Baseline EDSS Score Research Articles

CCR5 Δ32 and CTLA-4 +49 A/G Gene Polymorphisms and Interferon-β Treatment Response in Croatian and Slovenian Multiple Sclerosis Patients.

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-β treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders (n = 173) and non-responders (n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence (p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-β therapy in females (p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females (p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-β treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients.

Alemtuzumab treatment in real clinical practice: Experience in a multicenter cohort.

Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but in recent years safety-related concerns had emerged due to description of novel serious side effects not registered in CARE-MS I and CARE-MS II phase 3 studies, nor in TOPAZ extension study. Data about alemtuzumab use in real clinical practice are limited and based mainly on retrospective studies with small sample sizes. Therefore, more information about effectiveness and safety of alemtuzumab in this context is needed. A multicenter observational prospective study to investigate effectivity and safety of alemtuzumab in a real-world setting was performed. Primary endpoints were the change in annualized relapse rate (ARR), and in disability measured by EDSS score. Secondary endpoints were the cumulative probability of confirmed 6-month disability improvement and worsening. Disability worsening and disability improvement were considered when the EDSS score was increased or decreased, respectively, in 1 point if baseline EDSS score was <5.0, or in 0.5 point if baseline EDSS score was ≥5.5, confirmed over 6 months. Other secondary endpoint was the proportion of patients who achieved NEDA-3 status (absence of clinical relapses, disability EDSS progression, and MRI disease activity as depicted by new/enlarging T2 lesions or Gadolinium enhancing T1 lesions). Adverse events also were recorded. A total of 195 RRMS patients (70% female) who started alemtuzumab treatment were included. Mean of follow-up was 2.38 years. Alemtuzumab significantly reduced the annualized relapse rate from baseline with risk reductions of 86%, 83.5%, and 84%, at 12, 24, and 36 months of follow-up respectively (Friedman test, p-value < 0.05 for all comparisons). Alemtuzumab also significantly reduced EDSS score over one and two years after starting alemtuzumab treatment (Friedman test, p-value<0.001 for both comparisons). A high proportion of patients presented confirmed 6-month stability or disability improvement (92%, 82%, and 79%, over 1, 2 and 3 years of follow-up respectively). The proportion of patients who retained NEDA-3 status at 12, 24 and 36 months were 61%, 49%, and 42%, respectively. Baseline characteristics associated with a lower probability of achieving NEDA-3 were younger age, sex female, high ARR, elevated number of previous treatments, and switch from a second line therapy. Infusion related reactions were the most frequent adverse event observed. The most common infections were urinary tract infections (50%), and upper respiratory tract infections (19%) over the 3 years of follow- up. Secondary thyroid autoimmunity was developed in 18.5% of patients. Alemtuzumab has demonstrated in real clinical practice high effectiveness in controlling multiple sclerosis activity, and no unexpected adverse events were observed.

Efficacy and Safety Profile of Cladribine Tablets in an Italian Real-Life Cohort of Relapsing-Remitting Multiple Sclerosis Patients: A Monocentric Longitudinal Observational Study (P8-3.015)

