The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study

标题 霉酚酸酯药代动力学驱动给药的有效性和安全性 莫非替治疗儿童增生性狼疮性肾炎- A 双盲对照临床试验 儿童狼疮性肾炎吗替麦考酚酯（PLUMM）研究 项目概要： 成人荟萃分析表明，静脉注射环磷酰胺和 根据患者体重或体表面积（MMFBSA）给药时， 在美国治疗增生性狼疮性肾炎（LN）的标准治疗药物 霉酚酸酯（MMKPK）的指导精确给药可能会对当前的标准治疗进行有益的修改 因为MMKPK承诺比MMFBSA高30%以上的LN应答率。拟议的目标， 充分把握度、随机、双盲对照临床试验，比较 药代动力学指导的MMF精确给药（MMFPK）与常规MMF给药方案 （MMFBSA）的儿童增生性LN。在该双组104周研究中检验的主要假设 一项研究表明，与MMFBSA相比，MMFPK导致儿童肾脏缓解率显著升高 增殖性淋巴结炎主要终点是至少部分肾功能恢复的受试者比例。 在意向治疗人群中，研究第26周时的PRR。关键次要终点为 在研究第26周达到完全肾缓解（CRR）。我们的方法是招收105名 年龄在8岁或8岁以上的儿科受试者，新诊断为增殖性LN+， 选择霉酚酸酯诱导治疗加耐受口服霉酚酸酯。随机化将在基线（1：1）至 MMKPK组或MMFBSA组。第26周后，无应答者将停止接受治疗。 活性研究干预，以及基线时随机分配至MMFBSA组的达到PRR但未达到PRR的受试者 CRR将交叉到MMFPK组。体积吸收微取样（VAMS）装置将用于 便于估计全血中麦考酚酸（MPA）的暴露量， MMFPK组中的MMF给药。 将监测研究和MMF依从性。将在尿液中检测专利生物标志物，以支持 MMFPK在控制LN活性方面优于MMFBSA。在完成这项试验后，我们预计， 有明确的证据表明MMFPK治疗优于MMFBSA，并表明 MMFPK剂量耐受性良好，在儿童中具有可接受的安全性。 相关性： 拟议的试验与公共卫生有关，因为研究了LN的治疗方法，即疾病 这是大多数cSLE患儿的并发症。在这种情况下，优化药物使用有望 通过快速控制肾脏炎症，同时最大限度地减少 不必要地接触免疫抑制和致畸药物。这与以下部分有关： NIH的使命是促进治疗研究;传播研究信息 狼疮的进展LN是NIAMS战略计划及其狼疮研究议程的核心， 改善公共卫生和以患者为中心的个性化护理。

TITLE EFFICACY & SAFETY OF PHARMACOKINETICALLY-DRIVEN DOSING OF MYCOPHENOLATE MOFETIL FOR THE TREATMENT OF PEDIATRIC PROLIFERATIVE LUPUS NEPHRITIS - A DOUBLE-BLIND CONTROLLED CLINICAL TRIAL The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study PROJECT SUMMARY: Meta-analyses in adults suggest equivalence of clinical efficacy of intravenous cyclophosphamide and mycophenolate mofetil when dosed based on patient weight or body-surface-area (MMFBSA) as is the current standard for the treatment of proliferative lupus nephritis (LN) treatments in the U.S. Pharmacokinetically- guided precision dosing of MMF (MMKPK) may offer a beneficial modification of the current standard treatment in that MMKPK promises over 30% higher LN response rates than MMFBSA. The objective of the proposed, adequately powered, randomized, double-blind controlled clinical trial is to compare the efficacy and safety of pharmacokinetically-guided precision dosing of MMF (MMFPK) with conventional dosing regimens of MMF (MMFBSA) among children with proliferative LN. The principal hypothesis to be tested in this 2-arm 104-week study is that, compared to MMFBSA, MMFPK results in significantly higher rates of renal remission in children with proliferative LN. The primary endpoint is the proportion of subjects achieving at least partial renal remission (PRR) at week 26 of the study in the intention to treat population. The key secondary endpoint is achievement of complete renal remission (CRR) at week 26 of the study. Our approach will be to enroll 105 pediatric subjects, ages 8 years or older, who have been newly diagnosed with proliferative LN plus have chosen MMF for induction therapy plus tolerate oral MMF. Randomization will occur at baseline (1:1) to the MMKPK arm or the MMFBSA arm, respectively. After week 26, non-responders will be discontinued from the active study intervention, and subjects randomized at baseline to the MMFBSA arm who achieved PRR but not CRR will cross over to the MMFPK arm. Volumetric Absorptive Microsampling (VAMS) devices will be used to facilitate estimation of the exposure to mycophenolic acid (MPA) in whole blood as is needed to personalize MMF dosing in the MMFPK arm. Use of corticosteroid will be standardized and closely regulated during the study, and adherence to MMF will be monitored. Patented biomarkers will be assayed in the urine in support of the superiority of MMFPK over MMFBSA in controlling LN activity. Upon completion of this trial, we expect to have unequivocal evidence of the superiority MMFPK therapy compared to MMFBSA use, and to show that MMFPK dosage is well tolerated and has an acceptable safety profile in children. RELEVANCE: The proposed trial is relevant to public health because therapies for LN are investigated, i.e. disease complications that concern the majority of children with cSLE. In this setting, optimizing drug use promises to improve long-term disease outcomes through rapid control of kidney inflammation, while minimzing unnecessary exposures to an immunosuppressive and teratogenic medication. This is relevant to the part of NIH’s mission that pertains to fostering research in treatment; and the dissemination of information on research progress in lupus. LN is central to NIAMS Strategic Plan and its Lupus Research Agenda in pursuance of improved public health and patient-centered personalized care.