Five-year efficacy outcomes of ocrelizumab in relapsing multiple sclerosis: A propensity-matched comparison of the OPERA studies with other disease-modifying therapies in real-world lines of treatments.

Background: Clinical trials comparing the efficacy of ocrelizumab (OCR) with other disease-modifying therapies (DMTs) other than interferon (IFN) ß-1a in relapsing multiple sclerosis (RMS) are lacking. Objectives: To compare the treatment effect of OCR vs six DMTs' (IFN ß-1a, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, natalizumab) treatment pathways used in clinical practice by combining clinical trial and real-world data. Methods: Patient-level data from OPERA trials and open-label extension phase, and from the German NeuroTransData (NTD) MS registry, were used to build 1:1 propensity score-matched (PSM) cohorts controlling for seven baseline covariates, including brain imaging activity. Efficacy outcomes were time to first relapse and time to 24-week confirmed disability progression over 5.5 years of follow-up. Intention-to-treat analysis using all outcome data irrespective of treatment switch was applied. Results: The analyses included 611 OPERA patients and 7141 NTD patients. We built 12 paired-matched cohorts (six for each outcome, two for each DMT) to compare efficacy of OCR in OPERA with each DMT treatment pathway in NTD. Post-matching, baseline covariates and PS were well balanced (standardized mean difference <.2 for all cohorts). Over 5.5 years, patients treated with OCR showed a statistically significant reduction in the risk of relapse (hazard ratios [HRs] .30 to .54) and disability progression (HRs .51 to .67) compared with all index therapies and their treatment switching pathways in NTD. Treatment switch and/or discontinuation occurred frequently in NTD cohorts. Conclusion: OCR demonstrates superiority in controlling relapses and disability progression in RMS compared with real-world treatment pathways over a 5.5-year period. These analyses suggest that high-efficacy DMTs and high treatment persistence are critical to achieve greatest clinical benefit in RMS. Registration: OPERA I (NCT01247324), OPERA II (NCT01412333).

Overall and patient-specific comparative effectiveness of dimethyl fumarate versus teriflunomide: A novel approach to precision medicine applied to the German NeuroTrans Data Multiple Sclerosis Registry.

Background: Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses. Objective: This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS. Methods: A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression. Results: Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints (p = 0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI (p = 0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%). Conclusion: The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.

The natural history of primary progressive multiple sclerosis: insights from the German NeuroTransData registry.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is characterised by gradual worsening of disability from symptom onset. Knowledge about the natural course of PPMS remains limited. METHODS: PPMS patients from the German NeuroTransData (NTD) MS registry with data from 56 outpatient practices were employed for retrospective cross-sectional and longitudinal analyses. The cross-sectional analysis included a contemporary PPMS cohort with a documented visit within the last 2 years before index date (1 Jan 2021). The longitudinal analysis included a disease modifying therapy (DMT)-naïve population and focused on the evolution of expanded disability status scale (EDSS) from the first available assessment at or after diagnosis within the NTD registry to index date. Outcome measures were estimated median time from first EDSS assessment to first 24-week confirmed EDSS ≥ 4 and ≥ 7. Besides EDSS change, the proportion of patients on disability pension were described over time. RESULTS: The cross-sectional analysis included 481 PPMS patients (59.9% female, mean [standard deviation, SD] age 60.5 [11.5] years, mean [SD] EDSS 4.9 [2.1]). Estimated median time from first EDSS assessment after diagnosis to reach 24-week confirmed EDSS ≥ 4 for DMT-naïve patients was 6.9 years. Median time to EDSS ≥ 7 was 9.7 years for 25% of the population. Over a decade mean (SD) EDSS scores increased from 4.6 (2.1) to 5.7 (2.0); the proportion of patients on disability pension increased from 18.9% to 33.3%. CONCLUSIONS: This study provides first insights into the German NTD real-world cohort of PPMS patients. Findings confirm the steadily deteriorating course of PPMS accompanied by increasingly limited quality of life.

How do patients with secondary progressive multiple sclerosis enrolled in the EXPAND randomized controlled trial compare with those seen in German clinical practice in the NeuroTransData multiple sclerosis registry?

