Proportion Of Relapse-free Patients Research Articles

Adherence to subcutaneous interferon beta-1a treatment among patients with relapsing multiple sclerosis: the MAIN-MS study

Introduction and backgroundAdherence is a critical factor for optimal clinical outcomes in multiple sclerosis (MS) treatment. This study investigated the adherence and clinical outcomes of MS patients treated with subcutaneous (sc) interferon (IFN) (β)-1a, an established immunomodulatory treatment for relapsing MS. The benefits of a patient support programme (PSP) were also studied.MethodsThis phase-IV prospective, observational multicentre study enrolled patients with relapsing MS who were treated with sc IFN β-1a for 24 months was conducted at 53 centres across 17 countries. The primary endpoint was adherence to sc IFN β-1a treatment, as assessed using Morisky Green Levine Medication Adherence Scale (MGLS) scores at 24 months. The MGLS is a self-reported diagnostic tool to address medication non-adherence, with a score ranging from 0 to 4, with 0 representing high adherence, 1–2 representing medium adherence, and 3–4 representing low adherence. Other endpoints included time to study and treatment discontinuation over 24 months, the proportion of relapse-free patients, and Expanded Disability Status Scale (EDSS) progression (defined as ≥1.0 point increase sustained for 3 months) at 24 months. A subgroup analysis was performed for endpoints based on patients assigned to PSP (yes/no—PSP versus non-PSP subgroup).ResultsOf the 577 patients enrolled, 408 had evaluable MGLS scores at 24 months. A total of 336 (58.2%; 95% confidence interval [CI]: 54.1–62.3%) patients reported high adherence, 57 (9.9%; 95% CIs: 7.6–12.7%) reported medium adherence, and 15 (2.6%; 95% CI: 1.5–4.3%) reported low adherence at 24 months. The PSP subgroup reported higher adherence (n = 206; 65.8%) than the non-PSP subgroup (n = 130; 56.5%). By 24 months, 52.2% of the patients were relapse-free and 17.2% patients experienced ≥1 relapse. Expanded Disability Status Scale progression was observed in 12.3% of patients. Over the 24-month period, 30.8% of the patients discontinued treatment, and the most common reasons for treatment discontinuation were adverse events (AEs, 10.4%), being lost to followup (7.1%), and a lack of efficacy (5.5%). Overall, 39.6% patients experienced ≥1 AE, which ranged from mild to moderate.ConclusionThe study demonstrated high adherence to sc IFN β-1a treatment with an added benefit of PSP participation. More than half of the patients remained relapse-free over a 24-month period. No new safety concerns to sc IFN β-1a treatment were observed.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT02921035, NCT02921035.

A prospective observational longitudinal study with a two-year follow-up of multiple sclerosis patients on Cladribine

BackgroundCladribine was approved for the treatment of multiple sclerosis (MS). Real-world data is very limited. ObjectivesTo study the effectiveness and the safety of Cladribine treatment in only one group of MS patients after treatment with Cladribine for two years. MethodsThis observational, longitudinal prospective study. Eligible subjects were relapsing remitting MS patients who had at least two-year follow-up after Cladribine treatment. The primary endpoint was the proportion of relapse free patients. Secondary endpoints were ARR, change in EDSS scores, the proportion of patients with CDP, MRI activity, and NEDA-3 status, also the rate of occurrence of AEs. Patients were assessed for primary and secondary endpoints at the end of two years of follow-up. ResultsOf a total of seventy-two patients, 59 (81.9 %) were females, mean age of 36.32 + 10.06 years old, mean disease duration 7.21 + 6.19. Most patients (n = 32; 44.4 %) were naïve to any treatment. Forty patients (55.6 %) completed two courses of treatment. The primary endpoint showed that most of our cohort was relapse free (85 % versus 25 %; P < 0.001), Secondary endpoints showed that ARR was significantly reduced 0.15 + 0.36 versus 0.85 + 0.53; P < 0.01). Most of the cohort 90 % have no progression of disability. Few subjects had new T2 lesions (7.5 % versus 70.8 %; P < 0.001 and gadolinium enhancement 5 % versus 66.7 %; P < 0.001) in MRI compared to baseline. No evidence of disease activity 3 (NEDA-3) was achieved in 30 (75 %) patients. It was achieved in 87.5 % of naive patients versus 66.7 % in patients who received prior disease modification drugs before Cladribine initiation. Infections 6 (n = 6; 8.4 %) lymphocytopenia (n = 3; 4.2 %), and elevated liver enzymes (n = 1; 1.4 %) were reported. ConclusionCladribine treatment reduced significantly relapse rate and MRI activity. It was safe and tolerable. Early initiation of cladribine is associated with favorable outcomes.

