The STOP-PKD trial (SGLT2-inhibition TO improve Prognosis in Polycystic Kidney Disease), an investigator-driven, multi-center, randomized, placebo-controlled, double-blind trial to compare SGLT2-inhibition versus placebo in patients with ADPKD

• Applicant: Professor Dr. Roman-Ulrich Müller
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519109384

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common severe monogenic diseases with a genetic prevalence of ~1/1,000. Nearly all affected patients will show progressive formation and growth of innumerable kidney cysts. These cysts compress viable kidney tissue, leading to progressive renal failure, with ultimately a need to start kidney function replacement therapy (KFRT) in their 6th decade of life. Approximately 10% of all patients on dialysis or living with a kidney transplant had ADPKD as cause of kidney failure. Besides, chronic kidney disease (CKD) associated co-morbidities as well as a significant reduction in disability-adjusted life years add to the socioeconomic burden substantially. There is currently only one approved therapy for ADPKD, the V2R antagonist tolvaptan. However, its utility is limited by extreme aquaresis and potential liver toxicity. Consequently, new treatment opportunities are urgently awaited. The approval of SGLT2-inhibitors (SGLT2i) has been a milestone for the treatment of CKD with unexpected efficacy and highly positive safety profiles. However, ADPKD patients were excluded from the underlying trials, because of equivocal results from animal experiments. Consequently, there is no clinical data regarding the renoprotective efficacy of SGLT2i in ADPKD to date. Extrapolation of the results from the CKD trials to ADPKD is problematic due to the different pathophysiology compared to the CKD cases examined to date. However, both based on the mode of action and the metabolic implications of SGLT2i, these drugs are extremely interesting therapeutic candidates in ADPKD. Consequently, data obtained specifically in ADPKD is urgently required to open this novel treatment opportunity to ADPKD patients. It is now the time to obtain data on SGLT2i in ADPKD to enable these patients to benefit from this powerful approach. The current lack of accessibility of SGLT2i in ADPKD has also led to major concerns on the side of patients with ADPKD. We have been in close contact with both the German patient organization (Familiäre Zystennieren e.V.) and PKD International discussing this issue. These focus groups have revealed that patients feel a strong need for an SGLT2i trial in ADPKD. Importantly, the current situation is regarded as a major inequality concerning this large group of genetic kidney disease patients with strong criticism of previous trial design that led to their exclusion. We will now aim to fill this knowledge gap by implementing STOP-PKD, an investigator-driven, multi-center, randomized, placebo-controlled, double-blind trial to compare SGLT2i versus placebo in patients with ADPKD. STOP-PKD will examine this concept in 420 ADPKD patients. The primary endpoint is the comparison of the annual loss of kidney function between participants on SGLT2i and placebo over 3 years allowing for a reliable analysis of efficacy.

• DFG Programme: Clinical Trials