<h3>Objective:</h3> To report real-world findings about efficacy and safety of cladribine (CLAD) in relapsing-remitting multiple sclerosis (RRMS), identifying predictors of response. <h3>Background:</h3> CLAD induces a transient lymphocyte depletion followed by immune reconstitution, with improved immune tolerance. Real-world data on CLAD performance and its predictors of response are limited. <h3>Design/Methods:</h3> Monocentric, observational, real-world study on pwMS who started CLAD from April 2018 to November 2021, with a minimum 6 month-follow-up. <h3>Results:</h3> Our population comprised 114 pwMS, 71.9% females, 50% naïves, mean age 33.0 years, median disease duration 3.0 years, median baseline EDSS 2.0, mean 1 and 2 year-baseline ARR 1.3 and 1.2. Median follow-up: 23.8 months. 4.4% and 30.7% patients presented relapses and MRI activity in the first 6 months. When considering data re-baselined towards month 6, 12 relapses were reported. 84% (CI 76–92) and 76% (CI 67–87) patients had no MRI activity at 12 and 24 months, respectively. At month 24, NEDA-3 status was reached by 69% of naïves, and 81% and 55% of switchers from low and high-efficacy treatments, respectively. Eleven patients switched to other treatments. Younger age (HR 0.94, CI: 0.89–0.99, <i>p=0.011</i>), baseline EDSS score ≥ 3.0 (HR 4.29, CI: 1.83–10.05, <i>p=0.0008</i>) and gadolinium-enhancing lesion count ≥ 4 (HR 2.24, CI: 0.95–5.26, <i>p=0.065</i>) were risk factors for loss of NEDA-3. 20.0% of pwMS referred side effects: skin rash, fever/infections, fatigue. Lymphopenia was more likely at months 3 and 15. No grade-4 lymphopenia cases were observed. <h3>Conclusions:</h3> CLAD is more effective when placed early in the treatment algorithm: naïves or switchers from lower efficacy drugs seem to benefit more. Baseline age, disability and gadolinium-enhancing lesions are risk factors for loss of NEDA-3. CLAD was overall well tolerated. Real-world data on larger populations with longer follow-up are needed to confirm our findings. <b>Disclosure:</b> Chiara Zanetta has nothing to disclose. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Alessandro Meani has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Laura Ferrè, 3233 has received intellectual property interests from a discovery or technology relating to health care. Dr. Moiola has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Improvements in Quality of Life of Patients with Multiple Sclerosis receiving Alemtuzumab in Clinical Practice: LEMVIDA study (P7-3.018)

Improvements in Quality of Life of Patients with Multiple Sclerosis receiving Alemtuzumab in Clinical Practice: LEMVIDA study (P7-3.018)

Early beginning of alemtuzumab: Changing the multiple sclerosis treatment paradigm. Interim analysis of the LEMVIDA study

IntroductionLEMVIDA is a real-world prospective study of 3-year follow-up on quality of life of patients with multiple sclerosis (MS) receiving alemtuzumab in Spain. MethodsThis is an interim analysis evaluating the baseline characteristics of patients who started alemtuzumab between October 2016-September 2018. For 3 additional subanalysis patients were categorised by baseline EDSS score; time of alemtuzumab initiation during the recruitment period (cohort 1: October 2016-March 2017, cohort 2: April-September 2017, cohort 3: October 2017-March 2018 and cohort 4: April-September 2018); and the presence of highly active MS criteria. Results161 patients were analysed: 67.1% female, age 38.7 ± 9.4 years, MS duration 8.5 ± 6.0 years, EDSS 3.3 ± 1.7 and number of relapses in the previous 2 years 1.8 ± 1.3. 48.3% of patients presented gadolinium-enhanced (Gd+) lesions (mean: 5.2 ± 6.9) and 63.1% had received prior treatment with fingolimod or natalizumab. Baseline EDSS scores and number of Gd+ lesions were higher in cohort 1 than in cohort 4 (4.1 ± 1.8 vs 3.2 ± 1.7; P = .040 and 10.9 ± 11.9 vs 4.5 ± 5.7; P = .020). The frequency of prior treatment with fingolimod and natalizumab was lower in cohort 4 (60.6%) than in cohort 1 (70.6%) (comparison between groups not analysed). ConclusionsUnlike phase 3 studies of alemtuzumab, the patients included in LEMVIDA are older, have a longer duration of MS, higher disability and have received previous immunosuppressants. However, throughout the recruitment period, there is a tendency towards an early beginning of treatment with alemtuzumab, probably due to the evidence of higher effectiveness in the early stages of MS.