044 Safety and efficacy of dimethyl fumarate in ESTEEM UK cohort

IntroductionESTEEM (NCT02047097) is an ongoing 5-year, global study characterizing long-term safety and effectiveness of routinely prescribed dimethyl fumarate (DMF) in multiple sclerosis (MS) patients. We report results from an analysis of the UK cohort of ESTEEM.MethodsThe primary objective of ESTEEM is to assess the incidence, type, and patterns of serious adverse events (SAEs), and AEs leading to discontinuation of DMF in routine practice. Secondary objectives include assessment of annualized relapse rate (ARR) and proportion of patients without relapse at 6 and 12 months.ResultsOf 238 UK patients (median age 42 years, 187[79%] female), SAEs were reported in 14(6%) patients. AEs leading to discontinuation occurred in n=53(22.3%) patients; the most common of these were gas- trointestinal disorders (n=20;8.4%). Unadjusted ARR declined by 84%(95%confidence interval [CI]=68– 100%;P&lt;0.0001), from 0.74(95%CI=0.63–0.85) 12 months before enrollment to 0.12(95%CI=0.07–0.16) the year after enrollment. The proportion of relapse-free patients was 93.8%(n=223) and 87.9%(n=209) at 6 and 12 months, respectively.ConclusionsNo new safety signals were observed in patients treated with DMF routinely for one year. ARR was significantly reduced vs the year prior to enrollment. Safety/efficacy results were similar between the UK and overall ESTEEM populations.SupportBiogen; disclosures detailed on poster.fiona.syndercombe@biogen.com

Real-world effectiveness and safety of fingolimod in patients with multiple\xa0sclerosis in the Czech Republic: results from core and extension parts of the GOLEMS study up to 48\xa0months

BackgroundFingolimod, an oral sphingosine 1-phosphate receptor immunomodulator, is approved in Europe for people with multiple sclerosis (pwMS) with highly active disease despite a full and adequate course of treatment with ≥ 1 disease-modifying therapy or patients with rapidly evolving severe relapsing–remitting MS. GOLEMS, a national, multicenter, non-interventional, single-arm, real-world study showed a favorable benefit–risk profile of 12-month treatment with fingolimod in pwMS in the Czech Republic. Here, we evaluated the long-term effectiveness and safety of fingolimod and its impact on disability progression and work capability for up to 48 months in pwMS.MethodsThe endpoints assessed were the incidence and severity of MS relapses in fingolimod-treated patients and the proportion of relapse-free patients up to 48 months of fingolimod treatment, change from baseline in the Expanded Disability Status Scale (EDSS) score, and change from baseline in work capability assessment. Efficacy outcomes were analyzed in the completed and efficacy sets, and safety was evaluated in all the enrolled patients.ResultsOf 240 enrolled patients, 237 were included into efficacy set. Patients with a minimum of a 12-month observation period in the core study who continued fingolimod treatment, were eligible to participate in the extension phase. Of 211 patients enrolled in extension study, 155 were evaluated in the completed set. Based on analysis of 48-month period of fingolimod treatment, 95/237 patients (40.1%) in the efficacy set, 54/155 (34.8%) in the completed set were free of relapses. The majority of relapses reported were moderate in intensity. Mean EDSS score remained stable throughout 48-month study period (Baseline, 3.4; Month 48, 3.6). No trend was observed in changes in work capability assessment or number of missed days of work. Of 240 enrolled patients, 147 (61.3%) had ≥ 1 treatment-emergent adverse event (AE) and 20 (8.3%) reported serious AEs. In total, 45 patients (18.8%) permanently discontinued treatment because of AEs related to study drug; two patients reported pregnancy after treatment initiation and subsequently discontinued the treatment; no deaths were reported.ConclusionGOLEMS study demonstrated the sustained effectiveness and manageable safety profile of fingolimod under real-world conditions over 48 months in patients with MS.Trial registrationNot applicable.

Safety and efficacy of interleukin-6-receptor inhibitors in the treatment of neuromyelitis optica spectrum disorders: a meta-analysis

