Meaningful Outcomes and Multi-Site Readiness for Clinical Trials in Juvenile Neuronal Ceroid Lipofuscinosis

幼年神经元蜡质脂褐质沉积症临床试验的有意义的结果和多中心准备

• 批准号: 10335217
• 负责人: Erika Augustine
• 金额: $ 70.79万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335217
• 关键词: Address; Affect; Age; Assessment tool; Award; Biological Markers; Blindness; Brain; CLN3 gene; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Clinical assessments; Collaborations; Complex; Cross-Sectional Studies; Data; Decision Making; Development; Disease; Disease Progression; Ensure; Epilepsy; European; Evaluation; Event; Face; Fostering; Foundations; Future; Germany; Image; Impaired cognition; Individual; International; Life; Magnetic Resonance Imaging; Manuals; Measurable; Measurement; Measures; Modeling; Multicenter Trials; Natural History; Nerve Degeneration; Neuronal Ceroid-Lipofuscinosis; New York; Outcome; Patients; Phase; Phenotype; Preparation; Process; Qualifying; Rare Diseases; Readiness; Reproducibility; Research; Sampling; Severity of illness; Signs and Symptoms; Site; Spielmeyer-Vogt Disease; Staging System; Symptoms; Testing; Therapeutic; Therapeutic Effect; Therapeutic Trials; Thick; Time; Training Programs; United States Food and Drug Administration; Universities; Visit; biomarker validation; brain volume; clinical care; clinical outcome assessment; clinical phenotype; clinical trial implementation; clinical trial readiness; design; drug development; gray matter; inclusion criteria; indexing; interest; juvenile neuronal ceroid lipofuscinosis; longitudinal analysis; motor disorder; neuroimaging; neuroimaging marker; neuropathology; novel therapeutics; optimism; phase II trial; premature; programs; prospective; time interval; timeline; tool; tool development; white matter

The neuronal ceroid lipofuscinosis (NCL) therapeutic pipeline is rapidly expanding. The NCLs are rare, devastating, neurodegenerative lysosomal storage disorders that mainly affect children. Juvenile NCL (CLN3 disease) is the most prevalent form, with a complex set of multi-domain signs and symptoms that gradually progress over 20 years and culminate in premature death. Currently, there are no approved disease-modifying therapies. This proposal will foster collaboration between international leaders in NCL research, the University of Rochester (Rochester, New York) and the University of Hamburg (Hamburg, Germany). This multi-center, multi-national partnership mirrors the future model for clinical trial implementation and lays the foundation for development of novel therapeutics for CLN3 disease. The proposal will address critical challenges for the design and implementation of clinical trials in CLN3 disease: optimizing sensitive clinical assessments that measure how patients feel and function, validating early readouts of efficacy for go-no go decision making in phase 2 trials, and preparing for rigorous and consistent disease evaluation across multiple clinical trial sites. In parallel, our aims are: 1) to refine approaches to systematic and comprehensive assessment of CLN3 disease in order to best quantify progression in future trials, 2) to validate quantitative brain neuroimaging measurements as biomarkers of disease progression for phase 2 trials, and 3) to prepare for reproducible multi-site use of clinical outcome assessment tools. During the award period, we will engage the Food and Drug Administration in clinical outcome assessment and biomarker qualification processes to ensure optimal preparation for future regulatory review processes for emerging CLN3 disease therapeutic trials.

神经元蜡样质脂褐质沉积症（NCL）的治疗管道正在迅速扩大。NCL是一种罕见的、破坏性的神经退行性溶酶体贮积症，主要影响儿童。青少年NCL（CLN 3疾病）是最常见的形式，具有一组复杂的多领域体征和症状，在20年内逐渐进展并最终导致过早死亡。目前，没有批准的疾病改善疗法。这一提议将促进NCL研究领域的国际领导者、罗切斯特大学（罗切斯特，纽约）和汉堡大学（汉堡，德国）之间的合作。这种多中心、多国合作伙伴关系反映了临床试验实施的未来模式，并为开发CLN 3疾病的新型疗法奠定了基础。该提案将解决CLN 3疾病临床试验设计和实施的关键挑战：优化衡量患者感觉和功能的敏感临床评估，验证2期试验中进行-不进行决策的早期疗效读数，并准备在多个临床试验地点进行严格和一致的疾病评估。同时，我们的目标是：1）完善CLN 3疾病的系统和全面评估方法，以便在未来试验中最好地量化进展，2）验证定量脑神经成像测量作为2期试验疾病进展的生物标志物，以及3）为临床结局评估工具的可重复多中心使用做好准备。在授予期间，我们将与美国食品药品监督管理局（FDA）一起参与临床结果评估和生物标志物认证流程，以确保为未来新兴CLN 3疾病治疗试验的监管审查流程做好最佳准备。