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.

该提案的总体目标是加快针对继发于层粘连蛋白 α2 相关营养不良 (LAMA2-RD) 突变的 5 岁以下儿童的药物开发，不同严重程度的优秀小鼠模型提高了对 LAMA2-RD 发病机制的理解。，包括蛋白质替代和细胞凋亡抑制（第一阶段）、连接基因转移和补偿性基因上调（临床前概念证明），都处于不同的发展阶段，但预计尽管所有这些进展都充满希望，但目前尚无针对 LAMA2-RD < 5 岁儿童的有效临床结果评估 (COA)，因此需要验证结果测量和生物标志物。对于基因证实的 LAMA2-RD 儿童（< 5 岁）来说是紧迫的。成功转化任何疗法必须包括这些为年龄较大的“合作儿童”设计的基于力量或功能的方法对婴儿和临床试验准备不起作用的最小儿童。年幼的孩子特别重要，因为治疗干预如果成功，尽早给予可能会产生最佳反应，我们建议的具体目标是 1) 验证 LAMA2-RD 儿童的运动功能作为 COA，2) 建立最小的临床重要差异。通过将运动 COA 锚定到临床全球生物标志物量表，3) 确定哪些队列特征最能告知临床试验资格，以及 4) 验证新颖性（通过横断面测量二头肌和股直肌）为了实现这些目标，我们建议对入组时 44 名 5 岁以下的儿童进行一项 14 中心多中心前瞻性研究，对每个合作中心的至少两名临床评估人员进行详细培训。在入组前和第 3 年再次在牵头机构全国儿童医院进行了研究。我们根据其在儿科神经肌肉临床试验方面的专业知识选择了这些地点，这些试验非常罕见，而且这些儿童非常罕见。因此，我们还选择了不同的地理位置，以最大限度地减少旅行和参与试验的负担，这是在 COVID-19 大流行期间必要的一种新型 COA，它允许所有运动功能 COA，从而进一步减少儿童的旅行。与包括 Cure CMD（先天性肌营养不良症）和肌营养不良协会在内的倡导团体合作，我们将能够使用辐条和中心模型成功招募儿童。该提案将为 5 岁以下儿童开发和验证 COA。 LAMA2-RD 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 很可能对患有其他影响婴儿早期运动发育的罕见疾病的儿童取得成功。