014 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program

IntroductionThe TYSABRI Observational Program (TOP) is a large, ongoing observational study in relapsing- remitting multiple sclerosis (RRMS) patients treated with natalizumab. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) and cumulative probability of 24-week confirmed disability worsening (CDW; increase in Expanded Disability Status Scale [EDSS] score ≥1.5 from a baseline of 0.0,≥1.0 from a baseline between 1.0–5.5, or ≥0.5 from a baseline of ≥6.0) and improvement (CDI; decrease≥1.0 from a baseline EDSS score ≥2.0) were analysed in TOP UK (n=134) and global (N=6295) cohorts using data from July 2007 to November 2018. Updated data (as of November 2019) will be presented.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.19 on natalizumab (P&lt;0.0001), consistent with a global decrease from 2.00 to 0.21 (P&lt;0.0001). At 7 years, probabilities of CDW and CDI were, respectively, 26.2% and 35.3% in UK patients and 27.9% and 32.1% globally.ConclusionsThese TOP UK results show disease control that is generally consistent with global TOP results, supporting natalizumab’s long-term effectiveness in real-world settings.SupportBiogen. Disclosures: Included on the poster.richard.nicholas@btinternet.com

Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate

BackgroundMultiple sclerosis (MS) is an inflammatory autoimmune disorder and the most common cause of non-traumatic disability in young adults. The Phase 3 OPTIMUM study evaluated the efficacy and safety of oral ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 modulator, vs. teriflunomide in patients with relapsing multiple sclerosis (RMS). The aim of this analysis was to assess the effect of ponesimod and other disease modifying treatments (DMTs) compared to placebo, as measured by 12-week confirmed disability accumulation (CDA) and annualized relapse rate (ARR) in RMS patients. MethodsA database was developed by Certara Inc. (USA) based on relevant clinical trials identified from searching the following sources: PubMed, clinicaltrials.gov, FDA and EMEA documents, and conference abstracts. This database consisted of 203 unique randomized controlled trials (RCTs) with 74 MS treatments and was subsequently filtered to include RCTs with more than 25 patients receiving monotherapy to treat RMS for at least 48 weeks. A model-based meta-analysis (MBMA) was performed on the filtered database to assess treatment effects measured by CDA and ARR. Analyzed data for CDA were digitized from published Kaplan-Meier plots. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time (proportional hazards). HRs were estimated for 12-week CDA for 17 DMTs vs. placebo. Additionally, mean ARR for each treatment arm was modelled, where relative effect versus placebo was estimated as a fixed effect parameter for each unique drug. A dose-response relationship was included if data for multiple doses were available. Relative treatment effect covariates explored for CDA and ARR included: percent of patients with relapsing-remitting MS (RRMS), trial start year, mean duration of disease, percent of patients who received DMTs within the prior 2 years (pDMT), mean number of relapses in the prior year, mean age, mean baseline EDSS score, and mean treatment duration (for ARR). ResultsThe 12-week CDA model utilized longitudinal data from 26 RCTs (18 unique treatments [including placebo]), 69 treatment arms, 31,160 patients). The ARR model utilized data from 40 RCTs (18 unique treatments [including placebo], 100 treatment arms, 33,686 patients). Compared to placebo, ponesimod significantly reduced 12-week CDA by 39% (HR: 0.61; 95% CI: 0.45–0.82) and reduced ARR by 53% (rate ratio [RR]: 0.47; 95% CI: 0.39–0.58). Except for three DMTs (interferon β-1b, glatiramer acetate, ozanimod), HR of 12-week CDA vs. placebo was significantly lower for the DMTs included in this analysis (HR range: 0.41 to 0.79). The ARR was significantly reduced for all DMTs compared to placebo (RR range: 0.29 to 0.82). A dose-response relationship indicated a potential dose-dependent effect (12-week CDA: 6 treatments; ARR: 8 treatments). Relative treatment effect was found to be significantly smaller in trials including more patients with prior DMT usage. Cross-trial heterogeneity in relative effects was assessed and found to be negligible; however, there is a possibility that confounders remain which may impact estimated relative treatment effects. ConclusionsCompared to placebo, ponesimod 20 mg significantly reduced both the risk of 12-week CDA and mean ARR, suggesting it has robust efficacy in the treatment of RMS.The study was funded by Janssen Research & Development, LLC.

