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

基本信息

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
项目类别：
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

项目摘要

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局仍然不足。慢性肺同种异体功能障碍（clad）是最重要的免疫介导的肺移植并发症，代表肺接受者晚期死亡。在肺功能措施持续下降时，被诊断出来了诊断后的临床过程高度可变。尽管施加负担，但仍未得到批准疗法。在某种程度上，这涉及由于精确，可推广的稀少而设计的甲板试验的困难有关标准条件（SOC）条件下的外壳进展的信息以及缺乏既定的替代物用于外壳治疗研究的终点。推进外壳试验的另一个障碍是大量在安慰剂控制的研究中，需要参与者的参与者和道德问题具有重大死亡风险的疾病。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可用的肺接受者队列，并进行分析，以告知未来校友试验的合理设计。具体来说，要响应此特殊兴趣通知（NOSI）提案将通过先前的NIAID资助来整合成人肺接受者的纵向临床数据器官移植（CTOT）研究的临床试验，CTOT-20，并通过NHLBI资助的肺移植结果组（LTOG）研究。使用这些丰富的数据，AIM 1将精确定义肺的自然历史外壳后的功能进展，并采用纵向肺功能指标的潜在类别分析发现外层进展的亚表征，并结合了可能影响疾病的其他临床变量行为进入分析框架。包层试验的合理替代肺功能终点将是通过使用地标Cox评估每个已识别的类别和移植物损失/死亡之间的关联来识别比例危害模型。 AIM 2将评估这些实际肺移植数据集的实际使用作为外部SOC控制的来源，以补充未来的甲板试验。关键资格标准和终点通过正在进行的外壳试验中吸收的将应用于评估来自CTOT-20或LTOG的多少患者对于每个试验，可能被包括为现实世界外部控制。然后将进行模拟当假设外壳试验中使用外部控制时，评估工作特性。这项研究之所以创新，是因为它代表了与现有的甲板调查状态的实质性不同，即在应用现代统计方法（例如潜在类方法）中数据集和创新概念的检查，例如使用历史数据中的外部控制， FDA和行业兴趣不断增加的模型。这项研究很重要，因为它将确定在多中心现实世界中，外壳的自然历史并解决了外壳进展中的异质性；以在中心实践中可以推广的方式来告知未来介入的外壳试验。因此，与该NOSI的目标保持一致，预计这些数据将改善未来的CLAD试验的成功。