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：
10636959
负责人：
JOHN A BELPERIO
金额：
$ 297.4万
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/10636959
关键词：
Acute Acute Lung Injury Address Adult Affect 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 Electronics Enrollment Family Feasibility Studies Functional disorder Graft Rejection Human Immune Immune response Immunity Immunosuppression Individual Inflammation Inflammatory Inflammatory Response Pathway Innate Immune Response 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 Pathology Patient Outcomes Assessments Patients Pediatric Hospitals Pennsylvania Placebos Pneumonia Prevention Prophylactic treatment Pulmonary Inflammation Qualifying Quality of life Randomized 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 participant enrollment post-transplant prevent primary outcome programs prospective randomized, clinical trials 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.