Overview
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.
Description
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.
Eligibility
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
- Truncating PKD1 mutation OR
- eGFR loss \> 3ml/min/year (determined by ≥ 4 creatinine values within 4 years, ≥ 6 months measurement intervals) OR
- 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