Background: In EXPAND (NCT01665144), a phase 3 randomized clinical trial, siponimod reduced disability progression versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Aim: To understand how a real-world population with SPMS relates to that in EXPAND, we conducted a retrospective, observational cohort study using the German NeuroTransData (NTD) multiple sclerosis (MS) registry. Methods: The NTD MS registry is run by a Germany-wide network of physicians. Two cross-sectional analyses were performed using the NTD MS registry. The first included patients with SPMS, as recorded in the registry, and compared their characteristics between 1 January 2018 and 31 December 2018 with patients in EXPAND. The second described the characteristics of patients in the registry at the time of diagnosis of SPMS between 1 January 2010 and 31 December 2018. Results: The first analysis included 773 patients: patients were older in the NTD MS registry than in EXPAND (mean age, 57.9 vs 48.0 years) and had a longer duration of SPMS (mean, 6.2 vs 3.8 years). In the NTD MS registry, median Expanded Disability Status Scale (EDSS) scores were comparable to EXPAND (6.0 versus 6.0), although fewer patients had relapses in the previous 24 months (16% vs 36% [siponimod] and 37% [placebo]). Data on gadolinium-enhancing lesions were only available for 5.8% of patients in the NTD MS registry. The second analysis included 916 patients: at the time of SPMS diagnosis, the mean age was 53.2 years and the median EDSS score was 5.0. Conclusion: The population in the NTD MS registry was older to that in EXPAND, but were similar in terms of disability. Differences likely reflect the inclusion criteria of EXPAND but also highlight that real-world populations encompass a wider range of patient characteristics.

Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-ß.

BACKGROUND: Interferon-ß, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS. RESULTS: Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs. CONCLUSIONS: In comparison to other DMTs, we did not find evidence of protective effects of interferon-ß on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-ß. This study does not support the use of interferon-ß as a treatment to reduce COVID-19 severity in MS.

Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

Implementation of a data control framework to ensure confidentiality, integrity, and availability of high-quality real-world data (RWD) in the NeuroTransData (NTD) registry.

Objective: To implement a dynamic data management and control framework that meets the multiple demands of high data quality, rigorous information technology security, and flexibility to continuously incorporate new methodology for a large disease registry. Materials and Methods: Guided by relevant sections of the COBIT framework and ISO 27001 standard, we created a data control framework supporting high-quality real-world data (RWD) studies in multiple disease areas. We first mapped and described the entire data journey and identified potential risks for data loss or inconsistencies. Based on this map, we implemented a control framework adhering to best practices and tested its effectiveness through an analysis of random data samples. An internal strategy board was set up to regularly identify and implement potential improvements. Results: We herein describe the implementation of a data management and control framework for multiple sclerosis, one disease area in the NeuroTransData (NTD) registry that exemplifies the dynamic needs for high-quality RWD analysis. Regular manual and automated analysis of random data samples at multiple checkpoints guided the development and implementation of the framework and continue to ensure timely identification of potential threats to data accuracy. Discussion and conclusions: High-quality RWD, especially those derived from long-term disease registries, are of increasing importance from regulatory and reimbursement perspectives, requiring owners to provide data of comparable quality to clinical trials. The framework presented herein responds to the call for transparency in real-world analyses and allows doctors and patients to experience an immediate benefit of the collected data for individualized optimal care.

PHREND®-A Real-World Data-Driven Tool Supporting Clinical Decisions to Optimize Treatment in Relapsing-Remitting Multiple Sclerosis.

Background: With increasing availability of disease-modifying therapies (DMTs), treatment decisions in relapsing-remitting multiple sclerosis (RRMS) have become complex. Data-driven algorithms based on real-world outcomes may help clinicians optimize control of disease activity in routine praxis. Objectives: We previously introduced the PHREND® (Predictive-Healthcare-with-Real-World-Evidence-for-Neurological-Disorders) algorithm based on data from 2018 and now follow up on its robustness and utility to predict freedom of relapse and 3-months confirmed disability progression (3mCDP) during 1.5 years of clinical practice. Methods: The impact of quarterly data updates on model robustness was investigated based on the model's C-index and credible intervals for coefficients. Model predictions were compared with results from randomized clinical trials (RCTs). Clinical relevance was evaluated by comparing outcomes of patients for whom model recommendations were followed with those choosing other treatments. Results: Model robustness improved with the addition of 1.5 years of data. Comparison with RCTs revealed differences <10% of the model-based predictions in almost all trials. Treatment with the highest-ranked (by PHREND®) or the first-or-second-highest ranked DMT led to significantly fewer relapses (p < 0.001 and p < 0.001, respectively) and 3mCDP events (p = 0.007 and p = 0.035, respectively) compared to non-recommended DMTs. Conclusion: These results further support usefulness of PHREND® in a shared treatment-decision process between physicians and patients.

