Mycophenylate mofetil for treatment of chronic GVHD

描述（由申请人提供）：慢性移植物抗宿主病（GVHD）发生在40 - 60%的患者中，这些患者在接受同种异体供体造血干细胞移植治疗血液恶性肿瘤后存活超过3个月。除了复发性恶性肿瘤外，慢性GVHD是该患者群体死亡和发病的主要原因。长期以来，高剂量糖皮质激素一直是慢性GVHD的主要治疗手段，其代价是相当高的发病率。霉酚酸酯（Mycophenolate mofetil， MMF）是一种水解为霉酚酸的前药，可选择性抑制肌苷单磷酸脱氢酶，从而阻断淋巴细胞嘌呤合成的新生途径。至少五项II期研究的结果表明，MMF可能对治疗类固醇难治性慢性GVHD有效。本申请提出了一项多中心、III期随机双盲临床试验，以确定MMF是否有效治疗新诊断的慢性GVHD。该研究两组的所有患者都将接受强的松和钙调磷酸酶抑制剂（环孢素或他克莫司）作为慢性GVHD的标准治疗。一只手臂的患者将接受MMF治疗，而另一只手臂的患者将接受一种看起来相同的安慰剂治疗。疗效将根据治疗成功患者的比例进行评估，治疗成功定义为在入组后2年内停止所有免疫抑制治疗，慢性GVHD的所有可逆性表现都得到解决，没有二次治疗。每组入组115名患者将提供90%的能力来检测成功率从22%增加到42%，双侧α值为0.05。来自四种有效工具的健康相关生活质量评估将用于检验MMF治疗导致症状严重程度降低和身体功能改善的假设。

DESCRIPTION (provided by applicant): Chronic graft-versus-host-disease (GVHD) occurs in 40 - 60% of patients who survive for more than 3 months after hematopoietic stem cell transplantation from an allogeneic donor for treatment of hematological malignancy. Apart from recurrent malignancy, chronic GVHD is the leading cause of death and morbidity in this patient population. High-dose glucocorticoids have long served as the mainstay of treatment for chronic GVHD, at the cost of considerable morbidity. Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to mycophenolic acid, which selectively inhibits inosine monophosphate dehydrogenase, thereby blocking the de novo pathway of purine synthesis in lymphocytes. Results from at least five phase II studies have suggested that MMF may be effective for treatment of steroid-refractory chronic GVHD. This application proposes a multi-center, phase III randomized double-blind clinical trial to determine whether MMF is effective for treatment of newly diagnosed chronic GVHD. All patients in both arms of the study will receive prednisone and a calcineurin inhibitor (cyclosporine or tacrolimus) as standard therapy for chronic GVHD. Patients in one arm will be treated with MMF, while those in the other arm will be treated with an identical appearing placebo. Efficacy will be assessed according to the proportion of patients who have treatment success, defined as discontinuation of all immunosuppressive treatment within 2 years after enrollment, with resolution of all reversible manifestations of chronic GVHD and no secondary therapy. Enrollment of 115 patients in each arm will provide 90% power to detect an increase in the success rate from 22% to 42% with a two-sided alpha of 0.05. Health-related quality of life assessment from four well-validated instruments will be used to test the hypotheses that treatment with MMF leads to a decrease in symptom severity and an improvement in physical function.