A RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL OF CORTICOSTEROID THERAPY

皮质类固醇治疗的随机、双盲、安慰剂对照试验

• 批准号: 7950661
• 负责人: SAUL J. KARPEN
• 金额: $ 0.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950661
• 关键词: 2 year old; ATP phosphohydrolase; Accounting; Address; Adjuvant; Adrenal Cortex Hormones; Affect; Aftercare; Age-Months; Alkaline Phosphatase; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Ascites; Basophils; Bile fluid; Biliary; Biliary Atresia; Biliary cirrhosis; Bilirubin; Biochemical; Biological; Birth; Blood Circulation; Cardiovascular system; Cell Adhesion Molecules; Cells; Cellular Immunity; Child; Childhood; Cholestasis; Clinical; Clinical Research; Clinical Trials; Color; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Development; Diagnosis; Disease; Disease Progression; Dose; Drainage procedure; Edema; Effectiveness; Embryo; Endothelial Cells; Environmental Risk Factor; Epithelium; Etiology; Excretory function; Expenditure; Extrahepatic; Extrahepatic Bile Ducts; Fat-Soluble Vitamin; Feces; Fibroblasts; Fibrosis; Funding; Genetic; Gestational Age; Goals; Grant; Growth; Handedness; Health Care Costs; Health Expenditures; Height; Hepatic; Hepatobiliary; Hepatomegaly; Hyperbilirubinemia; IL2 gene; IL3 gene; IL6 gene; Icterus; Immune response; Immunologics; Incidence; Infant; Inflammation; Inflammation Mediators; Inflammatory; Injury; Institution; Interferon Type II; Interleukin-1; Intrahepatic bile duct; Lead; Left; Length; Life; Live Birth; Liver; Liver diseases; Lymphocyte; Mediating; Medical; Metabolic; Methylprednisolone; Modality; Modeling; Molecular; Morphogenesis; Obstruction; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathologic; Patients; Perinatal; Phase; Physiological; Placebos; Play; Population; Portal Hypertension; Probability; Process; Production; Property; Randomized; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Role; Sampling; Serum; Signal Transduction; Source; Staging; Sum; Supplementation; TNF gene; Testing; Therapeutic; Time; Toxic Environmental Substances; Transaminases; Transplantation; United States; United States National Institutes of Health; Urine; Virus Diseases; Visceral; Vitamins; Weight; base; bile formation; bile salts; biliary tract; cytokine; double-blind placebo controlled trial; early onset; fetal; gastrointestinal; improved; infancy; infant outcome; intrahepatic; liver transplantation; macrophage; monocyte; neonate; novel diagnostics; postnatal; prednisolone; prenatal; research study; total measurement Bilirubin; trait

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Biliary atresia is the most common cause of cholestasis in infants and the most frequent indication for pediatric liver transplantation. The disease results from a destructive inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tract. Although little is known about the etiology or pathogenesis of biliary atresia, epidemiologic and virologic studies point to a complex trait disorder, in which environmental factors trigger an inflammatory process that recognizes and abnormally targets the biliary system during a specific phase of postnatal development. Based on these data, the following unifying pathogenesis model can be preliminarily proposed: Regardless of initiating (environmental) and modifying (genetic) factors for disease development, the inflammatory and fibrosing destruction of the biliary epithelium is common to all clinical forms of biliary atresia. In this setting, the potential decrease of this inflammatory component by corticosteroid treatment may result in improved bile flow and