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. METHODS: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. RESULTS: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and ICU admission (aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92) and ICU admission (aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. DISCUSSION: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Development of Registry Data to Create Interactive Doctor-Patient Platforms for Personalized Patient Care, Taking the Example of the DESTINY System.

"Real-world evidence (RWE)" is becoming increasingly important in order to integrate the results of randomized studies into everyday clinical practice. The data collection of RWE is usually derived from large-scale national and international registries, often driven by academic centers. We have developed a digitalized doctor-patient platform called DESTINY (DatabasE-assiSted Therapy decIsioN support sYstem) that is utilized by NeuroTransData (NTD), a network of neurologists and psychiatrists throughout Germany. This platform can be integrated into everyday practice and, as well as being used for scientific evaluations in healthcare research, can also serve as an individual, personalized treatment application. Its various modules allow for a timely identification of side-effects or interactions of treatments, can involve patients via the "My NTC Health Guide" portal, and can collect data of individual disease histories that are integrated into innovative algorithms, e.g., for the prediction of treatment response [currently available for multiple sclerosis (MS), with other indications in the pipeline]. Here, we describe the doctor-patient platform DESTINY for outpatient neurological practices and its contribution to improved treatment success as well as reduction of healthcare costs. Platforms like DESTINY may facilitate the goal of personalized healthcare.

Impact of drug diversity on treatment effectiveness in relapsing-remitting multiple sclerosis (RRMS) in Germany between 2010 and 2018: real-world data from the German NeuroTransData multiple sclerosis registry.

OBJECTIVE: To evaluate the impact of drug diversity on treatment effectiveness in relapsing-remitting multiple sclerosis (RRMS) in Germany. DESIGN: This study employs real-world data captured in-time during clinical visits in 67 German neurology outpatient offices of the NeuroTransData (NTD) multiple sclerosis (MS) registry between 1 January 2010 and 30 June 2019, including 237 976 visits of 17 553 patients with RRMS. Adherence and clinical effectiveness parameters were analysed by descriptive statistics, time-to-event analysis overall and by disease-modifying therapies (DMTs) stratified by administration modes (injectable, oral and infusion). Three time periods were compared: 2010-2012, 2013-2015 and 2016-2018. RESULTS: Between 2010 and 2018, an increasing proportion of patients with RRMS were treated with DMTs and treatment was initiated sooner after diagnosis of MS. Introduction of oral DMT temporarily induced higher readiness to switch. Comparing the three index periods, there was a continuous decrease of annualised relapse rates, less frequent Expanded Disability Status Scale (EDSS) progression and increasing periods without relapse, EDSS worsening and with stability of no-evidence-of-disease-activity 2 and 3 criteria, lower conversion rates to secondary progressive MS on oral and on injectable DMTs. CONCLUSION: Sparked by the availability of new mainly oral DMTs, RRMS treatment effectiveness improved clinically meaningful between 2010 and 2018. As similar effects were seen for injectable and oral DMTs more than for infusions, a better personalised treatment allocation in many patients is likely. These results indicate that there is an overall beneficial effect for the whole patient with MS population as a result of the greater selection of available DMTs, a benefit beyond the head-to-head comparative efficacy, resulting from an increased probability and readiness to individualise MS therapy.

Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study.

BACKGROUND: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. OBJECTIVES: The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM. METHODS: Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed. RESULTS: Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21-85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p <  0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: - 9.99 vs. - 0.34 points; p <  0.001). Results were similar for MSIS-29 psychological impact. CONCLUSION: No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01480063.

B-Cell Activity Predicts Response to Glatiramer Acetate and Interferon in Relapsing-Remitting Multiple Sclerosis.

