Interferon Beta in the Management of Multiple Sclerosis

Intramuscular interferon beta-1a therapy provides a means of reducing the accumulation of physical disability in relapsing-remitting MS

Recent Advances in the Understanding, Diagnosis and Management of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and a common cause of disability in young adults. This brief review will focus on recent advances in the pathogenesis, diagnosis and management of MS

Analysis of NAMCS data for multiple sclerosis, 1998–2004

BACKGROUND: To our knowledge, no study to date has investigated the prescribing patterns of immunomodulatory agents (IMAs) in an outpatient setting in the United States. To address this issue, we performed retrospective data analyses on National Ambulatory Medical Care Survey (NAMCS) data for MS patient visits between 1998 and 2004. METHODS: NAMCS data are a weighted estimate of the nationwide frequency of patients' outpatient clinic visits. We analyzed NAMCS data in the following categories: (1) the proportion of MS patient visits to neurologists, family practitioners or internists, (2) age/gender/race/geographical distribution patterns in patient visits, and (3) the proportion of patients on IMA treatment among established MS patients. RESULTS: There were an estimated 6.7 million multiple sclerosis (MS) patient visits to the clinics between 1998–2004. Neurologists recorded the most patient visits, 50.7%. Patient visits were mostly in the fourth and fifth decade age group (57.9%). The male to female ratio was 1:4. No statistical evidence was observed for a decline or increase in IMA usage. About 62% patients visiting neurologists and 92% seen by family practitioners/internists were not using IMAs. Our results suggest that between the years 1998–2003, the use of interferon-1a tended to decline while the use of interferon-1b and glatiramer acetate, increased. CONCLUSION: Strategies that lead to improved use of IMAs in the management of MS in the outpatient setting are needed

The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses--number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence--to a lesser degree--its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients

Modelling disease progression in relapsing-remitting onset multiple sclerosis using multilevel models applied to longitudinal data from two natural history cohorts and one treated cohort

Background The ability to better predict disease progression represents a major unmet need in multiple sclerosis (MS), and would help to inform therapeutic and management choices. Objectives To develop multilevel models using longitudinal data on disease progression in patients with relapsing–remitting MS (RRMS) or secondary-progressive MS (SPMS); and to use these models to estimate the association of disease-modifying therapy (DMT) with progression. Design Secondary analysis of three MS cohorts. Setting Two natural history cohorts: University of Wales Multiple Sclerosis (UoWMS) cohort, UK, and British Columbia Multiple Sclerosis (BCMS) cohort, Canada. One observational DMT-treated cohort: UK MS risk-sharing scheme (RSS). Participants The UoWMS database has > 2000 MS patients and the BCMS database (as of 2009) has > 5900 MS patients. All participants who had definite MS (RRMS/SPMS), who reached the criteria set out by the Association of British Neurologists (ABN) for eligibility for DMT [i.e. age ≥ 18 years, Expanded Disability Status Scale (EDSS) score of ≤ 6.5, occurrence of two or more relapses in the previous 2 years] and who had at least two repeated outcome measures were included: 404 patients for the UoWMS cohort and 978 patients for the BCMS cohort. Through the UK MS RSS scheme, 5583 DMT-treated patients were recruited, with the analysis sample being the 4137 who had RRMS and were eligible and treated at baseline, with at least one valid EDSS score post baseline. Main outcome measures EDSS score observations post ABN eligibility. Methods We used multilevel models in the development cohort (UoWMS) to develop a model for EDSS score with time since ABN eligibility, allowing for covariates and appropriate transformation of outcome and/or time. These methods were then applied to the BCMS cohort to obtain a ‘natural history’ model for changes in the EDSS score with time. We then used this natural history model to predict the trajectories of EDSS score in treated patients in the UK MS RSS database. Differences between the progression predicted by the natural history model and the progression observed at 6 years’ follow-up for the UK MS RSS cohort were used as indicators of the effectiveness of the DMTs. Previously developed utility scores were assigned to each EDSS score, and differences in utility also examined. Results The model best fitting the UoWMS data showed a non-linear increase in EDSS score over time since ABN eligibility. This model fitted the BCMS cohort data well, with similar coefficients, and the BCMS model predicted EDSS score in UoWMS data with little evidence of bias. Using the natural history model predicts EDSS score in a treated cohort (UK MS RSS) higher than that observed [by 0.59 points (95% confidence interval 0.54 to 0.64 points)] at 6 years post treatment. Limitations Only two natural history cohorts were compared, limiting generalisability. The comparison of a treated cohort with untreated cohorts is observational, thus limiting conclusions about causality. Conclusions EDSS score progression in two natural history cohorts of MS patients showed a similar pattern. Progression in the natural history cohorts was slightly faster than EDSS score progression in the DMT-treated cohort, up to 6 years post treatment. Future work Long-term follow-up of randomised controlled trials is needed to replicate these findings and examine duration of any treatment effect. Funding details The National Institute for Health Research Health Technology Assessment programme

Alternative statistical methods for estimating efficacy of interferon beta-1b for multiple sclerosis clinical trials