better outcome after portoenterostomy. Therefore, in this clinical trial we propose to objectively determine whether corticosteroid treatment improves bile flow in infants with biliary atresia. The significance of the proposed trial is that it will determine whether corticosteroids are an effective medical treatment to improve bile drainage and long-term outcome, and whether its use reduces the need for liver transplantation in infants with biliary atresia. The trial will be performed by the NIH-supported Biliary Atresia Research Consortium (BARC). BARC has the infrastructure to prospectively follow a sufficiently large number of patients and to collect samples necessary for clinical research studies addressing etiology, pathogenesis, diagnosis, and treatment of children with biliary atresia. HYPOTHESES Our overall hypothesis is that therapy with corticosteroids following portoenterostomy will improve bile drainage and long-term outcome in infants with biliary atresia. This hypothesis will be tested through the following hypotheses: 1a: The probability of an infant having good bile drainage at 6 months after portoenterostomy (as defined by a serum total bilirubin level <1.5 ml/dL) will be greater in infants who are treated with corticosteroids than those treated with placebo. 1b: Improved bile drainage (as defined by a serum total bilirubin level <1.5 mg/dL); will remain for a longer period in infants treated with corticosteroids than those treated with placebo. 2: Survival without transplantation will be greater at 24 months of age in infants treated with corticosteroids than those treated with placebo. 3: Weight and height Z-scores at 12 and 24 months of age will be greater in the infants treated with corticosteroids than those treated with placebo. 4a: Treatment with corticosteroids leads to improved bile drainage (hypothesis 1) which, in turn, increases the probability that an infant will achieve vitamin sufficiency of each of the fat-soluble vitamins following supplementation of ADEK¿. 4b: Treatment with corticosteroids leads to improved bile drainage(hypothesis 1) which, in turn, reduces the dose required for supplementation and the length of time of supplementation for each of the fat-soluble vitamins. 5: The incidence of ascites will be decreased at 12 and 24 months of age in infants treated with corticosteroids than those treated with placebo. SPECIFIC AIMS: Portoenterostomy is the only operative procedure used currently to improve bile drainage in infants with biliary atresia. Although prompt diagnosis and surgical intervention may induce bile flow, progression to end-stage liver disease occurs in over 50% of the patients by 2 years of age. The biological basis for the progression of liver disease after portoenterostomy is not fully understood, but the presence of hepatobiliary inflammation and proinflammatory cytokines at the time of diagnosis suggests that inflammatory forces mediate, at least in part, the progressive injury. Consistent with this concept, prior clinical reports of corticosteroids as an adjuvant treatment following portoenterostomy for biliary atresia suggest that high doses of corticosteroids may lead to prolonged jaundice-free survival without liver transplantation. Based on these reports, we propose a multi-center randomized, double-blinded, placebo-controlled trial to prospectively determine the efficacy of corticosteroids on the outcome of infants with biliary atresia. The trial will be conducted by the NIDDK-funded network of ten clinical centers comprising the Biliary Atresia Clinical Research Consortium (BARC) whose goal is to study the etiology, pathogenesis, diagnosis, and treatment of infants with biliary atresia. The specific aims in support of this goal are below: Aim 1: To determine whether corticosteroid therapy decreases serum bilirubin concentration after portoenterostomy. Aim 2: To determine whether corticosteroid treatment after portoenterostomy will improve outcome as defined by survival without transplantation at 24 months of age. Aim 3: To determine whether corticosteroid treatment after portoenterostomy will improve growth of infants with biliary atresia. Aim 4: To determine whether corticosteroid treatment improves biochemical indicators of each of the fat-soluble vitamins after supplementation with standard doses. Aim 5: To determine whether corticosteroid treatment after portoenterostomy will decrease the incidence of persistent ascites or ascites that requires medical treatment. BACKGROUND AND SIGNIFICANCE Biliary atresia is a progressive fibro-inflammatory cholangiopathy of infancy that results in complete obliteration of the entire or portions of the extrahepatic biliary tree within 12 weeks of birth. This obstruction results in impaired bile drainage, reactive proliferation of intrahepatic bile ducts, cholestasis, and ongoing hepatocellular injury. If no therapy is implemented, ongoing injury leads to biliary cirrhosis, portal hypertension, and end-stage liver disease, leaving liver transplantation as the only therapeutic option for long-term survival. Biliary atresia is the most common cause of prolonged conjugated hyperbilirubinemia in neonates and is the most frequent indication for liver transplantation in children, accounting for 40-50% of all pediatric liver transplants. The disease respects no geographic boundaries; it occurs worldwide and affects approximately 1 in 8,000 to 1 in 15,000 live births. The health care costs associated with medical/surgical intervention and transplantation for infants with biliary atresia are significant, estimated to reach $65 million/year in the United States. From a total of $77 million spent annually on pediatric liver transplantation in the United States, about half relates to biliary atresia. Notably, this sum of money covers 0.2% of total health care expenditures for children, even though these children represent only 0.0006% of the total pediatric population. This disproportionate expenditure could be decreased by half if improved medical therapies were developed that reduce the need for liver transplantation. There are two well-recognized clinical forms of biliary atresia: embryonic and perinatal. These forms share the cardinal features of jaundice, acholic stools, and hepatomegaly but differ in the presence of associated anomalies, the timing of onset of jaundice, and perhaps clinical outcome. The embryonic form of biliary atresia (also referred to as "congenital" or "fetal") accounts for 10 to 20% of cases and is defined by the presence of congenital nonhepatic anomalies and earlier onset of disease. Among congenital nonhepatic anomalies, patients may have defects in laterality (or asymmetric left-right determination of visceral organs) poly- or asplenia, and gastrointestinal or cardiovascular anomalies. Infants present with pathologic jaundice at birth or shortly thereafter, frequently overlapping with physiologic jaundice such that there is no jaundice-free interval. There is some evidence that patients with this clinical form have worse outcome following portoenterostomy. The perinatal forms of biliary atresia (also referred to as acquired "or postnatal") accounts for the