New NAPRTCS Trials in Steroid-Free Immunosuppression

无类固醇免疫抑制的新 NAPRTCS 试验

• 批准号: 6784717
• 负责人: Oscar Salvatierra
• 金额: $ 169.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784717
• 关键词: FK506; adolescence (12-20); artificial immunosuppression; child (0-11); clinical research; clinical trials; cooperative study; cyclosporines; cytokine; drug screening /evaluation; human subject; human therapy evaluation; kidney pharmacology; kidney transplantation; light microscopy; microarray technology; monoclonal antibody; pediatric pharmacology; sirolimus; transplant rejection

DESCRIPTION (provided by applicant): This proposal presents a step-wise multi-center approach to provide meaningful new improvements in immunosuppression for pediatric kidney transplantation, using the first successful single center experience with complete steroid avoidance as a foundation proceeding to a modification to reduce calcineurin-inhibitor nephrotoxicity and chronic allograft nephropathy (CAN), and finally, the introduction of a tolerance induction protocol that could eliminate all maintenance immunosuppressive medication post-transplantation. Patient recruitment will be carried out at 30 centers through NAPRTCS. Project I will be a controlled, open-label, randomized (1:1), multi-center clinical trial in 300 patients aged 0-20 years that will compare two steroid-free immunosuppressive regimens, both with similar extended daclizumab induction to replace steroids: (1) the established single center protocol with standard dose tacrolimus and mycophenalate mofetit (MMF) and (2) the other, a new protocol with half-dose tacrolimus and substitution of sirolimus for MMF. The primary end point will be an improvement in graft function at 1 and 2 years, while maintaining equivalency for acute and sub-acute rejection. Project II will be a pilot study to establish renal allograft tolerance in ten pediatric kidney recipients aged 13-18 years, through a non-myeloablative conditioning regimen that includes cyclophosphamide, a humanized anti-CD2 monoclonal, antibody, thymic irradiation, followed by cyclosporine as the only post-transplant immunosuppressive agent. Cyclosporine will be withdrawn after 60 days in recipients with detectable multi-lineage white blood cell chimerism. The primary endpoint will be 24-month graft survival without maintenance immunosuppression. Protocol allograft biopsies and mechanistic studies will be linked to both projects to further elucidate the molecular mechanisms of graft rejection, drug nephrotoxicity, CAN and tolerance. These will include microarray analysis for global expression profiling of the allograft and periphery, quantitative RT-PCR for cytokine monitoring, sirius red staining for quantitation of allograft fibrosis, as well as chimerism and tolerance assays. The success of these protocols should result in elimination of steroid toxicity, normalization of growth, extended long-term graft survival with excellent function, and the potential applicability of these protocols to adults and other solid organ transplant recipients with significant economic benefit.

描述（由申请人提供）：该提案提出了一种逐步的多中心方法，以第一个成功的单中心完全避免类固醇的经验为基础，进行修改以减少儿童肾移植的免疫抑制方面的有意义的新改进。钙调神经磷酸酶抑制剂肾毒性和慢性同种异体移植肾病（CAN），最后引入耐受诱导方案，可以消除移植后所有维持免疫抑制药物。 患者招募将通过 NAPRTCS 在 30 个中心进行。项目 I 将是一项对照、开放标签、随机 (1:1)、多中心临床试验，在 300 名 0-20 岁患者中进行，将比较两种无类固醇免疫抑制方案，两者均采用类似的延长达克珠单抗诱导来替代类固醇：（1）已建立的单中心方案，采用标准剂量他克莫司和麦考酚那酯（MMF），（2）另一个，采用半剂量他克莫司和替代品的新方案西罗莫司用于 MMF。主要终点是 1 年和 2 年移植物功能的改善，同时保持急性和亚急性排斥反应的等效性。项目 II 将是一项试点研究，旨在通过非清髓性预处理方案，在 10 名 13-18 岁儿童肾接受者中建立同种异体肾移植耐受性，其中包括环磷酰胺、一种人源化抗 CD2 单克隆抗体、胸腺照射，然后使用环孢素作为治疗剂。唯一的移植后免疫抑制剂。对于可检测到多谱系白细胞嵌合的受者，环孢素将在 60 天后停用。主要终点是在不维持免疫抑制的情况下移植物的 24 个月存活率。同种异体移植物活检和机制研究将与这两个项目相关联，以进一步阐明移植物排斥、药物肾毒性、CAN 和耐受性的分子机制。这些将包括用于同种异体移植物和外周血整体表达谱的微阵列分析、用于细胞因子监测的定量RT-PCR、用于定量同种异体移植物纤维化的天狼星红染色，以及嵌合和耐受测定。这些方案的成功应导致消除类固醇毒性、生长正常化、延长移植物的长期存活率和良好的功能，以及这些方案对成人和其他实体器官移植受者的潜在适用性，并具有显着的经济效益。