The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study

标题 霉酚酸酯药动学驱动剂量的有效性和安全性 莫非替尔治疗儿童增生性狼疮性肾炎-A 双盲对照临床试验 霉酚酸酯治疗儿童狼疮性肾炎的临床研究 项目总结： 成人荟萃分析提示静脉注射环磷酰胺和环磷酰胺的临床疗效相当 霉酚酸酯根据患者体重或体表面积(MMFBSA)按当前剂量给药 美国增生性狼疮性肾炎(LN)治疗标准 MMF的引导精确剂量(MMKPK)可能是对当前标准治疗的有益修改 在这方面，MMKPK承诺的LN响应率比MMFBSA高30%以上。拟议的目标是， 充分动力、随机、双盲对照的临床试验是比较 药动学引导下的MMF精确给药与常规给药方案比较 (MMFBSA)在增生期LN儿童中的表达。在这个为期两周的104周中要检验的主要假设是 研究表明，与MMFBSA相比，MMFPK导致儿童肾脏缓解率明显更高 伴增生性LN。主要终点是至少获得部分肾功能的受试者的比例 在研究的第26周缓解(PRR)，意在治疗人群。关键辅助终结点是 在研究的第26周达到肾脏完全缓解(CRR)。我们的办法是招收105人 新诊断为增殖性LN+的8岁或以上的儿科受试者有 选择MMF作为诱导治疗加耐受性口服MMF。将在基线(1：1)处进行随机化 MMKPK臂或MMFBSA臂。第26周后，非响应者将不再参与 积极的研究干预，在基线时随机分配到MMFBSA组，他们达到了PRR，但没有 CRR将穿过MMFPK臂。体积吸附微采样(VAMS)设备将用于 便于估计个性化所需的全血中霉酚酸(MPA)的暴露 MMFPK臂中的MMF剂量。皮质类固醇的使用将被标准化，并在 研究，并将监测对MMF的依从性。专利生物标志物将在尿液中进行检测以支持 MMFPK在控制LN活性方面优于MMFBSA。在这项试验完成后，我们预计 有明确的证据表明，与使用MMFBSA相比，MMFPK疗法具有优越性，并表明 MMFPK剂量在儿童中耐受性良好，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 与大多数CSLE儿童有关的并发症。在这种情况下，优化药物使用有望 通过快速控制肾脏炎症改善长期疾病结局，同时将 不必要地接触免疫抑制和致畸药物。这与……部分有关 美国国立卫生研究院的使命是促进治疗研究；以及传播研究信息 狼疮的研究进展。LN是NIAMS战略计划及其狼疮研究议程的核心，以追求 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.