Meta-analyses in adults suggest equivalence of clinical efficacy of cyclophosphamide and mycophenolate mofetil (MMFBSA) when dosed based on patient weight or body-surface-area (BSA), as is the current standard for proliferative lupus nephritis (LN) treatments in the U.S. Pharmacokinetically-guided precision dosing of MMF (MMKPK) offers a beneficial modification of a current standard treatment, i.e. MMFBSA, that promises to yield improved LN response rates by 25 - 30%. Further, biomarkers measured in the urine, a.k.a. the LN-Panel, have been validated by our group and allow for improved surveillance of LN. The long-term goal of our research is to improve the prognosis of childhood-onset systemic lupus erythematosus (cSLE) through evidence-based therapies. The objective of this application is to plan a 2-year, 2-arm (MMFpk, MMFBSA) double-blinded 1:1 randomized clinical trial (RCT) in pediatric LN to estimate the benefits of pharmacokinetically-guided precision dosing of MMF, with biologic confirmation provided by the LN-Panel. The primary outcome is complete or partial remission of LN at week 24. The principal hypothesis to be tested is that, compared to MMFBSA, MMFPK results in significantly higher rates of complete or partial renal remission at 24 weeks in children with proliferative LN therapy.
Specific Aims of the Planning Application: 1: To establish consensus around the use of corticosteroids for children with proliferative LN. 2: To test the implementation of novel methods to therapeutic drug monitoring for the planned RCT. 3: To finalize the design of the planned trial, identify investigative sites and conduct activities towards the implementation of the trial. As part of the proposed planning activities site selection will be completed to ensure full enrollment of the RCT within 2 years. In addition, the full study protocol will be developed; centralized ethics committee approval will be obtained; contracts will be finalized; composition of a manual of operating procedures will be achieved; and electronic data capture systems and creation of relevant committees will be established. Upon completion of this planning grant, we expect to start enrolling a total of 90 patients into the planned RCT. Consensus around corticosteroid use during the RCT will have been achieved. Feasibility of therapeutic drug monitoring will be enhanced by newly introduced testing using dried blood spots and a smartphone application. LN-Panel biomarker measurement using a novel multiplex assay will be available for the planned multicenter RCT. The results of the planned RCT are anticipated to improve treatment success with MMF in the treatment of children with proliferative LN.
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 immunosuppressive and teratogenic medications. 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 Lupus Research Agenda in pursuance of improved public health.