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Brian Seed - One of the best experts on this subject based on the ideXlab platform.

  • the transcription factor mafb antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor irf3
    Nature Immunology, 2010
    Co-Authors: Brian Seed
    Abstract:

    Type I interferons (IFN-α and IFN-β) are key to antiviral immunity. Kim and Seed now demonstrate that the transcription factor MAFB acts as a metastable switch to control expression of IFN-β. Viral infection induces type I interferons (IFN-α and IFN-β) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1–like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.

  • the transcription factor mafb antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor irf3
    Nature Immunology, 2010
    Co-Authors: Hwijin Kim, Brian Seed
    Abstract:

    Viral infection induces type I interferons (IFN-alpha and IFN-beta) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.

Fred D. Lublin - One of the best experts on this subject based on the ideXlab platform.

  • natalizumab plus interferon beta 1a for relapsing multiple sclerosis
    The New England Journal of Medicine, 2006
    Co-Authors: W H Stuart, Fred D. Lublin, Daniel Wynn, Peter A Calabresi, Christian Confavreux, Steven Galetta, Ernst W Radue, F Lynn
    Abstract:

    Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T 2 -weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. Conclusions Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.)

  • natalizumab plus interferon beta 1a for relapsing multiple sclerosis
    The New England Journal of Medicine, 2006
    Co-Authors: W H Stuart, Fred D. Lublin, Daniel Wynn, Peter A Calabresi, Christian Confavreux, Steven Galetta, Ernst W Radue, F Lynn
    Abstract:

    Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T 2 -weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. Conclusions Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.)

  • enhanced spasticity in primary progressive ms patients treated with interferon beta 1b
    Neurology, 1998
    Co-Authors: Placido Bramanti, Edoardo Sessa, Carmela Rifici, Giangaetano Daleo, D Floridia, P Di Bella, Fred D. Lublin
    Abstract:

    Spasticity is a disabling symptom of MS that is enhanced during interferon beta-1b (IFNβ-1b) treatment. Nineteen patients with primary progressive MS were treated with IFNβ-1b; an additional 19 patients did not receive this treatment. Thirteen of the 19 patients treated with IFNβ-1b had increased spasticity requiring increased antispasticity drug administration. This observation suggests that further studies are needed before interferons can be so widely used in primary progressive MS patients.

  • management of patients receiving interferon beta 1b for multiple sclerosis report of a consensus conference
    Neurology, 1996
    Co-Authors: Fred D. Lublin, Barry G W Arnason, John N Whitaker, B H Eidelman, Aaron Miller, Jack S Burks
    Abstract:

    Article abstract-Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patient9s clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flulike symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy. NEUROLOGY 1996;46: 12-18

Jack H. Simon - One of the best experts on this subject based on the ideXlab platform.

  • Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta
    The Lancet. Neurology, 2010
    Co-Authors: Daniel Wynn, James Sheridan, Michael D. Kaufman, Xavier Montalban, Timothy Vollmer, Jack H. Simon, Jacob Elkins, Gilmore O'neill, Lauri Neyer, Chungchi Wang
    Abstract:

    Summary Background Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. Methods We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. Findings From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0·004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0·51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p Interpretation Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Funding Facet Biotech and Biogen Idec.

  • intramuscular interferon beta 1a for disease progression in relapsing multiple sclerosis
    Annals of Neurology, 1996
    Co-Authors: Lawrence Jacobs, Donald E Goodkin, J S Fischer, Diane L Cookfair, Robert M Herndon, Andres M Salazar, Carl V Granger, John R Richert, Jack H. Simon
    Abstract:

    The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase I11 trial of interferon beta-la. Interferon beta-la, 6.0 million units (30 μg), was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-la treatment produced a significant delay in time to sustained EDSS progression (p equals; 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-la-treated group. Patients treated with interferon beta-la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (pvalues ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-la-treated patients. There were no major adverse events related to treatment. Interferon beta- la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the hndamen- tal course of relapsing multiple sclerosis.

  • intramuscular interferon beta 1a for disease progression in relapsing multiple sclerosis
    Annals of Neurology, 1996
    Co-Authors: Lawrence Jacobs, Donald E Goodkin, J S Fischer, Diane L Cookfair, Robert M Herndon, Andres M Salazar, Carl V Granger, John R Richert, Jack H. Simon
    Abstract:

    The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase I11 trial of interferon beta-la. Interferon beta-la, 6.0 million units (30 μg), was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-la treatment produced a significant delay in time to sustained EDSS progression (p equals; 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-la-treated group. Patients treated with interferon beta-la also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (pvalues ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-la-treated patients. There were no major adverse events related to treatment. Interferon beta- la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the hndamen- tal course of relapsing multiple sclerosis.

