Dapagliflozin in Active Lupus Nephritis: A Pilot and Feasibility Randomized Trial - PROJECT SUMMARY/ABSTRACT Lupus nephritis is a chronic, life-threatening autoimmune glomerulonephritis that disproportionately impacts young people with devastating consequences. Despite current standard treatment with glucocorticoids, immunosuppressives, antimalarials, and renin-angiotensin-aldosterone system blockade, lupus nephritis carries a 10-30% risk of end-stage kidney disease as well as increased risks of cardiovascular disease and premature morality. Proteinuria, a key feature of lupus nephritis, is a major risk factor for progressive glomerular filtration rate (GFR) decline and end-stage kidney disease. It is increasingly understood that lupus nephritis needs to be rapidly and aggressively treated with multiple agents during an early window of opportunity, before irreversible kidney damage has occurred. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are now proven to reduce chronic kidney disease progression among patients with diabetic and non-diabetic kidney disease via hemodynamic and metabolic mechanisms that reduce proteinuria, lower blood pressure, and improve metabolic syndrome. Observational studies indicate a possible role for SGLT2i to improve kidney and cardiovascular outcomes for patients with lupus. However, patients with lupus nephritis were largely excluded from randomized controlled trials (RCT) of SGLT2i and are excluded from the current FDA indications. Thus, it is unknown whether SGLT2i use will be safe, tolerated, and effective in immunosuppressed patients with early and active lupus nephritis, who are often subjected to complex medication regimens, but this is a key target population in the early window for the prevention of ongoing and irreversible kidney damage. A large, multicenter RCT trial is needed to determine the safety and efficacy of SGLT2i in patients with active lupus nephritis. To enable the planning, design, and success of this future trial, we propose a two-site, three-year pilot and feasibility trial of dapagliflozin as add-on therapy to standard-of-care for 30 patients with biopsy-proven Class III, IV and/or V lupus nephritis. This will be a concealed allocation, blinded RCT with 2:1 allocation ratio of dapagliflozin 10 mg or matched placebo for 12 weeks. The eligible population will include patients with active lupus nephritis with ongoing proteinuria on standard immunosuppression regimens. We will assess the feasibility of recruiting patients with active lupus nephritis, and pilot test study procedures to incorporate patient preferences for study visit formats, including virtual visits (Aim 1). We will pilot test data collection methods for proposed future trial outcomes, including changes in proteinuria and eGFR, SLE disease activity indices, and patient reported outcomes, and we will estimate changes in proteinuria over 12 weeks with dapagliflozin or placebo (Aim 2). We will detect safety signals, especially genitourinary infections, other infections, and hypovolemia, as well as drug tolerability and adherence to the study intervention (Aim 3). This pilot and feasibility trial will provide critical early insights into the use of SGLT2i for patients with active lupus nephritis and will guide the planning of a larger, definitive multicenter RCT to determine the safety and efficacy of SGLT2i in treatment of active lupus nephritis.