BackgroundInterleukin-6-receptor inhibitors like Tocilizumab and Satralizumab are showing promising results in the treatment of Neuromyelitis Optica spectrum disorder (NMOSD). We aimed to investigate the efficacy and safety of various Interleukin-6-receptor inhibitors in the management of NMO/NMOSD.MethodsPubMed, Embase, and The Cochrane Library were systematically searched for suitable studies. Change in Annualized Relapse Ratio (ARR), Change in Extended Disability Status Scale (EDSS) s, the proportion of relapse-free patients and proportion of patients with adverse events, including serious adverse events and mortality were the parameters considered for the meta-analysis for Tocilizumab. Mean difference (MD) with 95% CI was used to quantify the change in ARR and change in EDSS before and after treatment. A forest plot was prepared to indicate the efficacy and adverse effects outcomes. The results were compared with those of Satralizumab included in two trials.ResultsA total of nine studies with 202 patients were included in our study. Tocilizumab found a good proportion (76.95% CI: 0.61–0.91; p < 0.001) of relapse free patients at follow up. It also significantly reduced mean ARR (mean difference: -2.6, 95% CI: − 2.71 to − 1.68; p < 0.001) and but did not show significant difference in change in EDSS score (mean difference = − 0.79, 95% CI: − 1.89 to − 0.31; p = 0.16). Also, the toxicity profile of Tocilizumab was acceptable considering the proportions of patients with adverse events 56% (95% C.I.;0.27–0.85, I2 = 88.95%, p < 0.001), proportions of patients with serious adverse events 11% (95% C.I.; 0.05 to 0.17, I2 = 0%, p < 0.001) and zero treatment related deaths. SAkura studies for Satralizumab showed similar relapse free patients (70% to 80%) and reduction of ARR and EDSS from baseline. Some studies of Tocilizumab have shown to reduce pain and fatigue while trials of Satralizumab had non-significant findings.ConclusionInterleukin-6-receptor inhibitors therapy showed a promising result with good efficacy and acceptable adverse events profile for treatment of NMOSD.

The results of a 24-month controlled, prospective study of relapsing multiple sclerosis patients at risk for progressive multifocal encephalopathy, who switched from prolonged use of natalizumab to teriflunomide.

BackgroundNatalizumab (NTZ) is a highly effective disease modifying treatment for relapsing multiple sclerosis (RMS), but it increases risk of progressive multifocal leukoencephalopathy (PML) in patients with serum anti- John Cunningham virus (JCV) antibodies.ObjectiveTo assess the safety and efficacy of rapid transition, from NTZ to teriflunomide (TFM) in RMS patients.MethodsClinically stable NTZ-treated, anti-JCV antibody positive RMS patients were switched to TFM 28 ± 7 days after their last dose of NTZ. The primary endpoint was proportion of relapse free patients at 24 months.ResultsMedian [IQR] age of the 55 enrolled patients was 47 [40.7, 56.3] years, 76% were female. The median [IQR] number of prior NTZ treatments was 34 [18, 64]. annualized relapse rate (ARR) was 0.07 and 77% of the patients were relapse free at 24 months. Mean time to first GAD + lesion was 19.6 months, and to new/enlarging T2 lesion was 19.2 months. Mean time to 3 month sustained disability worsening (SDW) was 22 months and proportion free of 3-month SDW was 0.87. There were no cases of PML.ConclusionsThe washout-free transition of NTZ to TFM was an efficacious and safe strategy for patients at risk of developing PML.ClinicalTrials.gov Identifier: NCT01970410

Safety and Efficacy of Fingolimod in Iranian Patients with Relapsing-remitting Multiple Sclerosis.

Introduction:Fingolimod is the first confirmed oral immune-modulator to treat Relapsing-Remitting Multiple Sclerosis (RRMS). This study aimed to investigate the safety and efficacy of fingolimod therapy in Iranian patients with RRMS.Methods:In our trial, 50 patients resistant to conventional interferon therapy were assigned to receive fingolimod 0.5 mg per day for 12 months. The number of Dadolinium (Gd)-enhanced lesions, enlarged T2 lesions, and relapses over 12 months were considered as endpoints and compared to baseline. Liver biochemical evaluations and lymphocyte count were done at baseline and in months 3, 6, and 12 of the study. Patients were also monitored for possible cardiovascular events within the first 24 h and other side effects routinely.Results:Among the patients who completed the trial, the number of Gd-enhanced and enlarged T2 lesions over 12 months significantly decreased (P=0.03 and P<0.001, respectively). The proportion of relapse-free patients was higher compared to the onset of fingolimod administration. There were no significant alterations in the Expanded Disability Status Scale (EDSS) scores. A slight, transient increase was recorded in liver enzymes among the participants. Lymphocyte count reduced by 61% at month 1 and displayed a gradual increase until month 12. No bradycardia and macular edema were recorded.Conclusion:These findings indicate an effective first-line fingolimod therapy for the first time in Iranian patients with RRMS. The decrease in the number of new attacks and the amelioration of MRI lesions were the benefits of fingolimod therapy, suggesting that it is preferred to other medicines to treat RRMS in Iran.

Adherence to self-administering interferon-β1a using RebiSmart® device in Mexican patients with relapsing multiple sclerosis.

