Design of a non-interventional post-marketing study to assess the long-term safety and effectiveness of ocrelizumab in German real world multiple sclerosis cohorts - the CONFIDENCE study protocol.
- 作者列表："Dirks P","Zingler V","Leemhuis J","Berthold H","Hieke-Schulz S","Wormser D","Ziemssen T
BACKGROUND:Multiple sclerosis (MS) is a chronic disease that requires lifelong treatment. A highly effective drug not only for relapsing but also for progressive forms of MS with a favorable safety profile is needed to further improve overall patient outcomes. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B-cells, is the first drug indicated for the treatment of adult patients with relapsing forms of MS (RMS) and primary progressive MS (PPMS). Its safety and effectiveness profile has yet to be studied in a large, real-world setting. CONFIDENCE aims to further characterize the safety profile of ocrelizumab in routine clinical practice. In addition, real-world effectiveness data will be collected to complement the efficacy data documented in the pivotal clinical trials. METHODS:CONFIDENCE is a non-interventional, prospective, multicenter, long-term study collecting primary data from 3000 RMS and PPMS patients newly treated with ocrelizumab and 1500 patients newly treated with other selected MS disease-modifying therapies (DMTs). Treatment must be in accordance with the local label and follow routine practice. Data will be collected at approximately 250 neurological centers and practices across Germany. The recruitment period of 30 months started in April 2018. The observation period per patient is planned 7.5 to 10 years, depending on the date of inclusion, regardless of whether patients discontinue treatment. Visits follow routine practice and will be documented approximately every 6 months. The primary endpoint is the incidence and type of uncommon adverse events and death. Statistical analyses will be mainly descriptive and exploratory. DISCUSSION:CONFIDENCE is a large, non-interventional, post-authorization safety study that assesses long-term safety and effectiveness of ocrelizumab and other DMTs in a real-world setting. Data collected in CONFIDENCE will also be integrated into studies that have been developed to fulfil international regulatory requirements.
背景: 多发性硬化 (MS) 是一种需要终身治疗的慢性疾病。需要一种非常有效的药物，不仅用于复发，而且用于具有有利的安全性特征的进展形式的MS，以进一步改善总体患者结果。Ocrelizumab是一种选择性靶向CD20-expressing b细胞的重组人源化单克隆抗体，是第一种用于治疗患有复发性MS (RMS) 和原发性进行性MS (PPMS) 的成人患者的药物。其安全性和有效性概况尚未在大型现实环境中进行研究。CONFIDENCE旨在进一步表征ocrelizumab在常规临床实践中的安全性。此外，将收集真实世界的有效性数据，以补充关键临床试验中记录的有效性数据。 方法: CONFIDENCE是一项非干预性、前瞻性、多中心、长期研究，收集了3000例新接受ocrelizumab治疗的RMS和PPMS患者以及1500例新接受其他选定MS疾病修饰疗法 (DMTs) 治疗的患者的主要数据。治疗必须符合当地标签并遵循常规做法。数据将在德国大约250个神经中心和实践中收集。30个月的招募期从2018年4月开始。每个患者的观察期计划为7.5至10年，取决于纳入日期，无论患者是否停止治疗。访问遵循常规做法，大约每6个月记录一次。主要终点是不常见不良事件和死亡的发生率和类型。统计分析将主要是描述性和探索性的。 讨论: 置信度是一项大型、非干预性、授权后安全性研究，评估ocrelizumab和其他DMTs在真实世界环境中的长期安全性和有效性。秘密收集的数据也将被纳入为满足国际监管要求而开发的研究。
METHODS:PURPOSE:The aim of the study was to assess dual-task cost to spatio-temporal gait parameters in people with multiple sclerosis and a matched control group. METHOD:The multiple sclerosis group was composed of 17 participants with a diagnosis of multiple sclerosis and an Expanded Disability Status Scale score of less than 6. A total of 17 healthy participants were allocated to the control group by stratification. Controls were matched on the basis of age, sex, sociocultural habits, and body structure. Dual-task cost was determined by within-group repeated-measures analysis of variance. Participants were instructed to ambulate under normal conditions and perform a discrimination and decision-making task concurrently. Then, between-group analysis of variance was used to assess differences in mean dual-task cost between groups and determine dual-task cost differential. Testing was performed using three-dimensional photogrammetry and an electronic walkway. RESULTS:Based on dual-task cost differential, gait cycle time increase (-5.8%) and gait speed decrease (6.3%) because of multiple sclerosis-induced impairment. CONCLUSIONS:During single- and dual-task conditions, gait speed was lower in multiple sclerosis participants, because of a shorter step length and increased swing time. Increased gait time might be the result of compensatory mechanisms adopted to maintain stability while walking specially during the double-support phases.
METHODS:OBJECTIVE:The aims of the study were to compare mobility in multiple sclerosis, Parkinson disease, and stroke, and to quantify the relationship between mobility and participation restrictions. DESIGN:This is a multicenter cross-sectional study. Included were compliant subjects with Parkinson disease, multiple sclerosis, and stroke seen for rehabilitation, with no comorbidities interfering with mobility. Functional scales were applied to each subject to investigate gait speed (10-meter walking test), balance while maintaining body position (Berg Balance Scale), dynamic balance and mobility (Timed Up and Go and Dynamic Gait Index), and participation (Community Integration Questionnaire). RESULTS:Two hundred ninety-nine patients (111 multiple sclerosis, 94 Parkinson disease, and 94 stroke) were enrolled. Stroke had the slowest gait speed (mean gait speed = 0.9 m/sec) compared with Parkinson disease (1.1 m/sec), and multiple sclerosis (1.2 m/sec) (P < 0.001). Multiple sclerosis was more limited than Parkinson disease and stroke in dynamic balance both in the Timed Up and Go Test (multiple sclerosis = 16.7 secs, Parkinson disease = 11.4 secs, stroke = 14.0 secs; P < 0.001) and Dynamic Gait Index (multiple sclerosis = 11.6 points, Parkinson disease = 12.9 points, stroke = 13.6 points; P = 0.03); ability to maintain balance and body position (Berg Balance Scale) was more affected in stroke and Parkinson disease than multiple sclerosis (multiple sclerosis = 42.6 points, Parkinson disease = 39.4 points, stroke = 39.7 points; P = 0.03). Balance disorders were associated with participation restrictions but not gait speed. CONCLUSIONS:Neurological conditions have differing impacts on gait and balance, leading to different levels of participation restriction.
METHODS:OBJECTIVES:Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression. MATERIALS AND METHODS:Neurofilament concentrations were measured using SIMOA (Single Molecule Array, Simoa HD-1 Analyzer; Quanterix). RESULTS:Neurofilament concentrations were measured on plasma samples of 70 progressive (27 PP and 43 SP), 21 RRMS patients, and 10 HCs. Longitudinal plasma NFL (pNFL) concentrations (median interval between sampling: 25 months) were available for nine PP/SP patients. PNFL concentrations were significantly higher in PP/SP compared to RRMS patients. They correlated with EDSS and MS Severity Score values. There was no difference in pNFL levels between PP/SP patients with EDSS progression in the preceding year (14% of patients) or during a median follow-up of 27 months (41%). In the longitudinal sub-study, pNFL levels increased in all patients between sampling by a mean value of 23% while EDSS mostly remained stable (77% of cases). CONCLUSION:In PP/SP progressive MS patients, pNFL levels correlate with disability and increase over time, but are not associated with prior/subsequent disability progression, as measured by EDSS, which may not be a sufficiently sensitive tool in this context.