Clinical Trial Readiness for Children 0-5 years with Congenital Muscular Dystrophy Secondary to LAMA2 Mutations

0-5 岁 LAMA2 突变继发先天性肌营养不良症儿童的临床试验准备情况

基本信息

批准号：
10686586
负责人：
Anne M Connolly
金额：
$ 129.55万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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：
2023-09-18 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686586
关键词：
5 year old Address Advocacy Affect Age Biological Markers Birth Blinded Breathing COVID-19 pandemic Capnography Carbon Dioxide Caregivers Certification Characteristics Chest Child Child Development Childhood Clinical Clinical Trials Clinical Trials Design Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Contracture Creatine Kinase Data Deglutition Development Diameter Disability Evaluation Disease Progression Duchenne muscular dystrophy Eligibility Determination Enrollment Equipment and supply inventories Evaluation Exclusion Criteria Exhalation Future Gene Transfer Genes Geography Goals Infant Inherited Inhibition of Apoptosis Joints Language Language Development Life Location Measures Medical Methods Modeling Motor Multicenter Studies Muscle Muscle Weakness Muscle hypotonia Muscular Atrophy Muscular Dystrophies Mutation Neuromuscular Diseases Neuromuscular conditions Outcome Outcome Assessment Outcome Measure Parents Participant Pathogenesis Pediatric Hospitals Persons Phase Philadelphia Proteins Quality of life Rare Diseases Research Personnel Respiratory Insufficiency Respiratory physiology Risk Secondary to Seizures Serum Severities Site Social Development Testing Therapeutic Therapeutic Intervention Therapeutic Trials Time Toddler Training Translating Travel United States National Institutes of Health Universities Up-Regulation Validation Visit Walking Washington World Health Organization age group biceps brachii muscle biomarker validation clinical outcome assessment clinical research site clinical trial readiness cognitive development cohort congenital muscular dystrophy data de-identification design drug development efficacy evaluation feeding impression improved inclusion criteria infancy intervention effect laminin alpha 2 mouse model neuromuscular novel novel marker pre-clinical preclinical development progression marker prospective rate of change recruit rectus femoris remote assessment response scoliosis treatment strategy trial design trial readiness ultrasound

项目摘要

This proposal’s overall goal is to hasten drug development for children < 5 years with congenital muscular dystrophy secondary to laminin α2-related dystrophies (LAMA2-RD) mutations. Excellent mouse models of differing severity improved the understanding of pathogenesis in LAMA2-RD. Therapeutic strategies, including protein replacement and apoptosis inhibition (Phase 1), linker gene transfer, and compensatory gene upregulation (pre- clinical proof of concept), are all at various developmental stages but are expected to come to clinical trials in 2-3 years. While all these advances are promising, currently, no validated clinical outcome assessments (COA) are available for children with LAMA2-RD < 5 years. Thus, the need to validate outcome measures and biomarkers is urgent for children (< 5 years) with genetically confirmed LAMA2-RD. Successfully translating any therapy must include these youngest children for whom strength or function-based approaches designed for older “cooperative children” do not work. Clinical trial readiness for infants and young children is particularly critical since therapeutic interventions, if successful, are likely to have the best response when given early. The specific aims of our proposal are to 1) Validate motor function as COA for children with LAMA2-RD, 2) Establish minimal clinically important differences for motor COAs by anchoring them to the clinical global impressions scale, 3) Determine what cohort characteristics will best inform clinical trial eligibility, and 4) Validate novel biomarkers (cross-sectionally measure biceps and rectos femoris by ultrasound) and creatine kinase levels over time. To achieve these aims, we propose a 14-site multicenter prospective 2-year study of 44 children < 5 years at enrollment. Detailed training of at least two clinical evaluators from each collaborating site will take place at the lead institution, Nationwide Children’s Hospital, before enrollment and again in Year 3. We selected the sites based on their expertise in pediatric neuromuscular clinical trials. LAMA2-RD is ultra-rare, and these children are often medically fragile. Therefore, we also selected geographically diverse locations to minimize travel and burden of trial participation. A novel COA developed by necessity during the COVID-19 Pandemic is video assessments of all motor function COAs, further allowing less travel for children. Our partnerships with advocacy groups, including Cure CMD (Congenital Muscular Dystrophy) and the Muscular Dystrophy Association, will allow us to successfully recruit children using a spoke and hub model. The proposal will develop and validate COAs for children < 5 years with LAMA2-RD and will inform future clinical trial design and interpretation. Furthermore, once validated, these COAs are very likely to be successful for children with other rare disorders affecting motor development in early infancy.

该提议的总体目标是为粘贴蛋白α2相关营养不良（LAMA2-RD）突变的先天性肌肉营养不良的儿童开发<5岁。优秀的分化严重程度的小鼠模型改善了对LAMA2-RD发病机理的理解。治疗策略，包括蛋白质替代和凋亡抑制作用（第1阶段），接头基因转移和补偿基因上调（临床前的概念证明），都处于各个发育阶段，但预计将在2-3年内进行临床试验。尽管所有这些进步都得到了承诺，但目前尚无验证的临床结果评估（COA），可用于LAMA2-RD <5年的儿童。这是迫切需要验证结果指标和生物标志物的儿童（<5岁），具有遗传确认的LAMA2-RD。成功翻译任何疗法都必须包括这些最小的孩子，为年龄较大的“合作儿童”设计的力量或功能基于功能的方法不起作用。婴儿和幼儿的临床试验准备就绪尤其至关重要，因为如果成功的治疗干预措施在早期给予的治疗干预措施（如果成功）中可能会具有最佳的反应。 The specific aims of our proposal are to 1) Validate motor function as COA for children with LAMA2-RD, 2) Establish minimal clinically important differences for motor COAs by anchoring them to the clinical global impressions scale, 3) Determine what cohort characteristics will best inform clinical trial eligibility, and 4) Validate novel biomarkers (cross-sectionally measure biceps and rectos femoris by ultrasound) and createine kinase levels over time.为了实现这些目标，我们提出了14个地点多中心的前瞻性2年研究，对44名儿童入学时<5岁。对每个协作站点的至少两个临床评估者进行了详细培训，将在全国儿童医院，在入学之前，再次在第三年进行。我们根据其儿科神经肌肉临床试验的专业知识选择了这些站点。 Lama2-RD是超稀有的，这些孩子通常在医学上脆弱。因此，我们还选择了地理上不同的位置，以最大程度地减少试验参与的旅行和燃烧。 COVID-19大流行期间必要性开发的一种新颖的COA是对所有运动功能COA的视频评估，进一步使儿童的出行率更少。我们与倡导团体的合作伙伴关系，包括Cure CMD（先天性肌肉营养不良）和肌肉营养不良协会，将使我们能够使用辐条和枢纽模型成功地招募儿童。该提案将开发和验证LAMA2-RD 5岁儿童的COA，并将为未来的临床试验设计和解释提供信息。此外，一旦经过验证，这些COA很可能对于其他罕见疾病的儿童很可能会成功，从而影响婴儿早期运动的运动。