BackgroundAdherence to disease-modifying therapies is determinant to attain maximal clinical benefit in multiple sclerosis (MS). RebiSmart® is an electronic auto-injector for subcutaneous delivery of interferon β-1a (INF-β1a) that monitors adherence by featuring a log of each drug administration for objective evaluation. The aim of this study was to assess long-term adherence to INF-β1a by using the RebiSmart® device in Mexican patients with relapsing MS.MethodsThis is an observational multicenter study on patients with relapsing MS treated with INF-β1a subcutaneously delivered by the RebiSmart® device. Adherence was computed as the number of injections received during the study period divided by the number of injections scheduled and expressed as percent.ResultsA total of 66 patients from 6 specialized MS centers were evaluated (45 females and 21 males, mean age 43.91±13.32 years). Mean adherence was 79.51±18% (median: 85.54%, range: 34.4–100%). During a median follow-up of 27.5 months (mean 33.36±29.39 months) the annualized relapse rate had a mean of 0.50±1.63. Mean initial EDSS was 1.90±1.52, and mean EDSS at the end of follow-up was 1.80±1.74. Compared with their counterparts, the mean number of relapses was significantly lower among patients with high (>80%) adherence (0.25±0.44 vs 0.67±92 relapses, respectively; P = 0.03). The proportion of relapse-free patients was 75.0% among patients with high adherence and 53.3% in low-compliant patients (P = 0.06). High adherence patients presented lower rates of EDSS worsening ≥1.0 at the end of treatment, as compared with low-compliant patients (11.1% vs 43.3%, respectively; P = 0.003). High schooling (>12 years) was the only predictor of a high adherence (OR: 2.97, 05% CI: 1.08–1.18; P = 0.03) and of being relapse-free during follow-up (OR: 3.22, 05% CI: 1.12–9.23; P = 0.03).ConclusionAdherence to INF-β1a using RebiSmart® in this Mexican cohort with MS was moderate, but associated with low relapse rate and influenced by high schooling.

Efficacy of satralizumab as monotherapy in pre-specified subgroups of SAkuraStar, a double-blind placebo-controlled phase 3 clinical study in patients with neuromyelitis optica spectrum disorder (NMOSD)

Interleukin-6 (IL-6) is implicated in the immune pathology of neuromyelitis optica spectrum disorder (NMOSD). Satralizumab, a humanized recycling monoclonal antibody that binds to the IL-6 receptor, reduced risk of relapse in patients with NMO or NMOSD as add-on therapy in the SAkuraSky study (NCT02028884) and as monotherapy in the SAkuraStar study (NCT02073279). Evaluate the efficacy of satralizumab monotherapy vs placebo for relapse prevention in pre-defined subgroups of the SAkuraStar study. SAkuraStar is a randomized, double-blind, Phase 3 study comparing satralizumab monotherapy with placebo. 95 patients with NMO or NMOSD, with ≥1 documented relapse in the year prior to screening, were randomized 2:1 to satralizumab (120 mg s.c.) or placebo. The primary endpoint was time to first protocol-defined relapse (PDR). Pre-specified subgroup analyses assessed treatment response by AQP4-IgG serostatus, prior therapy, and relapse history. Overall, satralizumab reduced risk of PDR by 55% vs placebo (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.23–0.89; p = .018). There was a 74% reduction in PDR risk with satralizumab vs placebo in AQP4-IgG-seropositive patients (HR 0.26; 95% CI 0.11–0.63). In AQP4-IgG-seronegative patients, the HR was 1.19 (95% CI 0.30–4.78). HRs for additional subgroups are provided in Table 1. The proportion of relapse-free patients at Weeks 48 and 96 in the AQP4-IgG-seropositive and seronegative subgroups will be presented. Conclusions Satralizumab was effective in reducing risk of PDR in patients with NMO or NMOSD, particularly in AQP4-IgG-seropositive patients. The study was not powered for subgroup analyses; therefore, results should be interpreted with caution.

Efectividad y seguridad del fingolimod en la práctica clínica habitual en pacientes con esclerosis múltiple remitente recurrente en España: análisis intermedio del estudio MS NEXT

