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interferon beta 1a [keywords]
- Interferon Beta Assessment in Non-Chinese and Chinese Subjects: Pharmacokinetics and Pharmacodynamic Activity of an Endogenous Cytokine Are Not Race Dependent. [JOURNAL ARTICLE]
- J Clin Pharmacol 2014 Apr 15.
Interferon beta-1a (IFNβ-1a) is a first-line therapy for relapsing multiple sclerosis when administered as 30 mcg intramuscularly (IM) once weekly. This endogenous cytokine displays pharmacokinetic (PK) attributes consistent with a glycoprotein of 20-kDa molecular weight that is administered IM. In this study, 24 healthy Chinese subjects (11 male, 13 female) each received 4 once-weekly 60-mcg IM doses of IFNβ-1a. Serial blood samples were drawn for PK and pharmacodynamic (PD) assessments following the first and last dose of drug. Results were compared with historical data from a recent PK/PD assessment conducted in non-Chinese subjects. Noncompartmental analysis revealed that no meaningful differences in either IFNβ-1a exposure or response were apparent between the Chinese and non-Chinese populations. Thus, it was concluded that no adjustment in dose regimen is warranted for future assessments of safety and efficacy in multiple sclerosis patients of Chinese origin.
- Interferon β-1a therapy for multiple sclerosis during pregnancy: an unresolved issue. [Journal Article]
- BMJ Case Rep 2014.
On the basis of evidence from clinical trials, contraindications to the use of interferon (INF) are pregnancy, epilepsy and depression. Management of multiple sclerosis during pregnancy is a difficult issue because of pregnancy-related complications and fear of congenital anomalies due to exposure to disease-modifying therapy. In different series, INF therapy was withdrawn before or after variable periods of exposure. This case illustrates a 26-year-old woman diagnosed with relapsing remitting multiple sclerosis who was treated with a weekly regimen of intramuscular INF-β 1a (Avonex). She had received this treatment throughout her pregnancy without any further exacerbations of symptoms or any untoward pregnancy-related complications. In contrast to different series, our patient had the longest exposure to INF-β during pregnancy.
- JC virus Reactivation During Prolonged Natalizumab Monotherapy for Multiple Sclerosis. [JOURNAL ARTICLE]
- Ann Neurol 2014 Mar 31.
Objective: To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods: We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy>18 months, 6 on interferon β-1a monotherapy>36 months and 5 untreated controls. We performed QPCR in cerebrospinal fluid (CSF), blood and urine for JCV DNA and we determined JCV-specific T cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results: JCV DNA was detected in the CSF of 2/27 (7.4%) natalizumab-treated MS patients who had no symptoms or MRI lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12/43 (27.9%) and in urine of 11/43 (25.6%) subjects without difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot, and JCV-specific T cell responses, mediated by both CD4(+) and CD8(+) T-lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T-cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p=0.05) and B cells (p=0.03). Interpretation: Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. ANN NEUROL 2014. © 2014 American Neurological Association.
- Recruitment of participants to a multiple sclerosis trial: The CombiRx experience. [Journal Article]
- Clin Trials 2014; 11(2):159-66.
and purpose Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multicenter, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing-remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the United States and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6-month start-up period. Instead, the investigators required 4.25 years to enroll 1008 patients.During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research, and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites.Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for rescreening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled.The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant.Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central institutional review boards (IRBs), master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites.
- MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. [JOURNAL ARTICLE]
- Neurology 2014 Apr 9.
RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%-29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.
- Alemtuzumab in the treatment of multiple sclerosis. [REVIEW]
- J Inflamm Res 2014.:19-27.
