CLINICAL TRIALS OF IMMUNOSUPPRESSION IN RENAL TRANSPLANT

终末期肾病是人类死亡的主要原因之一 美国的慢性残疾。虽然它可以由 无论是通过透析还是通过肾移植，它都是被广泛认可的 成功的肾移植与更好的 生活质量和更好的康复机会。目前， 肾移植成功应用的主要限制因素 (供体肾脏供应短缺除外)是发生的 急性和慢性排斥反应，每一种都会导致大约 在肾移植后的头五年里，五分之一的肾脏 移植。虽然在管理方面取得了重大进展 在过去的十年里全国一年的肾急性排斥反应 在过去的五年里，同种异体移植物的存活率并没有太大的改善。 一年后移植物损失率几乎没有变化， 由于慢性排斥反应，自移植时代开始以来 1960年。限制免疫抑制药物改善的主要因素 对于肾移植的治疗一直缺乏一个大的 多中心临床试验小组评估拟议的新药和新药物 养生要及时考虑因素。考虑到失败率不超过15%- 每年20%，对拟议的新疗法的研究将需要 接近2000岁的受试者发现临床显著差异 治疗组之间的结果，如果需要统计的话 显著性在0.05水平，幂至少为0.80。即使是那些 最大的中心缺乏足够的患者来完成新的研究 治疗周期不超过几年。美国国立卫生研究院现在提议 赞助开发这样的多中心合作临床试验 移植组。在这份申请中，爱荷华大学 移植服务公司提议加入这个由NIH赞助的试验小组。我们 建议有效利用有限的患者和资金 资源，研究设计应考虑同时析因分析 随机分为不同的治疗阶段，如诱导和治疗 维持免疫抑制疗法，并按顺序随机选择 其他治疗方法，如处理急性排斥反应和 长期免疫抑制的管理。发起这个学习小组 我们提出了一系列试验，使用上述设计来确定 是否a)加用抗淋巴细胞球蛋白诱导治疗， 或b)用RS-61443取代基线“三联”中的硫唑嘌呤 免疫抑制“将增加移植物存活的比例或 减少严重排斥反应的发生频率，c)是否 抗T细胞受体单抗T10B9.1A-31将作为 与OKT3一样有效地处理严重急性排斥反应，并将 与“首剂”副作用的严重程度降低有关，以及 是否停止类固醇治疗(同时继续使用环孢素和 硫唑嘌呤或RS-61443治疗肾移植受者 在接下来的前六个月内没有经历过严重的排斥反应 移植将改善动脉粥样硬化血管的危险因素 疾病(高血压、高脂血症、糖耐量低减、肥胖) 不会增加晚期排斥反应或肾移植的丢失。

End stage renal disease is one of the leading causes of death and chronic disability in the United States. Though it can be managed by either dialysis or by renal transplantation, it is widely recognized that successful renal transplantation is associated with a better quality of life and better chances of rehabilitation. Currently the major limitation to the successful application of renal transplantation (other than a shortage in the supply of donor kidneys) is the occurrence of acute and chronic rejection, each of which leads to loss of about one-fifth of kidneys over the first five years following renal transplantation. While there have been major advances in the management of acute rejection over the past ten years nationwide one year renal allograft survival has not improved much over the past five years. There has been little change in the rate of graft loss after one year, due to chronic rejection, since the beginning of the transplant era in 1960. A major factor limiting improvement in immunosuppressive therapies for renal transplantation has been the lack of a large multicenter clinical trial group to evaluate proposed new agent and new regimens in a timely factor. Given a failure rate of no more than 15% - 20% per year, studies of proposed new therapies will require numbers of subjects approaching 2000 to detect clinically significant differences in outcome between treatment groups, if one requires statistical significance at the 0.05 level and a power of at least 0.80. Even the largest centers lack sufficient patients to complete studies of new therapies in periods less than several years. NIH now proposes to sponsor the development of such a multicenter Cooperative Clinical Trial Group in Transplantation. In this application, the University of Iowa Transplant Service proposes to join this NIH sponsored trial group. We propose that to make efficient use of limited patient and fiscal resources, the study design should allow for simultaneous factorial randomized to different stages of therapy, such as induction and maintenance immunosuppression therapies, and sequential randomization to other therapies such as management of acute rejection episode and management of long term immunosuppression. To initiate this study group we propose a series of trials, using the above design, to determine whether a) addition of induction therapy with antilymphocyte globulin, or b) substitution of RS-61443 for azathioprine in baseline "triple immunosuppression" will increase the fraction of surviving grafts or decrease the frequency of severe rejection episodes, c) whether the anti-T-cell receptor monoclonal antibody T10B9.1A-31 will be as effective as OKT3 in management of severe acute rejection and will be associated with a reduced severity of "first-dose" side effects, and whether stopping steroid therapy (while continuing cyclosporine and either azathioprine or RS-61443) in renal allograft recipients who have not experienced a severe rejection within the first six months following transplant will improve the risk factors for atherosclerotic vascular disease (hypertension, hyperlipidemia glucose intolerance, obesity) without an increase in late rejection episodes or loss of renal grafts.