Fingolimod is a disease modifying therapies, which has showed clinical efficacy and an acceptable safety profile in clinical trials with relapsing-remitting multiple sclerosis (RRMS) patients. To assess fingolimod effectiveness and safety in patients with RRMS in clinical practice. We present an interim analysis (July 2015) of MS NEXT, an observational, retrospective and multicenter study. 442 patients were included (mean age: 41 ± 9 years; median baseline EDSS: 3.0; 70% female; 284 previously treated with first-line disease modifying therapies, 139 with natalizumab and 19 without a previous treatment; mean fingolimod treatment duration: 25 ± 9 months) treated with fingolimod from November 2011 and with at least 12 months follow-up. 56 neurology-unit Spanish hospitals enrolled patients. Basal clinical and demographic data were recorded. Relapses, EDSS scores and radiological activity were recorded at baseline and annually. Adverse events were also recorded during the follow-up period. After two years of follow-up: annual relapse rates decreased by 76%, the proportion of relapse-free patients was 67%, of disability progression-free patients confirmed at 3 months was 91%, of relapse and disability progression-free patients was 63%, of radiological activity-free patients was 50%, and the proportion of relapse, disability progression and radiological activity-free patients was 35%. Only 3.9% of patients discontinued fingolimod permanently during the first year of treatment. In this interim analysis, most of patients treated with fingolimod in clinical practice had a controlled clinical disease activity, stable disability progression and high persistency.

Effectiveness, safety and health-related quality of life of multiple sclerosis patients treated with fingolimod: results from a 12-month, real-world, observational PERFORMS study in the Middle East

BackgroundEvidence on the use of fingolimod in real-world clinical practice and data on patient-reported health-related quality of life (HRQoL) in countries such as the Middle East are sparse. The Prospective Evaluation of Treatment with Fingolimod for Multiple Sclerosis (PERFORMS) study assessed HRQoL and effectiveness and safety of fingolimod in patients with relapsing-remitting multiples sclerosis (RRMS), primarily in Middle Eastern countries.MethodsThis 12-month, observational, multicentre, prospective, real-world study was conducted in patients with RRMS who initiated fingolimod or another approved disease-modifying treatment (DMT) within 4 weeks before study entry. Patients were enrolled in a 2:1 ratio to obtain more data in fingolimod and parallel in other DMTs cohort by physicians during routine medical care. Key study outcomes included HRQoL assessed using MS International QoL (MusiQoL), MS relapses and disability. Safety was assessed throughout the study period. Due to the observational nature of the study, no neuroimaging assessments were mandated and central reading was not performed.ResultsOf 249 enrolled patients, 247 were included in the analysis (fingolimod cohort 172; other DMTs cohort 75). Overall, the mean age of patients was 36.5 years, 64.4% were women and ~90% were Caucasians. At baseline, mean MS duration since diagnosis was 7.2 years in the fingolimod and 4.8 years in the other DMTs cohorts. Overall, mean changes in MusiQoL index scores were −2.1 in the fingolimod cohort and −0.7 in the other DMTs cohort at Month 12, but improvement was not significant vs. baseline in both cohorts. Proportion of relapse-free patients increased significantly during the study vs. 0–12 months before the study in the fingolimod cohort (80.2% vs. 24.4%; p < 0.0001). Proportion of patients free from disability progression was 86.5% in the fingolimod cohort. The incidences of AEs were 59.9% and 50.6% in the fingolimod and other DMTs cohorts, respectively. First-dose monitoring of fingolimod observed no cases of symptomatic bradyarrhythmia. Three cases of bradycardia were reported in the fingolimod cohort: one after the first dose and two during the study. No cases of macular oedema were observed during the study.ConclusionsFingolimod treatment maintained QoL over 12 months and was effective in reducing relapse rate and disability progression. No new safety findings were observed in this real-world observational study in Middle Eastern countries.

The real-world effectiveness and safety of fingolimod in relapsing-remitting multiple sclerosis patients: An observational study.

Fingolimod approval was based mainly on two clinical trials, FREEDOMS and TRANSFORMS, which demonstrated the efficacy and safety of fingolimod in patients with multiple sclerosis (MS). We present an observational study that validates these trials findings in a real-world setting, whereby the effectiveness and safety of fingolimod was assessed in Seville’s’ (Spain) clinical practice.This retrospective study in MS patients assessed effectiveness (relapses, EDSS, gadolinium-enhancing T1 and new/enlarged T2-weighted lesions): total cohort (n = 249) and stratified according to prior treatment (glatiramer acetate/interferon beta-1 [immunomodulator], natalizumab, naïve), gender, basal EDSS score, basal Gd+ lesions, ARR prior to treatment, age at treatment initiation and number of prior treatments. A multivariante model was used to assess the ARR with baseline characteristics. The safety profile (adverse events [AEs]) was also described.Fingolimod reduced the annualized relapse rate (ARR) by 75%, 67% and 85% in the total cohort, patients previously treated with immunomodulatory and naïve patients (p<0.0001 all cases). However, patients previously treated with natalizumab kept a constant ARR. The ARR results and the consequent increase in the proportion of relapse-free patients were independent of the age at treatment initiation, number of prior treatments, gender and basal Gd+ lesions. Although fingolimod was effective regardless the basal EDSS score and ARR prior to fingolimod treatment, better outcomes were observed in patients with basal EDSS score <3 (0.2 vs. 0.4; p = 0.0244) and ARR ≥ 2 prior to fingolimod treatment (p = 0.0338). Only the basal EDSS score was association with ARR in the first 24 months of fingolimod treatment in the multivariante model (p = 0.0439). The cumulative probability of disability progression was 20% (month-24) in the total cohort, and was independent from prior treatment, age at treatment initiation, number of prior treatments, gender, basal EDSS score, basal Gd+ lesions and ARR prior to treatment.The real-world fingolimod benefits observed in this study seem to be similar than those observed in previous clinical trials.