Inicio temprano de alemtuzumab: cambio en el paradigma de tratamiento en esclerosis múltiple. Análisis intermedio del estudio LEMVIDA

IntroductionLEMVIDA is a real-world prospective study of 3-year follow-up on quality of life of patients with multiple sclerosis (MS) receiving alemtuzumab in Spain. MethodsThis is an interim analysis evaluating the baseline characteristics of patients who started alemtuzumab between October 2016-September 2018. For 3 additional subanalysis patients were categorized by baseline EDSS score; time of alemtuzumab initiation during the recruitment period (cohort 1: October 2016-March 2017, cohort 2: April-September 2017, cohort 3: October 2017-March 2018 and cohort 4: April-September 2018); and the presence of highly active MS criteria. Results161 patients were analyzed: 67.1% female, age 38.7±9.4 years, MS duration 8.5±6.0 years, EDSS 3.3±1.7 and number of relapses in the previous 2 years 1.8±1.3. 48.3% of patients presented gadolinium-enhanced (Gd+) lesions (mean: 5.2±6.9) and 63.1% had received prior treatment with fingolimod or natalizumab. Baseline EDSS scores and number of Gd+lesions were higher in cohort 1 than in cohort 4 (4.1±1.8 vs. 3.2±1.7; p=0.040 and 10.9±11.9 vs 4.5±5.7; p=0.020). The frequency of prior treatment with fingolimod and natalizumab was lower in cohort 4 (60.6%) than in cohort 1 (70.6%) (comparison between groups not analyzed). ConclusionsUnlike phase 3 studies of alemtuzumab, the patients included in LEMVIDA are older, have a longer duration of MS, higher disability and have received previous immunosuppressants. However, throughout the recruitment period, there is a tendency towards an early beginning of treatment with alemtuzumab, probably due to the evidence of higher effectiveness in the early stages of MS.

Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.

To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS. To be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required. Two hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1-9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening-free survival (95% confidence interval [CI]) was 85.5% (76.9%-94.1%) at 5 years and 71.3% (57.8%-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0% (59.4%-82.6%) and 57.2% (41.8%-72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year -0.09 [95% CI -0.15% to -0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14-0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007. aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity. This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach.

Serum neurofilament-light concentration and real-world outcome in MS

BackgroundPrognostication in multiple sclerosis (MS) remains challenging. Biomarkers capable of providing this information at diagnosis would be valuable in shaping therapeutic decisions. Measurement of neurofilament light (NfL) has shown promise in predicting clinical outcomes in established MS, but its ability to predict outcomes in real-world cohorts at diagnosis requires further validation. MethodsWe used linear regression to evaluate the relationship between serum NfL (sNfL), measured at the time of diagnosis with short-term (1-year) and medium-term (5-year) clinical outcomes in 164 people with MS from a real-world, population-based cohort. Cox proportional hazards regression was used to analyse the association between sNfL and subsequent hazard of relapse or sustained accumulation of disability (SAD). Analyses were adjusted for age and disease-modifying treatment (DMT). ResultssNfL concentration at diagnosis was modestly associated with baseline EDSS score (β = 0.272, 95% CI 0.051 to 0.494, p = 0.016). However, no significant associations were found between baseline sNfL and odds of relapse at 12-months, 5-year EDSS change, or the hazard of relapse or SAD over 5 years follow-up. Dichotomising baseline sNfL according to the median sNfL did not change these findings. ConclusionssNfL appears to be of limited clinical utility in predicting future irreversible neurological disability in a largely untreated real-world population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies may be needed for sNfL to be considered as a prognostic marker in the MS clinic. However the masking effect of DMTs on the natural disease trajectory will continue to pose challenges.

Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial

Objective: To determine whether differences in disability status, spasticity severity, and spasticity duration at treatment start in patients with resistant multiple sclerosis (MS) spasticity might influence response to add-on tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (nabiximols) versus further re-adjustment of optimized first-line antispasticity medication.Methods: Using the database from the Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) study, this post hoc analysis evaluated spasticity severity (0-10 numerical rating scale [NRS] scores) and pain severity (0–10 NRS scores) evolution from randomization (baseline) to week 12 (end of double-blind treatment) in defined subgroups: Expanded disability status scale [EDSS] score subgroups (<6 and ≥6); spasticity severity 0-10 NRS score subgroups (4 to ≤6 and >6), and spasticity duration subgroups (<5 and ≥5 years).Results: THC:CBD oromucosal spray (nabiximols) halved mean severity scores for spasticity and pain in all subgroups. Active treatment significantly improved mean spasticity severity scores versus placebo from week 4 onwards in both EDSS subgroups, in the severe spasticity subgroup, and in both spasticity duration subgroups. Active treatment significantly improved mean pain severity scores versus placebo in the ≥6 EDSS subgroup, in the severe spasticity subgroup and in both spasticity duration subgroups.Conclusion: Add-on THC:CBD oromucosal spray (nabiximols) consistently relieves resistant spasticity across subgroups defined by baseline EDSS score, spasticity severity NRS score and spasticity duration. Patients with moderate resistant MS spasticity benefit numerically from treatment; patients with severe resistant spasticity achieve significant therapeutic gains. Spasticity-associated pain often improves similarly in the same subgroups.

Efficacy and Safety of Ocrelizumab in Patients with Relapsing-Remitting Multiple Sclerosis with a Suboptimal Response to Previous Disease-Modifying Therapies (1-Year Interim Results)

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The aim of the prospective, multicentre, single-arm Phase IIIb CASTING study (NCT02861014) is to evaluate the efficacy and safety of ocrelizumab (OCR) in patients with RRMS who had a suboptimal response to an adequate course of 1 or 2 DMTs. Patients in CASTING (Expanded Disability Status Scale [EDSS] ≤4.0; disease duration ≤10 years; discontinued prior DMT of ≥6 months' duration due to suboptimal disease control) received intravenous OCR 600 mg/24 weeks (first dose, 2 × 300 mg, 14 days apart) for 96 weeks. The proportion of patients with NEDA was measured by an absence of protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1 gadolinium-enhancing lesions and new/enlarging T2 lesions and were calculated using the modified intent-to-treat population (mITT; patients receiving any dose who discontinued early without a protocol-defined event were imputed as having an event if the treatment discontinuation reason was lack of efficacy or death; others were excluded). MRI outcomes were rebaselined at Week 8 (prespecified analyses). A total of 680 patients (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; disease duration, 5.0 [2.7] years; pretreated with one DMT, n=411 [60.5%]; pretreated with two DMTs, n=265 [39.5%]) were enrolled in CASTING, most commonly for reasons of relapse on prior DMT, and are included in the mITT population. At Week 48, most patients had NEDA (N=586/674 [86.9%]). Rates of 24W-CDP (N=32/673 [4.8%]), PDR (N=28/674 [4.2%]), T1 gadolinium-enhancing lesions (N=19/673 [2.8%]) and new/enlarging T2 lesions (N=42/673 [6.2%]) were generally low; MRI outcomes were rebaselined at Week 8. The adjusted annualised relapse rate (negative binomial model) was 0.048. A total of 591 patients (86.9%) experienced ≥1 adverse event, and 34 patients (5.0%) experienced ≥1 serious adverse event (includes infusion-related reactions). Most patients in CASTING had no evidence of MS disease activity. As future data become available and are reported, CASTING will describe additional data on the efficacy and safety of ocrelizumab treatment in patients who had ongoing disease activity while receiving another DMT.

Impact of informative censoring on the treatment effect estimate of disability worsening in multiple sclerosis clinical trials

ObjectiveTo examine the impact of missing data when evaluating the confirmed disability worsening (CDW) endpoint in multiple sclerosis clinical trials and explore analytical methods for handling censored participants (those with missing confirmation data). MethodsCDW risk factors were assessed among participants with an initial disability worsening (≥ 1.0-point increase in Expanded Disability Status Scale [EDSS] score from a baseline score of ≥ 1.0; ≥ 1.5-point increase from a baseline of 0) using data from the DECIDE trial of daclizumab beta. A post-hoc simulation study was performed to evaluate three strategies for imputing confirmation status in censored participants: assume all were confirmed; assume none were confirmed (standard analytical approach); or use an observed rate multiple imputation (ORMI) approach based on treatment group and similar participant risk factors. Simulation study results were used to evaluate pre-specified analyses in DECIDE. ResultsIn DECIDE, larger change from baseline to initial disability worsening in EDSS score (p = 0.0003), higher baseline EDSS score (p = 0.0013), age (p = 0.004), and preceding relapse (p < 0.0001) were associated with 12-week CDW. In the simulation study, relative to the full dataset (no missing data), the strategy of assuming no censored participants were confirmed underestimated the treatment effect, and the strategy of assuming all censored participants were confirmed overestimated the treatment effect (hazard ratio 0.749 and 0.713 vs 0.733). ORMI correctly estimated treatment effect and increased study power by ~5–10% compared with the standard analytical approach. ConclusionThe ORMI approach based on CDW risk factors minimizes bias and is expected to provide the most accurate treatment effect estimate for the CDW endpoint.

