STOP-PKD: SGLT2-inhibition to Improve Prognosis in Polycystic Kidney Disease

STOP-PKD: SGLT2-inhibition to Improve Prognosis in Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease is the most common genetic cause of kidney failure. The only approved treatment for ADPKD - tolvaptan - is limited in its use by massive therapy-associated polyuria. This trial tests if the SGLT2-inhibitor dapagliflozin slows down the loss of kidney function in ADPKD.

ADPKD is a genetic disease characterized by the growth of fluid-filled renal cysts, leading to progressive loss of kidney function. SGLT2- inhibitors have recently become available for the treatment of chronic kidney disease (CKD). The landmark trials, which proved the positive effect of SGLT2-inhibitors in CKD, excluded patients with ADPKD. Accordingly, current ADPKD-guidelines do not recommend the use of SGLT2-inhibitors in ADPKD.

This investigator-driven, randomized, placebo-controlled, multi-center, double-blind trial will assess the effect of daily dapagliflozin (10mg) intake on the chronic eGFR-slope in 420 patients with ADPKD. As a secondary endpoint the study will assess a composite endpoint triggered by reaching either 40%-eGFR loss, kidney failure or renal death. Safety aspects will additionally be addressed by an interim safety analysis considering total kidney volume, eGFR and copeptin-levels.

Inclusion Criteria:

• Male and female patients with ADPKD (modified Ravine criteria) ≥ 18 and ≤ 60 years

• Patients 18 - 39 years: eGFR ≥25 ml/min; patients 40 - 60 years: eGFR ≥25 and <90 ml/min/1.73 m2

• Indicators of rapid progression, either of the following:

• Mayo class 1D-E

• Mayo class 1C AND EITHER

  1. Truncating PKD1 mutation OR
  2. eGFR loss > 3ml/min/year (determined by ≥ 4 creatinine values within 4 years, ≥ 6 months measurement intervals) OR
  3. PROPKD score > 6 (patient history)

• IF patient is on ACE-I /ARBs: stable dose for 4 weeks before screening

Exclusion Criteria:

• Treatment with tolvaptan, somatostatin analogue, lithium or SGLT2i within the last 3 months before screening
• Medical history of diabetic ketoacidosis, necrotizing fasciitis or organ transplantation
• Diabetes mellitus type 1 or any type of diabetes mellitus due to insulin deficiency
• Uncontrolled ongoing urinary tract or genital infections
• Known intolerance of the study medication ingredients
• Uncontrolled grade 2 hypertension (>160/100 mmHg)
• Symptomatic hypotension, or systolic blood pressure <90 mmHg
• Primary renal disease other than ADPKD
• Hepatic impairment (aspartate transaminase [AST] or alanine transaminase [ALT]>3x the up-per limit of normal [ULN]; or total bilirubin >2x ULN at time of enrolment)
• Pregnancy, breastfeeding or women of child-bearing potential not using effective contraception method
• Not able to comply with the study protocol, in the investigator's judgement
• Not able to provide informed consent
• Participation in any other interventional clinical trial in the last 2 months