Fingolimod Use for the Treatment of Multiple Sclerosis in a Clinical Practice Setting in Madrid.

To assess the effectiveness and safety of fingolimod use in a Spanish clinical practice setting. Retrospective study with multiple sclerosis patients who received at least 1 fingolimod dose between January 2004 and January 2015. Effectiveness and safety data were collected during the entire treatment of each patient. Analysis was performed for the total population and stratified according to prior treatment, sex, and age at treatment initiation. A total of 167 patients were included, 50.9% had prior immunomodulator use, 33.5% natalizumab use, and 15.6% were naive patients. The annual relapse rate (ARR) decreased for the total population at month 12 (62%) and month 24 (84%) (P < 0.0001, in both cases); for naive patients (P < 0.05) and patients with prior immunomodulator use (P < 0.0001); for patients with prior natalizumab use, the ARR kept low after treatment initiation (0.23). After 24 months, the proportion of relapse-free patients was 70% or greater and disability progression-free patients was 80% or greater. No significant differences were observed when the results were compared by prior treatment, sex, or age. Thirty-two patients (19.2%) reported adverse drug reactions and 9.6% discontinued: 4.8% due to adverse drug reactions and 4.8% for lack of effectiveness. The results support fingolimod use due to clinical effectiveness, tolerability, and ease of administration.

Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis.

This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks, and benefit-risk ratios of disease-modifying treatments (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS). In May 2016, we conducted a systematic review using the PubMed and Cochrane Central Register of Controlled Trials databases to identify phase III, randomized controlled trials with a duration of ≥2 years that assessed first-line (dimethyl fumarate [DMF], glatiramer acetate [GA], β-interferons [IFN], and teriflunomide) or second-line (alemtuzumab, fingolimod, and natalizumab) DMTs in patients with RRMS. Meta-analyses were performed to estimate relative risks (RRs) on annualized relapse rate (ARR), proportion of relapse-free patients (PPR-F), disability progression (PP-F-CDPS3M), and safety outcomes. NNTB and NNTH values were calculated applying RRs to control event rates. LHH was calculated as NNTH/NNTB ratio. The lowest NNTBs on ARR, PPR-F, and PP-F-CDPS3M were found with IFN-β-1a-SC (NNTB 3, 95% CI 2-4; NNTB 7, 95% CI 4-18; NNTB 4, 95% CI 3-7, respectively) and natalizumab (NNTB 2, 95% CI 2-3; NNTB 4, 95% CI 3-6; NNTB 9, 95% CI 6-19, respectively). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14, 95% 2-426) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22, 95% 17-41). LHHs >1 were more frequent with IFN-β-1a-SC and natalizumab. These metrics may be valuable for benefit-risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B (versus a common comparator in trial A and trial B, respectively) does not necessarily mean that the number of patients needed to be treated for one patient to encounter one aditional outcome of interest over a defined period of time is lower with drug A than with drug B. Overall, IFN-β-1a-SC and natalizumab seem to have the most favorable benefit-risk ratios among first- and second-line DMTs, respectively.

Use of fingolimod in patients with relapsing remitting multiple sclerosis in Kuwait

BackgroundPost-marketing studies are important to confirm what was established in clinical trials, and to assess the intermediate and long-term efficacy and safety. ObjectiveTo assess efficacy and safety of fingolimod in multiple sclerosis (MS) in Kuwait. MethodsWe retrospectively evaluated MS patients using the MS registries in 3 MS clinics. Relapsing remitting MS patients according to revised 2010 McDonald criteria who had been treated with fingolimod for at least 12 months were included. Primary endpoint was proportion of relapse-free patients at last follow-up. Secondary endpoints were mean change in EDSS and proportion of patients with MRI activity (gadolinium-enhancing or new/enlarging T2 lesions). Results76 patients met the inclusion criteria. Mean age and mean disease duration were 34.43 and 7.82 years respectively. Mean duration of exposure to fingolimod was 18.50 months. Proportion of relapse-free patients was 77.6% at last follow-up. Mean EDSS score significantly improved (2.93 versus 1.95; p<0.0001) while 17.1% of patients continued to have MRI activity versus 77.6% at baseline (p<0.0001). Four patients stopped fingolimod due to disease breakthrough (n=3) and lymphadenitis (n=1). ConclusionFingolimod is safe and effective in reducing clinical and radiological disease activity in relapsing remitting MS patients. Our results are comparable to reported results of phase III studies.