majority of the cases (80-90%) and occurs in the absence of other congenital anomalies. Most of the infants are born at term with an appropriate weight for gestational age. They have a variable jaundice-free interval after birth but develop jaundice, acholic stools, and dark-colored urine within the first few weeks of life. In contrast to the clinical setting observed in infants with the embryonic form, the presence of a jaundice-free period is more consistent with a biliary injury that results from a perinatal or early postnatal insult. Efforts to determine the biologic relationship of potential pathogenic mechanisms are particularly important to understand the molecular basis of the clinical forms and to develop new diagnostic/therapeutic modalities for infants with biliary atresia. Theoretical considerations of the pathogenesis of biliary atresia are based largely on epidemiologic and clinical features, reported predisposing genetic factors, and pace of disease progression. Based on these observations, five mechanisms have been proposed to play important roles in the pathogenesis of biliary atresia: defect in morphogenesis of the biliary tract, defect in fetal/prenatal circulation, immunologic dysregulation, viral infection, and environmental toxin exposure. Corticosteroid treatment may improve bile drainage following portoenterostomy by at least two proposed mechanisms. In the first, at pharmacologic doses, corticosteroids may stimulate bile salt-independent bile flow by inducing expression of hepatic Na-K adenosine triphosphatase, a sinusoidal transporter that helps maintain the osmotic and electrical forces necessary for bile formation. In the second, corticosteroids have well-described anti- inflammatory and immunomodulatory properties. For example, administration of corticosteroids decreases the number and immune response of lymphocytes, with suppression of interleukin (IL)1, IL2, IL3, IL6, TNF, and interferon gamma. The anti-inflammatory properties of corticosteroids also result from a much broader effect in a variety of cells, such as the decrease in production of cytokines, adhesion molecules, and metabolic signals by macrophages, monocytes, basophils, fibroblasts, and endothelial cells. These anti-inflammatory functions modulate both humoral and cellular immunity, and have assured a central role for corticosteroids in the treatment of allergic and immunologic disorders. With the increasing body of evidence that the livers of infants with biliary atresia produce inflammatory mediators, treatment of corticosteroids has the potential to decrease inflammation, edema, and progression of fibrosis. The effectiveness of corticosteroid therapy to improve bile drainage and clinical outcome in infants with biliary atresia has not been evaluated prospectively to date. However, four retrospective reports suggest that corticosteroids may improve bile drainage and outcome of patients with biliary atresia. In an initial clinical report, a short course of high doses of methylprednisolone in infants/children with reduced bile flow at variable lengths of time from the initial portoenterostomy for biliary atresia increased daily bilirubin excretion and decreased serum levels of bilirubin, alkaline phosphatase, and aminotransferases. Serum levels of bilirubin and aminotransferases also improved in another group of infants with biliary atresia receiving prednisolone 6-8 days after portoenterostomy, but the duration of corticosteroid use was not clearly stated. More recently, two reports described high doses of corticosteroids soon after portoenterostomy followed by a taper over 6-12 weeks in infants with biliary atresia. Both reports suggested improved bile drainage and increased survival with native liver in over 70% of patients.