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

The primary objective is to assess whether dapagliflozin improves the decline of kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD) during on-treatment period. This evaluation is clinically relevant as it addresses the potential disease-modifying effect of SGLT2 inhibition on progressive renal function deterioration in ADPKD, a condition characterized by cyst formation and gradual loss of kidney function.

The secondary objectives include:

• To assess the impact of dapagliflozin treatment in patients with ADPKD on the change in kidney function off-treatment.

• To assess the impact of dapagliflozin treatment in patients with ADPKD on a composite outcome: time to 40% decrease in eGFR, ESKD or renal death.

• To assess the impact of dapagliflozin treatment in patients with ADPKD on patient safety.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population comprised **male and female patients** diagnosed with **autosomal dominant polycystic kidney disease (ADPKD)** according to modified Ravine criteria, aged **18 to 60 years**. Participants were categorized into two age groups: patients aged 18 to 39 years required an **estimated glomerular filtration rate (eGFR)** of at least 25 ml/min, while those aged 40 to 60 years needed an eGFR of at least 25 and less than 90 ml/min/1.73 m². The trial population was selected based on indicators of rapid disease progression, including **Mayo class 1D-E** classification, or Mayo class 1C with additional criteria such as a **truncating PKD1 mutation**, eGFR loss exceeding 3 ml/min per year determined by at least four creatinine values within four years with measurement intervals of at least six months, or a **PROPKD score** greater than 6 based on patient history. Patients receiving **angiotensin-converting enzyme inhibitors (ACE-I)** or **angiotensin receptor blockers (ARBs)** were required to maintain a stable dose for four weeks prior to screening.

This is a randomized, double-blind, placebo-controlled Phase III clinical trial evaluating the efficacy and safety of **dapagliflozin** in patients with **autosomal dominant polycystic kidney disease** (ADPKD). The trial aims to assess whether dapagliflozin improves the decline of **kidney function** in patients with ADPKD during the on-treatment period, specifically between week 6 and end of treatment. The investigational medicinal product is administered as a **film-coated tablet** containing 10 mg of dapagliflozin for **oral use**, with a maximum daily dose of 10 mg. The matching **placebo** is used as the comparator in this controlled trial design.

Eligible participants include male and female patients aged 18 to 60 years with confirmed ADPKD according to modified Ravine criteria. For patients aged 18 to 39 years, an **estimated glomerular filtration rate** (eGFR) of at least 25 mL/min is required, while patients aged 40 to 60 years must have an eGFR of at least 25 and less than 90 mL/min/1.73 m². Participants must demonstrate indicators of rapid disease progression, including Mayo class 1D-E, or Mayo class 1C with additional criteria such as truncating **PKD1 mutation**, eGFR loss greater than 3 mL/min/year, or PROPKD score greater than 6. Patients receiving **ACE inhibitors** or **angiotensin receptor blockers** must be on a stable dose for 4 weeks before screening.

The primary endpoint is the annual slope of eGFR decline measured in mL/min/1.73 m² per year, calculated using linear mixed models with all available **creatinine** values from week 6 until end of treatment at week 156. Secondary endpoints include off-treatment eGFR change from before to after treatment, a composite outcome of sustained 40% decrease in eGFR from randomization or **end-stage kidney disease** (ESKD) or renal death, collection of **serious adverse events** and adverse events of special interest, and change in total **kidney volume** after 1 year in the first 150 patients.

The maximum treatment period is 156 weeks. Participant involvement includes a screening visit to assess eligibility criteria, followed by regular study visits throughout the treatment period for monitoring of kidney function, safety assessments, and collection of laboratory samples. An end-of-study visit occurs at week 156, with follow-up visits at weeks 162 and 168 to assess off-treatment parameters. For the first 150 enrolled patients, additional imaging assessments are performed at baseline and week 48 to evaluate changes in total kidney volume. The maximum total dose administered over the course of the trial is 10,920 mg. Early termination from the study may occur due to adverse events, withdrawal of consent, protocol violations, or other conditions as specified in the trial protocol. The estimated recruitment start date is October 2025, with an estimated trial completion date of September 2031.

The experimental treatment consists of **dapagliflozin**, administered as **Dapagliflozin Ascend 10 mg film-coated tablets**. The active substance is dapagliflozin, a chemical compound classified under **ATC code A10BK01**. The pharmaceutical form is film-coated tablets, and the product is manufactured by Ascend GmbH and authorized in Germany under marketing authorization number 7001787.00.00. The route of administration is **oral use**. The maximum daily dose is **10 mg**, administered once daily. The maximum total dose over the treatment period is **10920 mg**, corresponding to a maximum treatment duration of **156 weeks**. Participants will receive dapagliflozin continuously throughout the study period, with dosing compliance monitored according to the study protocol.

The comparator treatment consists of a **matching placebo** designed to correspond to Dapagliflozin Ascend 10 mg film-coated tablets. The placebo contains no active pharmaceutical ingredient and is formulated to be indistinguishable from the active treatment in appearance and administration characteristics. The placebo will be administered via the same oral route and according to the same dosing schedule as the active treatment to maintain blinding throughout the study. This ensures that participants and investigators remain unaware of treatment allocation during the trial conduct.

Efficacy will be assessed using the annual slope of **eGFR** decline, expressed in mL/min/1.73m² per year, as the primary endpoint. This chronic slope will be calculated using linear mixed models, incorporating all available creatinine values collected from week 6 until end of treatment at week 156. Secondary efficacy parameters include off-treatment **eGFR** change, evaluated by comparing the mean of two creatinine measurements obtained before treatment (week -4 and week 0) with measurements taken during follow-up (week 162 and week 168). A composite outcome will be assessed, comprising sustained 40% decrease in **eGFR** from randomization confirmed by a second measurement at the next scheduled visit or at the last study follow-up visit or last scheduled visit before death, or progression to **end-stage kidney disease** defined as initiation of dialysis, kidney transplantation, or sustained **eGFR** below 15 mL/min/1.73m², or renal death. Additional efficacy evaluation will include the change in total kidney volume after one year, measured between baseline and 48 weeks in the first 150 patients. Safety data, including serious adverse events and adverse events of special interest, will be collected throughout the study period.