Transdermal Application of Myelin Peptides in Multiple Sclerosis Treatment

Demonstration of efficacious antigen-specific therapy in multiple sclerosis. To assess the safety and efficacy of transdermally applied myelin peptides in patients with relapsing-remitting multiple sclerosis. One-year double-blind, placebo-controlled cohort study. Referral center. Thirty outpatients aged 18 to 55 years with relapsing-remitting multiple sclerosis. Skin patch with a mixture of 3 myelin peptides, MBP85-99, MOG35-55, and PLP139-155. MAIN OUTCOMES AND MEASURES Cumulative number of active gadolinium-enhanced (Gd+) lesions per patient per scan, mean volume of Gd+ lesions, cumulative number of new T2 lesions, and T2 lesion and T1 lesion volume change from baseline to the end of the study. Total number of relapses during the year of the study per patient (annual relapse rate), proportion of relapse-free patients, and proportion of patients with 3 months of confirmed disability worsening on the Expanded Disability Status Scale at month 12. All patients completed the study. Compared with placebo, treatment with a myelin peptide skin patch (1 mg) showed a 66.5% reduction in the cumulative number of Gd+ lesions (P = .02) during the 12 months of the study. The annual relapse rate in patients treated with a mixture of myelin peptides (1 mg) was significantly lower compared with the placebo group (0.43 vs 1.4; P = .007). Treatment with a myelin peptide skin patch was well tolerated and no serious adverse events were reported. In patients with relapsing-remitting multiple sclerosis, treatment with a myelin peptide skin patch significantly reduced both magnetic resonance imaging and clinically defined measures of disease activity and was safe and well tolerated.

Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial

BackgroundNatalizumab (NTZ) discontinuation leads to multiple sclerosis reactivation.The objective of this study is to compare disease activity in MS patients who continued on NTZ treatment to those who were switched to subcutaneous interferon 1b (IFNB) treatment.Methods1-year randomized, rater-blinded, parallel-group, pilot study (ClinicalTrial.gov ID: NCT01144052). Relapsing remitting MS patients on NTZ for ≥12 months who had been free of disease activity on this therapy (no relapses and disability progression for ≥6 months, no gadolinium-enhancing lesions on baseline MRI) were randomized to NTZ or IFNB. Primary endpoint was time to first on-study relapse. Additional clinical, MRI and safety parameters were assessed. Analysis was based on intention to treat.Results19 patients (NTZ n=10; IFNB n=9) with similar baseline characteristics were included. 78% of IFNB treated patients remained relapse free (NTZ group: 100%), and 25% remained free of new T2 lesions (NTZ group: 62.5%). While time to first on-study relapse was not significantly different between groups (p=0.125), many secondary clinical and radiological endpoints (number of relapses, proportion of relapse free patients, number of new T2 lesions) showed a trend, or were significant (new T2 lesions at month 6) in favoring NTZ.ConclusionsDe-escalation therapy from NTZ to IFNB over 1 year was associated with some clinical and radiological disease recurrence. Overall no major safety concerns were observed.

CPC-033 Comparing Effectiveness of First-Line Disease Modifying Drugs in Relapsing-Remitting Multiple Sclerosis Patients

BackgroundImmunomodulatory drugs represent the best therapeutic option in first-line treatment of relapsing-remitting multiple sclerosis (RRMS). This group includes glatiramer acetate (GA) and three formulations of Interferon β (IFNβ): subcutaneous IFNβ1a...

Endovascular treatment of chronic cerebrospinal venous insufficiency in multiple sclerosis: a retrospective study

