Lung Transplant Clinical Trial Network (LT-CTN)

肺移植临床试验网络（LT-CTN）

基本信息

批准号：
10282197
负责人：
JOHN A BELPERIO
金额：
$ 298.12万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-13 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10282197
关键词：
Acute Acute Lung Injury Address Adult Affect Aftercare Allografting Antiviral Agents Bilateral Biology Biopsy Bone Marrow Transplantation Bronchiolitis Child Childhood Chronic Clinic Clinical Research Clinical Trials Clinical Trials Network Communicable Diseases Cytokine Receptors Cytokine Signaling Cytomegalovirus Cytomegalovirus Infections Data Data Collection Development Diagnosis Enrollment Family Feasibility Studies Functional disorder Graft Rejection Human Immune Immune response Immunity Immunology Immunosuppression Individual Inflammation Inflammatory Inflammatory Response Pathway JAK1 gene JAK2 gene JAK3 gene Janus kinase Leadership Liquid substance Lung Lung Inflammation Lung Transplantation Lung diseases Lymphocyte Measures Mediating Mission Morbidity - disease rate Multicenter Studies Mus Natural Immunity North America Organ Transplantation Outcome Outcome Measure Participant Pathology Patient Outcomes Assessments Patients Pediatric Hospitals Pennsylvania Placebos Pneumonia Prevention Prophylactic treatment Quality of life Randomized Randomized Clinical Trials Research Research Design Research Personnel Risk Risk Factors Safety Science Signal Transduction Site Solid Source Structure Structure of parenchyma of lung T-Lymphocyte TYK2 Testing Tissues Transplant Recipients Transplantation Universities Up-Regulation Washington Work adaptive immune response clinical efficacy clinical practice cytokine design double-blind placebo controlled trial effective therapy experience follow-up graft vs host disease high risk immune activation improved inhibitor/antagonist lung allograft member mortality novel novel strategies novel therapeutics overexpression post-transplant prevent primary outcome programs prospective risk sharing transplant model treatment effect

项目摘要

ABSTRACT This Lung Transplant Clinical Trials Network (LT-CTN) CTOT-CA consortium includes eight of the leading high- volume, research-oriented adult and pediatric lung transplant programs in North America. Long-term survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), the final manifestation of chronic lung transplant rejection. CLAD is not effectively prevented by lung transplant immunosuppression, as over 50% of transplant patients develop CLAD within five years. Growing evidence suggests upregulation of inflammatory cytokines in the lung allograft contributes to CLAD development through innate immunity and allorecognition- driven adaptive immune responses. Our preliminary data demonstrate that post-transplant acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP), or acute lung injury (ALI) increase CLAD risk and are associated with elevations of Types I & II cytokines in the lung fluid. Because Type I/II cytokines share signaling through the Janus Kinase (JAK) family, blocking the relevant JAKs could be an effective strategy to limit inflammatory cytokine responses and prevent CLAD. Our data demonstrate that itacitinib, a selective JAK1 and partial JAK2 inhibitor being tested in patients with bone marrow transplant, is effective in preventing AR in a fully mismatched murine orthotopic lung transplant model, and that JAK1 is highly overexpressed in human lung transplant CLAD. Thus, we hypothesize that addition of itacitinib to standard post-transplant immunosuppression will reduce inflammation due to cytokine signaling, diminish further innate and adaptive immune responses, and prevent CLAD. To test this, we propose to complete the INhIBIT-CLAD (ItacitiNIB randomized, multi-center, double-blind, placebo-controlled trial to reduce lung Inflammation and prevenT CLAD) study, enrolling 450 bilateral lung transplant recipients over two years and randomizing 280 of those at higher CLAD risk (evidence of AR, LB, OP, or ALI) to treatment with itacitinib or placebo and follow-up over three to five years, to detect the primary outcome of CLAD. We also will collect biospecimens from all enrolled participants and conduct mechanistic studies using lung fluid and tissue from randomized patients to determine how innate immunity and adaptive immune responses that contribute to CLAD development are mitigated by selective JAK inhibition with itacitinib. Finally, as Cytomegalovirus (CMV) is another key CLAD risk factor – and preventable – we propose a multi-center infectious disease study targeting prevention of CMV infection after lung transplant using novel measures of CMV-specific immunity to personalize antiviral prophylaxis duration. Our highly qualified team of investigators bring longstanding, collaborative, highly relevant experience, including leading the adult CTOT-20 and-22 and the pediatric CTOTC-03, -05, -08, and -11 studies. Successfully completed, the studies now proposed have potential to transform clinical practice, improve lung transplant outcomes, and expand treatment paradigms for immune suppression and anti-viral prophylaxis after solid organ transplantation.

抽象的该肺移植临床试验网络（LT-CTN）CTOT-CA联盟包括八个领先的高级北美的数量，面向研究的成人和小儿肺移植计划。长期生存肺移植后，慢性同种异体移植功能障碍（clad）限制了慢性的最终表现肺移植排斥。肺移植免疫抑制不会有效防止外壳，因为超过50％移植患者在五年内发展出甲壳动物。越来越多的证据表明炎症上调肺同种异体移植中的细胞因子通过先天的免疫和同种异体认识来促进甲壳的发育。驱动的适应性免疫再次。我们的初步数据表明，移植后急性排斥（AR），淋巴细胞性支气管炎（LB），组织肺炎（OP）或急性肺损伤（ALI）会增加甲壳的风险，并且是与肺液中I型和II型细胞因子的升高有关。因为类型I/II细胞因子共享信号通过Janus激酶（JAK）家族，阻止相关的Jaks可能是限制的有效策略炎症性细胞因子反应并防止外壳。我们的数据表明itacitib，选择性JAK1和在骨髓移植患者中测试的部分JAK2抑制剂可有效防止AR完全不匹配的鼠矫形肺移植模型，JAK1在人肺中高表达移植物。这是我们假设将itacitib添加到标准移植后免疫抑制作将减少由于细胞因子信号传导而减少炎症，减少先天性和适应性免疫反应，以及防止外壳。为了测试这一点，我们建议完成抑制性粘膜（itacitib toctionib随机，多中心，双盲，安慰剂对照试验，以减少肺部炎症和防止甲壳的研究，招募450 双侧肺移植受者在两年内，随机280个处于较高clad风险的人（证据） AR，LB，OP或ALI）用Itacitinib或安慰剂治疗，并在三到五年内进行随访，以检测外壳的主要结果。我们还将从所有注册参与者那里收集生物测量并进行行为使用随机患者的肺液和组织的机械研究来确定先天免疫组织化学和通过选择性的JAK抑制，可以减轻有助于外壳发育的自适应免疫反应 itacitinib。最后，由于巨细胞病毒（CMV）是另一个关键的外壳风险因素，并且可预防 - 我们提出了一个多中心传染病研究针对预防肺移植后使用新型CMV感染的靶向CMV感染 CMV特异性免疫的度量，以个性化抗病毒预防持续时间。我们高素质的团队调查人员带来了长期，协作，高度相关的经验，包括领导成人CTOT-20 AND -22和小儿CTOTC -03，-05，-08和-11研究。成功完成，现在研究拟议的有可能改变临床实践，改善肺移植结果并扩大治疗固体器官移植后免疫抑制和抗病毒预防的范例。