OBJECTIVE: We investigated the predictive value of the enzyme-linked immunospot technique (ELISPOT) in identifying patients with relapsing-remitting multiple sclerosis (RRMS) who will respond to treatment with glatiramer acetate (GA) or interferon-ß (IFN-ß), based on the brain-reactive B-cell activity of peripheral blood cells. METHODS: In this retrospective, cross-sectional, real-world multicenter study, we identified patients with RRMS in the NeuroTransData MS registry and stratified them based on their documented treatment response (relapse-free in the first 12 months of treatment) to GA or IFN-ß. The GA group comprised 73 patients who responded to GA and 35 nonresponders. The IFN-ß group comprised 62 responders to IFN-ß and 37 nonresponders. Patients with previous or current therapy affecting B-cell activity were excluded. We polyclonally stimulated mononuclear cells from peripheral blood samples (collected after participant selection) and investigated brain-reactive B-cell activity after incubation on brain tissue lysate-coated ELISPOT plates. Validity metrics of the ELISPOT testing results were calculated (Python 3.6.8) in relation to the clinical responsiveness in the 2 treatment groups. RESULTS: The ELISPOT B-cell activity assay showed a sensitivity of 0.74, a specificity of 0.76, a positive predictive value of 0.78, a negative predictive value of 0.28, and a diagnostic OR of 8.99 in predicting clinical response to GA vs IFN-ß therapy in patients with RRMS. CONCLUSION: Measurement of brain-reactive B-cell activity by ELISPOT provides clinically meaningful predictive probabilities of individual patients' treatment response to GA or IFN-ß. The assay has the potential to improve the selection of optimal first-line treatment for individual patients with RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with RRMS, the brain reactivity of their peripheral-blood B cells predicts clinical response to GA and IFN-ß.

The Multiple Sclerosis Data Alliance Catalogue: Enabling Web-Based Discovery of Metadata from Real-World Multiple Sclerosis Data Sources.

BACKGROUND: One of the major objectives of the Multiple Sclerosis Data Alliance (MSDA) is to enable better discovery of multiple sclerosis (MS) real-world data (RWD). METHODS: We implemented the MSDA Catalogue, which is available worldwide. The current version of the MSDA Catalogue collects descriptive information on governance, purpose, inclusion criteria, procedures for data quality control, and how and which data are collected, including the use of e-health technologies and data on collection of COVID-19 variables. The current cataloguing procedure is performed in several manual steps, securing an effective catalogue. RESULTS: Herein we summarize the status of the MSDA Catalogue as of January 6, 2021. To date, 38 data sources across five continents are included in the MSDA Catalogue. These data sources differ in purpose, maturity, and variables collected, but this landscaping effort shows that there is substantial alignment on some domains. The MSDA Catalogue shows that personal data and basic disease data are the most collected categories of variables, whereas data on fatigue measurements and cognition scales are the least collected in MS registries/cohorts. CONCLUSIONS: The Web-based MSDA Catalogue provides strategic overview and allows authorized end users to browse metadata profiles of data cohorts and data sources. There are many existing and arising RWD sources in MS. Detailed cataloguing of MS RWD is a first and useful step toward reducing the time needed to discover MS RWD sets and promoting collaboration.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.

[Data on multiple sclerosis in Germany and their representation in the ambulatory registry NeuroTransData (NTD) network]. / Daten zur Multiplen Sklerose in Deutschland und ihre Abbildung im Register des ambulanten Netzwerkes NeuroTransData (NTD).

AIMS AND METHODOLOGY: Description of basic data, common symptoms and their medical, non-drug and combined symptomatic treatment in a large sample of MS patients undergoing outpatient treatment of the German NeuroTransData (NTD) physician network. RESULTS: Currently there are 21,407 patients in the registry. Average age is 49.0 ± 13.0 years, 72,3 % of them female, average disease duration is 14.3 ± 8,9 years. Relapsing-remitting MS (RRMS) was present in 77 %, secondary-progressive MS (SPMS) 15 %, PPMS 5 %. The mean EDSS score of the total sample was 2.8 (range 0,5-8). Fatigue was the most common symptom in all subtypes (96 %), followed by spasticity (all 31 %, SPMS: 47 %; PPMS 36 %). Regarding symptomatic drug treatment, non-drug treatment and combined treatment, there was a wide range of variation. While spasticity was treated in 81 %, only 21 % of patients with fatigue receiving any form of therapy, Also, fecal and urine incontinence often remained untreated in 69 % resp. 56 % of cases. CONCLUSIONS: Setup, development and maintenance of a registry for a complex and chronic disease like MS represents an instrument to assess and improve patient care in the outpatient setting. Our results are hard to compare with the DMSG-registry, another German, more hospital-based data collection. However, both registries identify fatigue as the most common symptom in MS.

Comparative effectiveness of delayed-release dimethyl fumarate versus interferon, glatiramer acetate, teriflunomide, or fingolimod: results from the German NeuroTransData registry.