<p>Abstract</p> <p>Background</p> <p>In the randomized study of interferon beta-1b (IFN beta-1b) for multiple sclerosis (MS), it has usually been evaluated the simple annual relapse rate as the study endpoint. This study aimed to investigate the performance of various regression models using information regarding the time to each recurrent event and considering the MS specific data generation process, and to estimate the treatment effect of a MS clinical trial data.</p> <p>Methods</p> <p>We conducted a simulation study with consideration of the pathological characteristics of MS, and applied alternative efficacy estimation methods to real clinical trial data, including 5 extended Cox regression models for time-to-event analysis, a Poisson regression model and a Poisson regression model with Generalized Estimating Equations (GEE). We adjusted for other important covariates that may have affected the outcome.</p> <p>Results</p> <p>We compared the simulation results for each model. The hazard ratios of real data were estimated for each model including the effects of other covariates. The results (hazard ratios of high-dose to low-dose) of all models were approximately 0.7 (range, 0.613 - 0.769), whereas the annual relapse rate ratio was 0.714.</p> <p>Conclusions</p> <p>The precision of the treatment estimation was increased by application of the alternative models. This suggests that the use of alternative models that include recurrence event data may provide better analyses.</p

An open-label, multicenter study to evaluate the safe and effective use of the single-use autoinjector with an Avonex® prefilled syringe in multiple sclerosis subjects

<p>Abstract</p> <p>Background</p> <p>The ability to self-inject in patients with multiple sclerosis (MS) has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patients' independence. However, injection anxiety, needle phobia and disease-related disability are major barriers to a patient's ability to self-administer treatment. Use of an autoinjector may improve patients' ability to self-inject. This study evaluated the safe and effective use of Avonex Pen™ (prefilled pen), a single use autoinjector, for intramuscular delivery of interferon beta-1a (IM IFNβ-1a, Avonex) in MS patients.</p> <p>Methods</p> <p>This was a Phase IIIb, open-label, single-country, multicenter trial in MS patients currently using IM IFNβ-1a prefilled syringes. Patients received weekly 30 mcg IM IFNβ-1a treatment over 4 weeks. On Day 1, patients self-administered IM IFNβ-1a using a prefilled syringe at the clinic. On Day 8, patients received training on the prefilled pen and self-administered IM IFNβ-1a using the device. On Day 15, patients self-administered IM IFNβ-1a at home using the prefilled pen. A final injection occurred at the clinic on Day 22 when patients self-administered IM IFNβ-1a using the prefilled pen while clinic staff observed and completed a detailed questionnaire documenting patients' ability to self-inject with the device. Serum neopterin levels were evaluated pre and post-injection on Days 1 and 8. Adverse events were monitored throughout.</p> <p>Results</p> <p>Seventy-one (96%) patients completed the study. The overall success rate in safely and effectively using the prefilled pen was 89%. No device malfunctions occurred. One unsuccessful administration occurred at Day 22 due to patient error; no patient injury resulted. Patients gave the prefilled pen high ratings (8.7-9.3) on a 10-point scale for ease of use (0 = extremely difficult, 10 = extremely easy). Ninety-four percent of patients preferred the prefilled pen over the prefilled syringe. Induction of serum neopterin levels, serving as a biomarker for type 1 interferon action, was similar to that of the prefilled syringe. The prefilled pen demonstrated a safety profile comparable to the prefilled syringe.</p> <p>Conclusions</p> <p>The prefilled pen is a safe and effective device for administration of IM IFNβ-1a and represents an alternative method for self-injection for MS patients using this therapy.</p> <p>Trial registration</p> <p>This study is registered at clinicaltrials.gov, identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00828204">NCT00828204</a></p

Current trends in the cardiovascular clinical trial arena (I)

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular). The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients. As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series

Epidemiology of multiple sclerosis: results from a large observational study in the UK

Multiple sclerosis (MS) progression to mortality may not be solely determined by the underlying autoimmune process. We conducted a study in a large cohort of MS patients with the aim of describing characteristics of MS patients and identification of predictors for all-cause mortality in this patient group. We performed a retrospective analysis of primary care data from the UK Clinical Practice Research Datalink. Incident MS cases diagnosed between 1993 and 2006 were identified and validated using electronic and original medical records. Patients were followed to identify deaths; hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox proportional regression with age as time-scale. In total, 1713 incident MS cases were identified. Following MS diagnosis, frequent comorbidities were infections (80 %), and depression (46 %). Adjusted HRs (95 % CIs) for all-cause mortality were: 2.0 (1.2–3.4) for current smoking; 7.6 (3.2–17.7) for alcohol abuse; 2.7 (1.6–4.5) for pneumonia and influenza; 4.1 (2.7–6.3) for urinary tract infections; 2.2 (1.2–4.2) for heart disease and 4.9 (2.9–8.0) for cancer. Our results suggest that MS survival is influenced not only by the underlying autoimmune process, but also by patient comorbidities and lifestyle factors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00415-015-7796-2) contains supplementary material, which is available to authorized users