Background: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed to be associated with multiple sclerosis (MS). Zamboni et al. reported significant improvement in neurological outcomes in MS patients who underwent percutaneous transluminal angioplasty (PTA). Objectives: To retrospectively evaluate the neurological outcomes in MS patients who underwent PTA. Method: Relapsing remitting MS patients who underwent PTA and completed at least 1 year post-PTA were assessed. Patients with clinically isolated syndrome or progressive forms of MS were excluded. Primary endpoint was the proportion of relapse-free patients at 1 year. Secondary endpoints were change in mean Expanded Disability Status Scale (EDSS) score and proportion of patients with new magnetic resonance imaging (MRI) activity (defined as either gadolinium-enhancing or new T2 lesions) at 1 year. Results: Forty-five patients satisfied the inclusion criteria. Females constituted 71.1%. The mean age and mean disease duration were 33.76 and 7.16 years, respectively. At 1-year post-PTA, the proportion of relapse-free patients decreased from 84.44% to 66.67% (p = 0.085), whereas the mean EDSS score increased (p = 0.017). The proportion of patients with new MRI activity increased significantly from 17.78% to 44.44% (p = 0.012). A total of 35.6% of patients stopped their disease modifying therapies (DMTs). There was no difference among the patients who stopped their DMTs with respect to relapses, EDSS score or new MRI activity. Conclusion: The study revealed that PTA in relapsing remitting MS patients was not associated with any neurological improvement. However, there was an increase in disease activity irrespective of the adherence to DMTs. Further evidence of the association between CCSVI and MS is required.

BAF312, a Selective Sphingosine-1-Phosphate Receptor Modulator Improves MRI and Clinical Outcomes in Relapsing-Remitting Multiple Sclerosis (RRMS) (S30.001)

Objective: To report relapse data and MRI findings from a double-blind, placebo-controlled, adaptive design phase II dose-finding study of BAF312 in patients with RRMS. Background BAF312, a next generation selective sphingosine-1-phosphate receptor (S1PR-1/5) modulator, significantly reduces MRI lesion activity in RRMS, and has demonstrated a 3-month dose-MRI response curve 1 . Here we report 6-month relapse data. Design/Methods: Patients were randomized to two sequential cohorts: Cohort 1 (n=188), received once-daily BAF312 10mg, 2mg, 0.5mg or placebo for 6mo; Cohort 2 (n=109), 1.25mg, 0.25mg (doses selected following Cohort 1 interim analysis) or placebo for 3mo. Brain MRI was performed monthly. Patients completing the core study were eligible for the extension study. Annualized relapse rate (ARR), calculated from confirmed relapses in 6mo, was analyzed post-hoc: Cohort 1 (6mo core data), Cohort 2 (3mo core plus 3mo extension data). Results: At 6mo, adjusted proportion of relapse-free patients (Cohort 1 only), was 84%, 92% and 77% for BAF312 10mg, 2mg and 0.5mg, respectively, vs 72% for placebo (p=0.014 for BAF312 2mg vs placebo). In the 6mo post-hoc analysis, ARR was lower with BAF312 10mg, 2mg, and 1.25mg (0.30, 0.20, 0.23, respectively) compared to BAF312 0.5mg, 0.25mg and placebo (0.61, 0.55, and 0.58, respectively). BAF312 three highest doses resulted in 48%-66% ARR reduction over placebo (p=0.044 for 2mg vs placebo). A significant dose-response relationship at 3mo was previously demonstrated (p=0.0001) 1 . The MRI dose-response curve estimated at 3mo indicated near-maximal efficacy at 2mg and submaximal efficacy at 0.5mg (∼50% reduction vs placebo). BAF312 reduced brain MRI lesion numbers up to 80% vs placebo. Most frequent adverse events were headache, bradycardia, dizziness and nasopharyngitis; highest in BAF312 10mg. Conclusions: BAF312 1.25-10mg reduces relapses in RRMS, correlating with MRI efficacy estimated from the 3mo dose-response curve. Overall safety and tolerability was favorable. Reference 1. Selmaj et al. ECTRIMS 2011. Supported by: Novartis-sponsored. Disclosure: Dr. Stuve has received personal compensation for activities with Teva Neuroscience, Novartis, Roche, Genzyme, EMD Serono, and Sanofi-Aventis. Dr. Stuve has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Li has received personal compensation for activities with Genzyme, Novartis and Nuron as a consultant.Dr. Li has receved research support from Angiotech, Bayer, Berlex-Schering, Bio-MS, Boehringer-Ingelheim, Centocor, Daiichi Sankyo, Genentech, Hoffmann-LaRoche, Merck-Serono, Perceptives, Schering-Plough, Teva Neurosciences,Sanofi-Aventis, Transition Therapeutics, and Novartis. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Genzyme Corporation, EMD Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Freedman has received research support from Genzyme Corporation and Bayer Healthcare. Dr. Rieckmann has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Boehringer-Ingelheim, Novartis, Merck-Serono, TEVA, and Sanofi-Aventis as a speaker. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. Pohlmann has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Mercier has received personal compensation for activities with Novartis as an employee. Dr. Dahlke has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Wallstrom has received personal compensation for activities with Novartis as an employee. Dr. Wallstrom holds stock and/or stock options in Novartis.