Chris H Polman - One of the best experts on this subject based on the ideXlab platform.

  • magnetic resonance imaging effects of interferon beta 1b in the benefit study
    2015
    Co-Authors: Frederik Barkhof, Chris H Polman, Hans-peter Hartung, L. Kappos, Ernstwilhelm Radue, M S Freedman, G Edan, David H Miller, Peter Poppe, Marlieke De Vos
    Abstract:

    Results: Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P.001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P.001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P=.02). Conclusions: Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration: clinicaltrials.gov Identifier: NCT00185211

  • comparison of two dosing frequencies of subcutaneous interferon beta 1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis reflex a phase 3 randomised controlled trial
    Lancet Neurology, 2012
    Co-Authors: Giancarlo Comi, Chris H Polman, Frederik Barkhof, Nicola De Stefano, Mark S Freedman, Bernard M J Uitdehaag, Florence Cassetsemanaz, Brian Hennessy, Margaretha Stam Moraga, Sanda Rocak
    Abstract:

    Summary Background In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. Methods We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18–50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. Findings 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p Interpretation Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. Funding Merck Serono SA, Geneva, Switzerland.

  • recommendations for clinical use of data on neutralising antibodies to interferon beta therapy in multiple sclerosis
    Lancet Neurology, 2010
    Co-Authors: Chris H Polman, Antonio Bertolotto, Florian Deisenhammer, Bernhard Hemmer, Joep Killestein, Henry F Mcfarland, Joel Oger, Gavin Giovannoni, Andrew R. Pachner
    Abstract:

    The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available Interferon-Beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to Interferon-Beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-Interferon-Beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity.

  • magnetic resonance imaging effects of interferon beta 1b in the benefit study integrated 2 year results
    JAMA Neurology, 2007
    Co-Authors: Frederik Barkhof, Chris H Polman, Hans-peter Hartung, Xavier Montalban, L. Kappos, Ernstwilhelm Radue, M S Freedman, G Edan, David H Miller, Peter Poppe
    Abstract:

    Background In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions. Objective To examine detailed MRI findings from the first 2 years of this trial. Design Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study. Setting Ninety-eight centers worldwide. Patients A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis. Interventions Patients were randomized to receive interferon beta-1b, 250 μg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered. Main Outcome Measures Reported MRI data from patients completing 2 years of follow-up. Results Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P P P P  = .02). Conclusions Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration clinicaltrials.gov Identifier:NCT00185211

Frederik Barkhof - One of the best experts on this subject based on the ideXlab platform.

  • magnetic resonance imaging effects of interferon beta 1b in the benefit study
    2015
    Co-Authors: Frederik Barkhof, Chris H Polman, Hans-peter Hartung, L. Kappos, Ernstwilhelm Radue, M S Freedman, G Edan, David H Miller, Peter Poppe, Marlieke De Vos
    Abstract:

    Results: Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P.001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P.001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P=.02). Conclusions: Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration: clinicaltrials.gov Identifier: NCT00185211

  • comparison of two dosing frequencies of subcutaneous interferon beta 1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis reflex a phase 3 randomised controlled trial
    Lancet Neurology, 2012
    Co-Authors: Giancarlo Comi, Chris H Polman, Frederik Barkhof, Nicola De Stefano, Mark S Freedman, Bernard M J Uitdehaag, Florence Cassetsemanaz, Brian Hennessy, Margaretha Stam Moraga, Sanda Rocak
    Abstract:

    Summary Background In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. Methods We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18–50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. Findings 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p Interpretation Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. Funding Merck Serono SA, Geneva, Switzerland.

  • magnetic resonance imaging effects of interferon beta 1b in the benefit study integrated 2 year results
    JAMA Neurology, 2007
    Co-Authors: Frederik Barkhof, Chris H Polman, Hans-peter Hartung, Xavier Montalban, L. Kappos, Ernstwilhelm Radue, M S Freedman, G Edan, David H Miller, Peter Poppe
    Abstract:

    Background In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions. Objective To examine detailed MRI findings from the first 2 years of this trial. Design Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study. Setting Ninety-eight centers worldwide. Patients A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis. Interventions Patients were randomized to receive interferon beta-1b, 250 μg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered. Main Outcome Measures Reported MRI data from patients completing 2 years of follow-up. Results Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P P P P  = .02). Conclusions Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration clinicaltrials.gov Identifier:NCT00185211