BACKGROUND: Comparative effectiveness (CE) research allows real-world treatment comparisons using outcome measurements important to physicians/patients. This German NeuroTransData registry-based analysis compared delayed-release dimethyl fumarate (DMF) effectiveness with interferons (IFN), glatiramer acetate (GA), teriflunomide (TERI), or fingolimod (FTY) in patients with relapsing-remitting multiple sclerosis (RRMS) using propensity score matching (PSM). METHODS: Data from registry patients aged ≥ 18 years with RRMS, ≥ 1 relapse, and Expanded Disability Status Scale (EDSS) assessment(s) after index therapy initiation underwent 1:1 PSM to match DMF with comparator populations baseline characteristics. Primary outcome measurement was time to first relapse (TTFR). Secondary outcome measurements included annualised relapse rate (ARR), proportion of patients relapse free at 12 and 24 months, time to index therapy discontinuation (TTD), and reasons for discontinuation. Exploratory analyses included time to 3- and 6-month EDSS confirmed disability progression (CDP). Non-pairwise censoring was the primary analysis method; pairwise censoring was the main sensitivity analysis method. FINDINGS: Post-matched cohorts were well-balanced. By non-pairwise censoring, TTFR and ARR were significantly lower in DMF populations versus matched IFN, GA, and TERI, but there was no evidence of difference between DMF and FTY. TTD was similar between DMF and IFN, GA, and TERI, but significantly shorter versus FTY. Time to CDP generally showed no evidence of difference between DMF and comparator populations. Pairwise censored analysis results confirmed the non-pairwise censoring results. INTERPRETATION: These results support previous CE studies in demonstrating relative improvement in real-world effectiveness with DMF versus first-line agents IFN, GA, and TERI, and similar effectiveness versus FTY.

Neurologist adherence to clinical practice guidelines and costs in patients with newly diagnosed and chronic epilepsy in Germany.

PURPOSE: The aim of this study was to evaluate physician adherence to the German Neurological Society guidelines of 2008 regarding initial monotherapy and to determine the cost-of-illness in epilepsy. METHODS: This was an observational cohort study using health data routinely collected at 55 outpatient neurology practices throughout Germany (NeuroTransData network). Data on socioeconomic status, course of epilepsy, anticonvulsive treatment, and direct and indirect costs were recorded using practice software-based questionnaires. RESULTS: One thousand five hundred eighty-four patients with epilepsy (785 male (49.6%); mean age: 51.3±18.1years) were enrolled, of whom 507 were newly diagnosed. Initial monotherapy was started according to authorization status in 85.9%, with nonenzyme-inducing drugs in 94.3% of all AEDs. Drugs of first choice by guideline recommendations were used in 66.5%. Total annual direct costs in the first year amounted to €2194 (SD: €4273; range: €55-43,896) per patient, with hospitalization (59% of total direct costs) and anticonvulsants (30%) as the main cost factors. Annual total direct costs decreased by 29% to €1572 in the second year, mainly because of a 59% decrease in hospitalization costs. The use of first choice AEDs did not influence costs. Chronic epilepsy was present in 1077 patients, and total annual direct costs amounted to €1847 per patient, with anticonvulsants (51.0%) and hospitalization (41.0%) as the main cost factors. Potential cost-driving factors in these patients were active epilepsy and focal epilepsy syndrome. CONCLUSION: This study shows excellent physician adherence to guidelines regarding initial monotherapy in adults with epilepsy. Newly diagnosed patients show higher total direct and hospital costs in the first year upon diagnosis, but these are not influenced by adherence to treatment guidelines.

Tolerability of tiagabine: a prospective open-label study.

Tiagabine was used as add-on therapy in the treatment of epilepsy with partial and/or secondarily generalised seizures to evaluate tolerability and efficacy. Five hundred and seventy-four patients (299 men and 275 women, mean age 38.1 years), with refractory partial seizures, were enrolled in this prospective, open-label study. Tiagabine was added to one (44.1%) or more (up to nine) antiepileptic drugs. The median daily dose of tiagabine was 30 mg (mean 29.1, SD 12.0). The mean duration of follow-up was 94.9 42.7 days. 12.3% of patients were completely seizure-free at the end of the observation period. Median total seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. Adverse events occurred in 78 patients (13.6%). Tiagabine proved to be a well-tolerated AED.