Trial Readiness and Endpoint Assessment in LGMDR1 (TREATing-LGMDR1)

LGMDR1 中的试验准备和终点评估 (TREATing-LGMDR1)

基本信息

批准号：
10575492
负责人：
Nicholas Elwood Johnson
金额：
$ 113.9万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10575492
关键词：
Address Advocacy Affect Area Biological Markers Characteristics Clinical Clinical Research Clinical Trials Collaborations Communities Dependovirus Development Disease Disease Progression Disease model Duchenne muscular dystrophy Ensure Europe European Exclusion Criteria FDA approved Fatty acid glycerol esters Follow-Up Studies Future Gene Delivery Gene Targeting Genes Goals Hip region structure Individual Industry Collaboration Limb Development Limb structure Limb-Girdle Muscular Dystrophies Longitudinal Studies Longitudinal, observational study Lower Extremity Lung Magnetic Resonance Imaging Measures Medical Methods Monitor Motor Muscle Muscle function Muscular Dystrophies Natural History Nature Occupations Outcome Outcome Measure Participant Patient Outcomes Assessments Patients Performance Pharmaceutical Preparations Phase Phenotype Population Readiness Regenerative Medicine Reporting Research Research Personnel Running Sample Size Shoulder Signal Transduction Site Spinal Muscular Atrophy Standardization Structural Genes Subgroup Technology Testing Therapeutic Therapeutic Trials Time Training Upper Extremity Validation Visit Walking autosome burden of illness clinical development clinical outcome assessment disability functional outcomes functional status gene replacement therapy gene therapy loss of function meter muscle form muscle strength preclinical development primary endpoint primary outcome prospective regression trees standard measure targeted treatment therapeutic development tool trial readiness

项目摘要

The overall goal of this project is to develop reliable and valid clinical outcome assessments (COAs) and biomarkers for limb girdle muscular dystrophy R1 (LGMDR1) to hasten therapeutic development. LGMDR1 is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need. LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that the NorthStar ambulatory assessment for LGMD (NSAD), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle fat fraction, is required for early phase therapeutic trials to provide an early signal of effect. We propose the following Specific Aims: 1) To validate the NSAD as a primary endpoint for LGMDR1; and 2) To validate quantitative muscle MRI as a monitoring biomarker in LGMDR1. To achieve our aims, we plan to leverage an existing LGMD Clinical Research Network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our LGMD Research Network. We hypothesize that the NSAD will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle fat fraction is likely to demonstrate progression in advance of change on the NSAD. Combined, we will model disease progression to define the range of scores on the NSAD that would define the optimal therapeutic trial population. At the completion of this study, we will have validated the NSAD as a primary endpoint for LGMDR1; validated muscle fat fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate COAs and biomarkers for this population is an urgent need.

该项目的总体目标是开发可靠有效的肢带型肌营养不良症 R1 (LGMDR1) 临床结果评估 (COA) 和生物标志物，以加快治疗开发。 LGMDR1 是 LGMD 的一种常染色体隐性遗传形式，由于肌肉结构基因 CAPN3 功能丧失而导致。这种功能丧失导致肩部和髋部肌肉逐渐无力，从而导致逐渐残疾，包括丧失行走能力或维持工作的能力。 FDA 尚未批准针对 LGMDR1 的治疗方法，这代表着巨大的未满足的医疗需求。 LGMDR1 适合基因替代疗法；近年来，一种针对脊髓性肌萎缩症的全身基因疗法已被批准，并且正在针对 LGMDR4 进行开发。至少有五家公司正在开发 LGMDR1 的基因靶向疗法或再生医学方法，造成治疗开发超出了我们准备临床试验的能力。这项研究的基本原理是 LGMD (NSAD) 的 NorthStar 动态评估是根据广泛接受的相关疾病功能评估进行修改的，需要将其作为 LGMDR1 的主要终点进行验证。鉴于病情缓慢进展的性质，我们还预计早期治疗试验需要生物标志物，例如肌肉脂肪分数，以提供早期效果信号。我们提出以下具体目标： 1) 验证 NSAD 作为 LGMDR1 的主要终点； 2) 验证定量肌肉 MRI 作为 LGMDR1 的监测生物标志物。为了实现我们的目标，我们计划利用现有的 LGMD 临床研究网络，对 LGMD 研究网络 12 个地点的 100 名临床受影响、流动和基因定义的 LGMDR1 个体进行为期 24 个月的纵向观察研究。我们假设 NSAD 将适合多地点培训，可靠，与患者确定的疾病影响领域相关，并且对于即将进行的临床试验的功效和样本量规划有用。肌肉脂肪分数可能会在 NSAD 变化之前表现出进展。结合起来，我们将对疾病进展进行建模，以确定 NSAD 的评分范围，从而确定最佳治疗试验人群。本研究完成后，我们将验证 NSAD 作为 LGMDR1 的主要终点；验证肌肉脂肪分数是 LGMDR1 的理想生物标志物；建立了临床试验特征，包括纳入/排除标准、样本量和治疗试验的临床重要差异。鉴于 LGMDR1 治疗开发取得了重大进展，迫切需要为该人群开发合适的 COA 和生物标志物。