Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

INTRODUCTIONFSGS, the most common primary glomerular disease leading to ESKD, is characterized by podocyte injury and depletion, while Minimal Change Disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase in podocytes. Conversely, in FSGS, AMPK-activation using Metformin mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of Metformin on proteinuria and CKD outcomes in diabetes. A randomized controlled trial (RCT) to test Metformin in podocyte injury with FSGS has not been conducted before.METHODSWe report the rationale and design of, phase-II, double-blind, placebo-controlled RCT evaluating the efficacy and safety of Metformin as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to Metformin or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury/depletion and evaluate outcomes after 6-months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies.RESULTS and CONCLUSIONOur phase-II trial will provide insight into the potential efficacy and safety of Metformin as adjunctive therapy in FSGS -a crucial step to developing a larger phase-III study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.