Lung Transplant Clinical Trial Network (LT-CTN)

肺移植临床试验网络（LT-CTN）

• 批准号: 10469461
• 负责人: JOHN A BELPERIO
• 金额: $ 297.54万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10469461
• 关键词: Acute; Acute Lung Injury; Address; Adult; Affect; Aftercare; Allografting; 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; Immunosuppression; Individual; Inflammation; Inflammatory; Inflammatory Response Pathway; JAK1 gene; JAK2 gene; JAK3 gene; Janus kinase; Leadership; Liquid substance; Lung; 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; Pulmonary Inflammation; 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; Transplantation Immunology; Universities; Up-Regulation; Viral; 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; lung allograft; member; mortality; novel; novel strategies; novel therapeutics; overexpression; post-transplant; prevent; primary outcome; programs; prospective; risk sharing; transplant model; treatment effect

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 联盟包括八家领先的高 北美以研究为导向的成人和儿童肺移植项目。长期生存 肺移植后受到慢性肺同种异体移植功能障碍（CLAD）的限制，这是慢性肺移植功能障碍的最终表现 肺移植排斥反应。肺移植免疫抑制不能有效预防 CLAD，超过 50% 的移植患者在五年内出现 CLAD。越来越多的证据表明炎症的上调 同种异体肺移植物中的细胞因子通过先天免疫和同种异体识别促进 CLAD 的发展 驱动适应性免疫反应。我们的初步数据表明，移植后急性排斥反应（AR）， 淋巴细胞性细支气管炎 (LB)、机化性肺炎 (OP) 或急性肺损伤 (ALI) 会增加 CLAD 风险，并且 与肺液中 I 型和 II 型细胞因子的升高有关。因为 I/II 型细胞因子共享信号传导 通过 Janus 激酶 (JAK) 家族，阻断相关的 JAK 可能是限制的有效策略 炎症细胞因子反应并预防 CLAD。我们的数据表明，itacitinib（一种选择性 JAK1）和 部分 JAK2 抑制剂正在骨髓移植患者中进行测试，可有效预防 AR 不匹配的小鼠原位肺移植模型，并且 JAK1 在人肺中高度过表达 移植CLAD。因此，我们假设将伊他替尼添加到标准移植后免疫抑制中 将减少细胞因子信号传导引起的炎症，进一步减少先天性和适应性免疫反应，并且 预防 CLAD。为了测试这一点，我们建议完成 INhIBIT-CLAD（ItacitiNIB 随机、多中心、 减少肺部炎症和预防 CLAD 的双盲、安慰剂对照试验，招募了 450 名患者 两年内对双侧肺移植受者进行随机分组，其中 280 名 CLAD 风险较高的受者随机分组（证据 AR、LB、OP 或 ALI）接受 itacitinib 或安慰剂治疗并随访三至五年，以检测 CLAD 的主要结局。我们还将收集所有注册参与者的生物样本并进行 使用随机患者的肺液和组织进行机制研究，以确定先天免疫和 选择性 JAK 抑制可减轻有助于 CLAD 发育的适应性免疫反应 伊他替尼。最后，由于巨细胞病毒 (CMV) 是另一个关键的 CLAD 风险因素——而且是可以预防的——我们建议 使用新型药物预防肺移植后巨细胞病毒感染的多中心传染病研究 巨细胞病毒特异性免疫措施，以个性化抗病毒预防持续时间。我们的高素质团队 研究人员带来长期、协作、高度相关的经验，包括领导成人 CTOT-20 和-22 以及儿科 CTOTC-03、-05、-08 和 -11 研究。已顺利完成，现在正在学习 提议有可能改变临床实践、改善肺移植结果并扩大治疗范围 实体器官移植后免疫抑制和抗病毒预防的范例。