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.

NARRATIVE The planned multi-site randomized trial aims to proof the superiority of personalized precision dosing of mycophenolate mofetil over current standard of care for the treatment of proliferative lupus nephritis in children. The proposed trial is relevant to public health because, if successful, it promises to improve long- term disease outcomes through rapid control of kidney inflammation, while minimizing unnecessary exposures to immunosuppressive and teratogenic medications.