration, inflammation, pain, necrosis and non-specific reactions), insomnia, influenza-like syndrome, asthenia, headache, myalgia, hypoesthesia, nausea, paresthesia, myasthenia, chills and depression. Efficacy of IFN-β1b in relapsing-remitting MS is higher than that of IFN-β1a, and similar to the efficacy of glatiramer acetate. These facts promote IFN-β1b as one of the most important drugs in the spectrum of immunological therapies for this debilitating disease.Journal of Inflammation Research 03/2010; 3(1):25-31. DOI:10.2147/JIR.S9480
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ABSTRACT: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p<0.0001), whereas injection-site reactions were more common in patients treated with glatiramer acetate (p=0.0005). Patient attrition rates were 17% (153 of 888) on 250 microg interferon beta-1b, 26% (227 of 887) on 500 microg interferon beta-1b, and 21% (93 of 445) for glatiramer acetate. 500 microg interferon beta-1b was not more effective than the standard 250 microg dose, and both doses had similar clinical effects to glatiramer acetate. Although interferon beta-1b and glatiramer acetate had different adverse event profiles, the overall tolerability to both drugs was similar. Bayer HealthCare Pharmaceuticals.The Lancet Neurology 09/2009; 8(10):889-97. DOI:10.1016/S1474-4422(09)70226-1 · 21.90 Impact Factor
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ABSTRACT: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist. We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT). Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥ 2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤ 35, >35-40, >40-45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤ 5, >5-15, >15-40, >40 months) on de novo liver enzyme abnormality. Over a mean treatment period of 38.7 months (SD=34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR=3.8(95% CI: 1.6-9.2) for IFNβ-1a 44 µg SC, and OR=3.4 (95% CI: 1.5-7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤ 40 years), male gender, and ≤ 15 months of IFNβ exposure were also independent predictors. A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated.Multiple Sclerosis 12/2010; 17(3):361-7. DOI:10.1177/1352458510388823 · 4.82 Impact Factor