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

肺移植受者的长期结果仍然不充分。慢性移植肺功能障碍(CLAD) 是肺移植中最重要的免疫介导性并发症，是导致 肺移植受者晚期死亡。慢性阻塞性肺疾病是在肺功能指标持续下降后被诊断出来的，但 确诊后的临床病程变化很大。尽管穿着衣服的负担，仍然没有批准 治疗。在一定程度上，这与由于缺乏精确的、可推广的试验而导致的包裹性试验设计的困难有关。 关于在标准护理(SOC)条件下的衣着进展和缺乏既定代孕者的信息 用于包衣治疗研究的终点。推进包衣试验的另一个障碍是大量的 关于参加进步的安慰剂对照研究的参与者的需求和伦理关切 具有相当大的死亡风险的疾病。为了解决这些差距，该提案将创建最大的多中心 在已发表的文献中可获得的肺移植受者的队列，并进行分析，以告知 未来包衣试验的合理设计。具体地说，为了回应这份特别利益通知(Nosi) 该提案将整合通过NIAID资助的先前的成人肺移植患者收集的纵向临床数据 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，目标1将准确地定义肺的自然历史 覆盖后的功能进展和应用纵向肺功能措施的潜在分类分析 发现包裹性进展的亚型，结合其他可能影响疾病的临床变量 将行为纳入分析框架。CLAD试验的合理替代肺功能终点将是 通过使用里程碑式的COX评估每个识别的类别与移植物丢失/死亡之间的关联来确定 比例风险模型。Aim 2将评估这些真实世界的肺移植数据集的实际用途 作为外部SOC控制的来源，以补充未来的CLAD试验。关键资格标准和终端 来自正在进行的CLAD试验的同化将应用于评估来自CTOT-20或LTOG的患者的数量 可能会被纳入每项试验的真实世界外部控制。然后，将进行模拟以 评估外部对照在假设的CLAB试验中使用时的操作特性。这项研究 是创新的，因为它代表着与现有的隐蔽调查状态的实质性背离，即 在应用现代统计方法，如潜类法，对大型多中心覆盖层 在审查创新概念方面，如利用历史数据的外部控制， 这是FDA和业界越来越感兴趣的一种模式。这项研究具有重要意义，因为它将建立 衣着的自然历史，并解决多中心现实世界队列中衣着进展的异质性； 以一种可跨中心实践推广的方式通知未来干预性包裹性试验的设计。 因此，与这项NOSI的目标相一致，这些数据有望改善未来CLAD试验的成功。

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.