Five-year outcome in the copaxone observatory: a nationwide cohort of patients with multiple sclerosis starting treatment with glatiramer acetate in France

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing–remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator’s normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39–0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9–47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials.

Efficacy and safety of onabotulinumtoxin A 100U for treatment of urinary incontinence due to neurogenic detrusor overactivity in non-catheterising multiple sclerosis patients

Objectifs We evaluated the efficacy/safety of onabotulinumtoxin A 100U versus placebo for treatment of urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO) in non-catheterising multiple sclerosis (MS) patients inadequately managed by ≥ 1 anticholinergic. Methodes A multicentre, double-blind study randomised patients 1:1 to onabotulinumtoxin A 100U ( n = 66) or placebo ( n = 78). Assessments (week 6 primary endpoint) included change from baseline in UI episodes (UIE)/day (primary endpoint), maximum cystometric capacity (MCC), maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC), incontinence-quality of life (I-QOL) total summary score, and proportions of patients achieving 100% UIE reduction. Median duration of effect (DOE), initiation of clean intermittent catheterisation (CIC), and adverse events (AEs) were also assessed. Resultats Baseline characteristics were similar between groups. The mean baseline EDSS score was 4.7. Onabotulinumtoxin A 100U significantly improved UIE (–3.3 vs–1.1; P P 2 O; P P P P Conclusion In non-catheterising MS patients with UI, onabotulinumtoxin A 100U resulted in significant and clinically-meaningful improvements in UI, MCC, MDP at first IDC, and QOL versus placebo and was well-tolerated.

Prognostic factors for long-term outcomes in relapsing-remitting multiple sclerosis.

ObjectiveThe objective of this article is to investigate potential clinical and MRI predictors of long-term outcomes in multiple sclerosis (MS).MethodsThis was a post hoc analysis using data from all 382 patients in the PRISMS long-term follow-up (LTFU) study collected up to eight years after randomisation. An additional analysis was performed including only those patients originally randomised to receive early subcutaneous interferon (IFN) β-1a (n = 259). Baseline/prestudy variables, indicators of early clinical and MRI activity (baseline to month 24), and indicators of IFN β-1a treatment exposure (including medication possession ratio (MPR)) were investigated as candidate prognostic factors for outcomes measured from baseline and from month 24 to LTFU. Explanatory variables identified from univariate regression models (p ≤ 0.15) were selected for inclusion in stepwise multiple regression models.ResultsCandidate prognostic factors selected by the univariate analysis (p ≤ 0.15) included age, MS duration, baseline brain volume, EDSS score, and log(T2 burden of disease (BOD)). In most of the multivariate regression models applied, higher baseline brain volume and MPR predicted better long-term clinical outcomes, while higher baseline and greater early increase in EDSS score predicted worse outcomes.ConclusionIdentification of markers that may be prognostic for long-term disability could help identify MS patients at higher risk of disability progression.

Benign multiple sclerosis: physical and cognitive impairment follow distinct evolutions.

