The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study

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.

Grant Number: 5R01AR079124-04
NIH Institute/Center: NIH
Principal Investigator: Hermine Brunner