Alemtuzumab (formerly known as Campath-1H) has recently been approved by the European Medicines Agency for highly-active, relapsing-remitting multiple sclerosis (MS). The molecule targets the CD52 surface glycoprotein on certain T cells and B cells and is thought to exert its effect in MS through a "resetting" of the lymphocyte population. Approval was granted on the strength of two pivotal studies, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS)-1 in the first-line setting and CARE-MS-2 in patients who had failed first-line therapy. In both studies, alemtuzumab significantly reduced the relapse rate compared to the comparator, interferon beta-1a (44 μg) given subcutaneously three-times per week (Rebif®). In the first-line study, alemtuzumab was also found to significantly reduce the number of patients with sustained progression compared to interferon beta-1a therapy. Autoimmune disorders represent the major side effect of alemtuzumab therapy although they can be managed by careful monitoring and early treatment. Overall, alemtuzumab is likely to be a valuable addition to the neurologist's armamentarium for the treatment of relapsing-remitting MS.
- Thrombotic microangiopathy associated with interferon beta. [Letter, Research Support, Non-U.S. Gov't]
- N Engl J Med 2014 Mar 27; 370(13):1270-1.
- A case of septal panniculitis secondary to interferon treatment. [JOURNAL ARTICLE]
- Cutan Ocul Toxicol 2014 Mar 18.
Abstract The most common side effects of interferon-beta therapy following subcutaneous administration include pain, inflammation and induration at the injection site, which occur in approximately 20-60% of patients. Besides, transient injection-site erythema is frequently seen in beta-interferon therapy. Less frequent reactions at injection sites include vascular thrombosis, mucinosis, dermal and systemic sclerosis, necrosis, and ulceration. Here, we report a 44-year-old case diagnosed with multiple sclerosis, who developed pain and swelling following interferon-beta 1a treatment after an improperly administered intramuscular injection; and with this case report, we would like to draw attention to septal panniculitis, a serious drug complication, that develops following interferon-beta 1a treatment after an improperly administered intramuscular injection.
- Effect of treatment with interferon Beta-1a on changes in voxel-wise magnetization transfer ratio in normal appearing brain tissue and lesions of patients with relapsing-remitting multiple sclerosis: a 24-week, controlled pilot study. [Journal Article]
- PLoS One 2014; 9(3):e91098.
This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing-remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN β-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318).Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN β-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed-rank or Wilcoxon rank-sum test.A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0-15278]; 342 [0-951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6-11577]; 360 [0-1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0-6141]; 297 [0-852] mm3; p<0.001).The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN β-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS disease activity.ClinicalTrials.gov NCT01085318.
- Alemtuzumab: a review of its use in patients with relapsing multiple sclerosis. [Journal Article]
- Drugs 2014 Mar; 74(4):489-504.
Alemtuzumab (Lemtrada™) is a humanized therapeutic monoclonal antibody, which has been approved for use in patients with B-cell chronic lymphocytic leukaemia for several years, and has recently become approved in the EU and several other countries for use in adult patients with active relapsing-remitting multiple sclerosis. This article reviews the available pharmacological properties of intravenous infusions of alemtuzumab and its clinical efficacy and tolerability in adult patients with relapsing-remitting multiple sclerosis. Alemtuzumab is an effective treatment for patients with relapsing-remitting multiple sclerosis, and has a generally acceptable tolerability profile. In phase III trials, it was shown to be more effective than a current first-line treatment, subcutaneous interferon beta-1a, in decreasing relapse rate in treatment-naïve and previously treated patients and in decreasing disability progression in previously treated patients. Of note, these results appear to have extended into the long-term follow-up, despite no further treatment. There was an increased risk of autoimmunity and infection associated with alemtuzumab in these trials; while these adverse events were generally mild to moderate, some were severe. Alemtuzumab is a highly convenient treatment, requiring hospital attendance for an intravenous infusion for a handful of days on two consecutive years, with no treatment required in between; however, this convenience is counterbalanced by the need for regular monitoring for the increased risk of autoimmunity. More investigation is required before final conclusions can be drawn on the correct placement of alemtuzumab in multiple sclerosis treatment; however, it is of a certainty a welcome addition to the treatment options for these patients.