Secondary Analyses to Support the Rational Design of Clinical Trials in Chronic Lung Allograft Dysfunction

支持慢性同种异体肺功能障碍临床试验合理设计的二次分析

• 批准号: 10586182
• 负责人: Jamie Lynn Todd
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586182
• 关键词: Address; Adult; American; Bayesian Method; Behavior; Cessation of life; Characteristics; Chronic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collaborations; Communities; Complement; Complication; Cox Proportional Hazards Models; Data; Data Set; Diagnosis; Disease; Disease Progression; Eligibility Determination; Enrollment; Ethics; Event; Exhibits; Functional disorder; Funding; Future; Goals; Heterogeneity; Immune; Immune response; Industry; Intervention; Intervention Trial; Investigation; Literature; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Methods; Modeling; Modernization; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Natural History; Organ Transplantation; Outcome; Participant; Patient Selection; Patients; Pattern; Phenotype; Population; Progressive Disease; Publishing; Pulmonary function tests; Randomized; Rare Diseases; Research; Risk Factors; Sample Size; Source; Statistical Methods; Statistical Models; Surrogate Endpoint; Time; Transplant Recipients; Transplantation; Transplanted Lung Complication; United States National Institutes of Health; Work; arm; cohort; data integration; design; follow-up; graft dysfunction; high risk; improved; information gathering; innovation; interest; longitudinal analysis; lung allograft; mortality risk; multidisciplinary; placebo controlled study; pre-clinical; pulmonary function; pulmonary function decline; rational design; response; secondary analysis; simulation; standard of care; statistics; success; transplant centers; treatment effect; treatment trial; trial design

Long-term outcomes for lung transplant recipients remain inadequate. Chronic lung allograft dysfunction (CLAD) is the most important immune-mediated complication of lung transplantation, representing the leading cause of late death among lung recipients. CLAD is diagnosed upon a sustained decline in lung function measures, yet the clinical course after diagnosis is highly variable. Despite the burden of CLAD, there remain no approved therapies. In part, this relates to difficulties in the design of CLAD trials due to a paucity of precise, generalizable information on CLAD progression under standard-of-care (SOC) conditions and lack of established surrogate endpoints for use in CLAD treatment studies. An additional barrier to advancing CLAD trials is the large number of participants needed and ethical concerns regarding enrollment in placebo-controlled studies for a progressive disease with substantial mortality risk. To address these gaps this proposal will create the largest multicenter cohort of lung recipients with CLAD available in the published literature and perform analyses that will inform the rational design of future CLAD trials. Specifically, to be responsive to this Notice of Special Interest (NOSI) this proposal will integrate longitudinal clinical data collected on adult lung recipients through a prior NIAID-funded Clinical Trials in Organ Transplantation (CTOT) study, CTOT-20, and through the NHLBI-funded Lung Transplant Outcomes Group (LTOG) study. Using these rich data, Aim 1 will precisely define the natural history of lung function progression after CLAD and employ latent class analyses of longitudinal lung function measures to discover subphenotypes of CLAD progression, incorporating other clinical variables that may influence disease behavior into the analytical framework. Plausible surrogate lung function endpoints for CLAD trials will be identified by assessing the association between each identified class and graft loss/death using landmarked Cox proportional hazards models. Aim 2 will evaluate the practical use of these real-world lung transplant datasets as a source of external SOC controls to complement future CLAD trials. Key eligibility criteria and endpoints assimilated from ongoing CLAD trials will be applied to evaluate how many patients from CTOT-20 or LTOG could potentially be included as real-world external controls for each trial. Simulations will then be conducted to assess operating characteristics when the external controls are used in hypothetical CLAD trials. This research is innovative because it represents a substantive departure from the existing state of CLAD investigation, namely in the application of modern statistical methods, such as latent class methods, to a large multicenter CLAD dataset and in the examination of innovative concepts, such as the use of external controls from historical data, a model of increasing interest to the FDA and industry. This research is significant because it will establish the natural history of CLAD and resolve the heterogeneity in CLAD progression in a multicenter real-world cohort; informing the design of future interventional CLAD trials in a way that is generalizable across center practices. Thus, aligned with the goals of this NOSI, these data are expected to improve the success of future CLAD trials.

肺移植受者的长期结果仍然不足。慢性肺移植功能障碍（CLAD） 是肺移植最重要的免疫介导的并发症，代表了 肺移植受者的晚期死亡。CLAD是在肺功能指标持续下降后诊断的，但 诊断后的临床过程是高度可变的。尽管拉丁美洲和加勒比发展委员会的负担沉重， 治疗在某种程度上，这与CLAD试验设计中的困难有关，因为缺乏精确的、可推广的 标准治疗（SOC）条件下CLAD进展的信息和缺乏确定的替代治疗 用于CLAD治疗研究的终点。推进CLAD试验的另一个障碍是大量 需要的参与者数量和关于渐进性安慰剂对照研究入组的伦理问题 有严重死亡风险的疾病。为了解决这些差距，该提案将创建最大的多中心 已发表文献中提供了患有CLAD的肺受体队列，并进行分析，为研究提供信息 未来CLAD试验的合理设计。具体而言，为了响应本特别关注通知（NOSI）， 一项提案将整合通过先前NIAID资助的一项研究收集的成人肺受体纵向临床数据。 器官移植临床试验（CTOT）研究，CTOT-20，并通过NHLBI资助的肺移植 结果组（LTOG）研究。利用这些丰富的数据，Aim 1将精确定义肺的自然史 CLAD后的肺功能进展，并采用纵向肺功能指标的潜在类别分析， 发现CLAD进展的亚表型，结合可能影响疾病的其他临床变量 行为纳入分析框架。CLAD试验的合理替代肺功能终点将是 通过使用标志性考克斯（Cox）评估每个已识别类别与移植物丢失/死亡之间的相关性来识别 比例风险模型目标2将评估这些真实世界肺移植数据集的实际使用 作为外部SOC控制的来源，以补充未来的CLAD试验。关键合格性标准和终点 从正在进行的CLAD试验中吸收的数据将用于评估CTOT-20或LTOG 可能作为每项试验的真实外部对照。然后将进行模拟， 在假设的CLAD试验中使用外部对照时，评估操作特性。本研究 是创新的，因为它代表了对CLAD调查现状的实质性偏离，即 在应用现代统计方法，如潜在类方法，以一个大的多中心CLAD 数据集和创新概念的检查，例如使用历史数据的外部控制， FDA和行业越来越感兴趣的模型。这项研究意义重大，因为它将建立 CLAD的自然史，并解决多中心真实世界队列中CLAD进展的异质性; 以可在各中心实践中推广的方式为未来的干预性CLAD试验的设计提供信息。 因此，与本NOSI的目标一致，这些数据有望提高未来CLAD试验的成功率。