Pilot CMV Prevention Trial in Pediatric Lung Transplant

描述（由申请人提供）： 本提案的总体目标是确定小儿肺移植受者巨细胞病毒（CMV）感染的流行病学和最佳预防方案。在儿科肺移植中，CMV感染发生在23%的受者中，并且在单中心研究中与死亡或再次移植的四倍增加相关。预防CMV感染的最佳方法尚不确定。 此外，尚未在该人群中记录CMV预防方案的具体副作用特征。这些研究获得的数据将为前瞻性临床试验的发展提供背景信息，以回答如何最好地预防儿科肺移植受者感染相关的发病率和死亡率的问题。 将完成以下目标：（1）扩展申请人发起的单中心先导试验，以评估更昔洛韦长期静脉给药的可行性、毒性和短期疗效;（2）评估成人肺移植受者中缬更昔洛韦（VGCV）的副作用;（3）至少11个临床中心受试者的多中心研究。该试验性研究旨在确定更昔洛韦预防治疗从6周延长至12周在儿童肺移植受者中的可行性、安全性和短期疗效。成人初步研究旨在评估成人肺移植受者口服VGCV的副作用特征。 该多中心研究旨在评估CMV感染对移植后第一年死亡/再次移植和其他移植相关发病率的影响，以及评估CMV超免疫球蛋白（CMVIG）对CMV感染率的影响。在实现这些目标的同时，申请人将有机会完成一个结构化的5年职业发展计划，发展成为一名独立的临床研究者。职业发展计划的目标包括：1）研究方法、流行病学、生物统计学、病毒学和免疫学方面的高级培训，（2）患者使用-一种以研究为导向的方法，以确认小儿肺移植后第一年内可改变的感染对小儿肺移植受者的影响，并确定小儿肺移植后第一年内各种CMV预防方案的影响。3）使用以患者为导向的研究的结果来开发前瞻性干预试验，以降低儿科肺移植受者中与CMV相关的发病率和死亡率，以及4）发展成为儿科感染性疾病的医生科学家，在主要学术中心进行独立的以患者为导向的研究。 需要在儿科肺移植受者中进行具体研究，评估长期预防方案的可行性、CMV感染的影响以及各种预防方案的作用，以降低儿科肺移植后的发病率和死亡率。 估计VGCV在成人肺受体中的副作用将加速儿童向口服药物的过渡。 完成后，申请人将有足够的初步数据，以提出在儿科肺移植受者中进行CMV感染的多中心预防试验。

DESCRIPTION (provided by applicant): The overall objectives of this proposal are to determine the epidemiology and best prevention regimens for cytomegalovirus (CMV) infection for pediatric lung transplant recipients. In pediatric lung transplantation, CMV infection occurs in 23% of recipients and was associated with a four-fold increase in death or retransplantation in a single-center study. The optimal methods for prevention of CMV infection are uncertain. Further, the specific side effect profile of CMV prevention regimens has not been documented in this population. The data gained in pursuit of these studies will provide background information for the development of prospective clinical trials to answer the questions of how to best prevent infection related morbidity and mortality in pediatric lung transplant recipients. The following aims will be accomplished (1) extension of the single-center pilot trial initiated by the applicant to evaluate the feasibility, toxicity and short-term efficacy of prolonged intravenous ganciclovir; (2) assessment of valganciclovir (VGCV) side effects in adult lung transplant recipients; and (3) a multi-center study with subjects from at least 11 clinical sites. The pilot study aims to determine the feasibility, safety and short-term efficacy of prolonging ganciclovir prophylaxis from 6 weeks to 12 weeks in pediatric lung transplant recipients. The adult pilot study aims to assess the side effect profile of oral VGCV in adult lung transplant recipients. The multi-center study aims to evaluate the impact of CMV infection on death/retransplantation and other transplant-related morbidity in the first year after transplantation as well as to evaluate the impact of CMV hyperimmune globulin (CMVIG) on the rate of CMV infection. While accomplishing these aims, the applicant will have the opportunity to complete a structured 5-year career development program to develop into an independent clinical investigator. The objectives of the career development plan include, 1) advanced training in research methods, epidemiology, biostatistics, virology and immunology, 2) use of patient-oriented research approach to confirm the impact of a modifiable infection in pediatric lung transplant recipients in the first year after pediatric lung transplantation and to determine the impact of various preventative regimens for CMV during the first year after pediatric lung transplantation, 3) using the results of the patient-oriented research to develop prospective intervention trials to decrease the morbidity and mortality associated with CMV in pediatric lung transplant recipients, and 4) development into a physician scientist in Pediatric Infectious Diseases performing independent patient-oriented research in a major academic center. Specific studies in pediatric lung transplant recipients evaluating the feasibility of prolonged prevention regimens, the impact of CMV infection and role of various prevention regimens are needed to reduce morbidity and mortality after pediatric lung transplantation. Estimating the side effects of VGCV in adult lung recipients will expedite the transition to oral agents in children. After completion, the applicant will have sufficient preliminary data to propose a multi-center prevention trial for CMV infection in pediatric lung transplant recipients.