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

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

Patient-rated suitability of a novel electronic device for self-injection of subcutaneous interferon beta-1a in relapsing multiple sclerosis: an international, single-arm, multicentre, Phase IIIb study

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) currently requires long-term treatment with disease-modifying drugs, administered parenterally up to once daily. The need for regular self-injection can be a barrier to treatment for many patients. Autoinjectors can help patients overcome problems or concerns with self-injection and could, therefore, improve treatment adherence. This study was performed to assess the suitability of a new electronic device for the subcutaneous (sc) administration of interferon (IFN) beta-1a, 44 mcg three times weekly, for relapsing MS.</p> <p>Methods</p> <p>In this Phase IIIb, multicentre, single-arm study, patients with relapsing MS who had been consistently self-injecting sc IFN beta-1a using an autoinjector for at least 6 weeks were taught to use the new device and self-administered treatment for 12 weeks thereafter. Patient-rated suitability of the device was assessed at the end of Week 12 using the Patient User Trial Questionnaire. Patient satisfaction with, and evaluation of, the injection process was assessed using the MS Treatment Concern Questionnaire. Trainers evaluated the device using the Trainer User Trial Questionnaire.</p> <p>Results</p> <p>At Week 12, 71.6% (73/102) of patients considered the device 'very suitable' or 'suitable' for self-injection; 92.2% (94/102) reported some degree of suitability and only 7.8% (8/102) found the device 'not at all suitable'. At Weeks 4, 8 and 12, most patients reported that injection preparation and clean-up, performing injections and ease of device use in the previous 4 weeks compared favourably with, or was equivalent to, their previous experience of self-injection. Injection-related pain, injection reactions and 'flu-like' symptoms remained stable over the 12 weeks. Each device feature was rated 'very useful' or 'useful' by at least 80% of patients. All trainers and 95.2% (99/104) of patients found device functions 'very easy' or 'easy' to use. Overall convenience was considered the most important benefit of the device.</p> <p>Conclusions</p> <p>Most patients considered the new electronic injection device suitable for the sc injection of IFN beta-1a. They found the device easy to use with useful features, and reported benefits such as overall convenience. The device may, therefore, increase treatment adherence in patients with MS, particularly those with injection-related issues.</p> <p>Trial registration</p> <p>NCT00735007</p

Serum S100B in primary progressive multiple sclerosis patients treated with interferon-beta-1a

S100B belongs to a family of calcium-binding proteins implicated in intracellular and extracellular regulatory activities. This study of serum S100B in primary progressive multiple sclerosis (PPMS) is based on data obtained from a randomized, controlled trial of Interferon β-1a in subjects with PPMS. The key questions were whether S100B levels were associated with either disability or MRI findings in primary progressive MS and whether Interferon β-1a has an effect on their S100B levels. Serial serum S100B levels were measured using an ELISA method. The results demonstrated that serum S100B is not related to either disease progression or MRI findings in subjects with primary progressive MS given Interferon β-1a. Furthermore there is no correlation between S100B levels and the primary and secondary outcome measures

Management of breakthrough disease in patients with multiple sclerosis: when an increasing of Interferon beta dose should be effective?

<p>Abstract</p> <p>Background</p> <p>In daily clinical setting, some patients affected by relapsing-remitting Multiple Sclerosis (RRMS) are switched from the low-dose to the high-dose Interferon beta (IFNB) in order to achieve a better control of the disease.</p> <p>Purpose</p> <p>In this observational, post-marketing study we reported the 2-year clinical outcomes of patients switched to the high-dose IFNB; we also evaluated whether different criteria adopted to switch patients had an influence on the clinical outcomes.</p> <p>Methods</p> <p>Patients affected by RRMS and switched from the low-dose to the high-dose IFNB due to the occurrence of relapses, or contrast-enhancing lesions (CELs) as detected by yearly scheduled MRI scans, were followed for two years. Expanded Disability Status Scale (EDSS) scores, as well as clinical relapses, were evaluated during the follow-up period.</p> <p>Results</p> <p>We identified 121 patients switched to the high-dose IFNB. One hundred patients increased the IFNB dose because of the occurrence of one or more relapses, and 21 because of the presence of one or more CELs, even in absence of clinical relapses. At the end of the 2-year follow-up, 72 (59.5%) patients had a relapse, and 51 (42.1%) reached a sustained progression on EDSS score. Overall, 85 (70.3%) patients showed some clinical disease activity (i.e. relapses or disability progression) after the switch.</p> <p>Relapse risk after increasing the IFNB dose was greater in patients who switched because of relapses than those switched only for MRI activity (HR: 5.55, p = 0.001). A high EDSS score (HR: 1.77, p < 0.001) and the combination of clinical and MRI activity at switch raised the risk of sustained disability progression after increasing the IFNB dose (HR: 2.14, p = 0.01).</p> <p>Conclusion</p> <p>In the majority of MS patients, switching from the low-dose to the high-dose IFNB did not reduce the risk of further relapses or increased disability in the 2-year follow period.</p> <p>Although we observed that patients who switched only on the basis on MRI activity (even in absence of clinical attacks) had a lower risk of further relapses, larger studies are warranted before to recommend a switch algorithm based on MRI findings.</p

Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study

<p>Abstract</p> <p>Background</p> <p>Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS).</p> <p>Methods</p> <p>BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device.</p> <p>Results</p> <p>Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (<it>P </it>= 0.821) or PASAT (<it>P </it>= 0.952) scores, or pre-study therapy (<it>P </it>= 0.303). No significant changes (baseline-Week 12) in mean HADS depression (<it>P </it>= 0.482) or anxiety (<it>P </it>= 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu-like' symptoms (<it>P </it>= 0.022) and global side effects (<it>P </it>= 0.002) significantly improved from Week 4-12. Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (<it>P </it>< 0.001). Adverse events were mild/moderate. No new safety signals were identified.</p> <p>Conclusion</p> <p>Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a.</p> <p>Trial registration</p> <p>EU Clinical Trials Register (EU-CTR; <url>http://www.clinicaltrialsregister.eu</url>): 2009-013333-24</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

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