Benign multiple sclerosis (BMS) definitions rely on physical disability level but do not account sufficiently for cognitive impairment which, however, is not rare. To study the evolution of physical disability and cognitive performance of a group of patients with BMS followed at an University Hospital Multiple Sclerosis Center. A consecutive sample of 24 BMS cases (diagnosis according to 2005 McDonald's criteria, relapsing-remitting course, disease duration ≥ 10 years, and expanded disability status scale [EDSS] score ≤ 2.0) and 13 sex- and age-matched non-BMS patients differing from BMS cases for having EDSS score 2.5-5.5 were included. Main outcome measures were as follows: (i) baseline and 5-year follow-up cognitive impairment defined as failure of at least two tests of the administered neuropsychological battery; (ii) EDSS score worsening defined as confirmed increase ≥ 1 point (or 0.5 point if baseline EDSS score = 5.5). At inclusion, BMS subjects were 41 ± 8 years old and had median EDSS score 1.5 (range 0-2), while non-BMS patients were 46 ± 8 years old and had median EDSS score 3.0 (2.5-5.5). At baseline 16% of patients in both groups were cognitively impaired. After 5 years, EDSS score worsened in 8% of BMS and 46% of non-BMS patients (P = 0.008), while the proportion of cognitively impaired subjects increased to 25% in both groups. Patients with BMS had better physical disability outcome at 5 years compared to non-BMS cases. However, cognitive impairment frequency and decline over time appeared similar. Neuropsychological assessment is essential in patients with BMS given the distinct pathways followed by disease progression in cognitive and physical domains.

DESIGN AND BASELINE CHARACTERISTICS OF PASSAGE AND UK UPDATE

<h3>Background</h3> Fingolimod, 0.5 mg once-daily, is the first oral therapy approved for treatment of relapsing remitting multiple sclerosis (RRMS). PASSAGE consists of two long-term, prospective, multi-national, parallel-cohort, post-authorisation safety studies (PASS) and aims to monitor the overall long term safety profile of fingolimod (minimum 5 years) in MS patients treated according to routine medical practice and explore the incidence of selected safety outcomes. <h3>Design/Methods</h3> PASSAGE includes MS patients newly starting on fingolimod or being treated with other approved DMTs. As patients are treated in accordance with the local license, PASSAGE in the UK will recruit highly active RRMS patients. The study plans to recruit 7,500 patients globally and 400 in the UK. <h3>Results</h3> In global-PASSAGE at last data cut-off, 470 patients on fingolimod and 133 patients on other DMT were enrolled. For the fingolimod-cohort, mean duration of MS was 12.3 years, average number of relapses one year prior to study entry was 1.0 and mean baseline EDSS score was 3.2. For those with confirmed fingolimod administration records (343/470 patients), SAEs were reported in 4.1% and bradycardia in 2.3% of patients. <h3>Conclusions/relevance</h3> This global, long-term, observational study will provide data to support the well-characterized safety and tolerability profile for fingolimod.

Relapsing-remitting multiple sclerosis: patterns of response to disease-modifying therapies and associated factors: a national survey.

IntroductionCurrent treatments for relapsing–remitting multiple sclerosis (RRMS) are only partially effective. The objective of this study was to characterize treatment response in RRMS patients in Portugal to 12-month therapy with first-line disease-modifying therapies.MethodsIn this retrospective study, neurologists at participating centers completed survey questionnaires using records of patients with RRMS who had received first-line treatment with one of five European Medicine Agency-approved agents in the 12 months prior to inclusion in the survey. Sub-optimal responders included patients treated for at least 1 year, and who had ≥1 relapse(s) or an increase of 1.5 points on the Expanded Disability Status Scale (EDSS; if baseline EDSS was 0) or an increase of ≥0.5 points (baseline EDSS ≥1). Optimal responders included patients treated for at least 1 year without relapse and who had an increase of <1.5 points on EDSS (if baseline EDSS was 0) or no increase in EDSS (baseline EDSS ≥1).ResultsData for 1,131 patients from 15 centers were analyzed. Twenty-six percent (95% confidence interval 23–28%) of patients had sub-optimal treatment response. Duration of therapy (P < 0.001), age at the start of therapy (P = 0.03), and baseline EDSS score (P < 0.001), were significantly different among treatments. Sub-optimal treatment response appeared to be related only to a more severe EDSS score at baseline and did not differ among therapies.ConclusionNeurologists should closely monitor patients to optimize treatment strategies and better control disease, improving prognosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-014-0019-4) contains supplementary material, which is available to authorized users.