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 胆道闭锁是婴儿胆汁淤积的最常见原因，也是小儿肝移植的最常迹象。该疾病是由影响胆管内和外脑外胆管导致的破坏性炎症过程引起的，导致胆道的纤维化和闭塞。尽管对胆道闭锁的病因学或发病机制知之甚少，但流行病学和病毒学研究表明了一种复杂的性状疾病，在该特定后，环境因素会触发炎症过程，该过程识别并绝对靶向胆汁系统，这是在生后发育的特定阶段。基于这些数据，可以先提出以下统一的发病机理模型： 不管疾病发育的起始（环境）和修饰（遗传）因素如何，胆道上皮的炎症和纤维化破坏都是胆道闭锁的所有临床形式共同的。在这种情况下，通过皮质类固醇治疗的这种炎症成分的潜在减少可能会导致胆汁流量的改善和portoteenterostomy后的更好结果。因此，在这项临床试验中，我们建议客观地确定皮质类固醇治疗是否可以改善胆道闭锁婴儿的胆汁流量。该试验的意义在于，它将确定皮质类固醇是否是改善胆汁排水和长期结局的有效医疗，以及其使用是否减少了胆道闭锁婴儿肝移植的需求。 该试验将由NIH支持的胆道闭锁研究联盟（BARC）进行。 BARC具有前瞻性遵循大量患者的基础设施，并收集针对临床研究所需的样本，以解决胆道闭锁儿童的病因，发病机理，诊断和治疗。 假设 我们的总体假设是，术后治疗皮质类固醇的治疗将改善胆汁性闭锁婴儿的胆汁引流和长期结局。该假设将通过以下假设进行检验： 1A：在port骨术后6个月内具有良好胆汁排水的婴儿（由血清总胆红素总水平<1.5 ml/dl定义）​​的概率比接受安慰剂治疗的婴儿的胆红素总水平<1.5 mL/dl）更大。 1B：改善胆汁排水（由血清总胆红素水平<1.5 mg/dl定义）​​；与接受安慰剂治疗的婴儿相比，用皮质类固醇治疗的婴儿将保持更长的时间。 2：用皮质类固醇治疗的婴儿在24个月大时，没有移植的生存率将大于接受安慰剂治疗的生存。 3：用皮质类固醇治疗的婴儿在12和24个月大的体重和身高z得分要比接受安慰剂治疗的婴儿更大。 4A：用皮质类固醇的治疗导致胆汁排水的改善（假设1），这又增加了补充Adek®后，婴儿将获得每种脂溶性维生素的维生素充分性的可能性。 4B：用皮质类固醇的治疗导致胆汁排水的改善（假设1），进而减少补充剂量和补充每种脂溶性维生素所需的剂量。 5：与接受安慰剂治疗的婴儿相比，用皮质类固醇治疗的婴儿在12岁和24个月大的时候将改善腹水的事件。 具体目的：遗传造口术是目前用于改善胆道闭锁婴儿胆汁排水的唯一操作程序。尽管迅速的诊断和手术干预可能会引起胆汁流量，但到2岁时，超过50％的患者出现了末期肝病的进展。遗传性遗传造口后肝病进展的生物学基础尚不完全了解，但是在诊断时，肝胆胆感感染和促炎细胞因子的存在表明，至少部分促进炎症力介导，至少部分是进行性损伤。与这个概念一致，在门肠造口术后对皮质类固醇作为可调节治疗的先前临床报道表明，高剂量的皮质类固醇可能导致无肝移植的无Janundice无生存期。基于这些报告，我们提出了一个多中心随机，双盲，安慰剂对照试验，以预期确定皮质类固醇对胆道闭锁婴儿结果的效率。该试验将由NIDDK资助的十个临床中心的网络完成，该网络完成了胆道上闭锁临床研究联盟（BARC），其目标是研究病因，发病机理，发病机理，诊断和胆道胸围婴儿的治疗。支持该目标的具体目的如下： 目的1：确定皮质类固醇治疗是否会降低port骨术后血清胆红素的浓度。 AIM 2：确定porte骨术后的皮质类固醇治疗是否会改善未在24个月大时移植而无法移植的生存定义的结果。 AIM 3：确定端肠造口术后皮质类固醇的治疗是否会改善胆道闭锁的婴儿的生长。 目标4：确定皮质类固醇治疗是否可以改善用标准剂量补充后每种脂溶性维生素的生化指标。 目标5：确定port骨术后的皮质类固醇治疗是否会减少需要医疗治疗的持续性腹水或腹水的事件。 背景和意义 胆道闭锁是婴儿期的渐进性纤维炎性胆管疾病，可在出生后12周内完全消除整个或部分外腹膜外胆道树。该物体会导致胆汁排水损害，肝内胆管的反应性增殖，胆汁淤积和持续的肝细胞损伤。如果未实施治疗，则持续的损伤会导致胆道肝硬化，门静脉高血压和终点肝病，从而使肝移植成为长期生存的唯一治疗选择。 胆道闭锁是新生儿延长共轭高胆红素血症的最常见原因，并且是儿童肝移植最常见的迹象，占所有儿科肝移植的40-50％。该疾病没有地理边界；它发生在世界范围内，影响15,000个活产中约1分之一。与胆道闭锁婴儿有关的医疗/外科干预和移植有关的医疗保健费用很大，估计在美国每年6500万美元。每年总共花费7700万美元用于美国的儿科肝移植，大约一半与胆道闭锁有关。值得注意的是，这笔款项占儿童总医疗保健支出的0.2％，尽管这些儿童仅占小儿总人口的0.0006％。如果开发了改进的医疗疗法，可以改善这种不成比例的支出，从而减少对肝移植的需求。 胆道闭锁有两种公认的临床形式：胚胎和围产期。这些形式具有Janide，Acholicant凳子和肝肿大的基本特征，但在存在相关异常的情况下不同，Janide的发作时间以及临床结果。胆道闭锁的胚胎形式（也称为“先天性”或“胎儿”）占病例的10％至20％，并由先天性非脑异常和疾病早期发作而定义。在先天性的非脑异常中，患者可能患有横向性（或内脏器官的不对称左右确定）多膜或asplenia，以及胃肠道或心血管异常。婴儿出生时或此后不久有病理性的Janide，经常与生理学的Janide重叠，因此没有无Janide的间隔。有证据表明，这种临床形式的患者在port骨术后的结果较差。 胆道闭锁的围产期形式（也称为“或后产后”）占多数病例（80-90％），并且发生在没有其他先天性异常的情况下。大多数婴儿在学期出生，适合胎龄。他们出生后有一个可变的珍妮丝间隔，但在生命的头几周内开发了珍妮丝，粪便和深色的尿液。与在具有胚胎形式的婴儿中观察到的临床环境相反，无Janide时期的存在与由于产后或早期产后损伤造成的胆道损伤更加一致。确定潜在致病机制的生物学关系的努力对于了解临床形式的分子基础并为患有胆道闭锁的婴儿开发新的诊断/治疗方式特别重要。 胆道闭锁发病机理的理论考虑很大程度上基于流行病学和临床特征，报道了易感性遗传因素以及疾病进展的空间。基于这些观察结果，已经提出了五种机制在胆道闭锁的发病机理中起重要作用：胆道的形态发生缺陷，胎儿/产前循环缺陷，免疫失调，病毒感染和环境毒素暴露。 皮质类固醇治疗可能会通过至少两种提议的机制来改善左旋肠造口术后的胆汁排水。首先，在药物剂量下，皮质类固醇可以通过诱导肝素Na-k腺苷三磷酸酶的表达来刺激胆汁盐独立的胆汁流，这是一种正弦转运蛋白，有助于维持胆汁形成所需的渗透和电力。在第二个中，皮质类固醇具有良好描述的抗炎和免疫调节特性。例如，皮质类固醇的给药减少了淋巴细胞的数量和免疫反应，并抑制了白介素（IL）1，IL2，IL3，IL3，IL6，TNF和Interferon Gamma。皮质类固醇的抗炎特性还来自多种细胞的效果，例如巨噬细胞，单核细胞，嗜碱性粒细胞，成纤维细胞，成纤维细胞和内皮细胞的细胞因子，粘合剂分子的产生和代谢信号的降低。这些抗炎功能调节体液和细胞免疫学，并在治疗过敏和免疫疾病中扮演了皮质类固醇的核心作用。随着越来越多的证据表明，胆道闭锁的婴儿的生命会产生炎症介质，皮质类固醇的治疗可能会减少感染，水肿和纤维化进展。 迄今为止尚未对胆道闭锁婴儿的胆汁排水和临床结局的有效性进行预期评估。但是，四个回顾性报告表明，皮质类固醇可以改善胆道闭锁患者的胆汁引流和预后。在最初的临床报告中，在最初的左右左侧骨膜造口术时，胆汁流量降低的婴儿/儿童中，胆汁流量降低的婴儿/儿童的短剂量高剂量的高剂量疗程会增加每日胆红素的每日排泄，并增加了胆红素的排泄并扩大了胆红素，酒精磷酸酶，磷酸化酶，和氨基酸酶的水平。左侧骨术后6-8天，胆红素和氨基转移酶的血清水平也有所改善，但胆汁闭锁的婴儿接受泼尼松酮，但皮质类固醇的持续时间尚未清楚地说明。最近，两份报告描述了左侧造口术后不久的高剂量皮质类固醇，然后在胆道闭锁的婴儿中逐渐减少了6-12周的锥度。两项报告都表明，超过70％的患者在70％的患者中改善了胆汁排水和与天然肝脏的生存率提高。