Evaluation of Dapagliflozin on Renal Function Preservation in Kidney Transplant Recipients: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to demonstrate that the yearly loss of renal function, as measured by the estimated glomerular filtration rate (**eGFR**) from plasma creatinine concentrations over time, is reduced with the administration of the **SGLT2 inhibitor dapagliflozin** compared to a placebo in patients who have undergone kidney transplantation. This is clinically relevant as preserving renal function is crucial for the long-term success of kidney transplants and the overall health of transplant recipients.

Secondary objectives include evaluating whether treatment with dapagliflozin over time may reduce inflammation, fibrosis, and vasculopathy in renal grafts, as well as alter degenerative pathways as visualized by mRNA sequencing and proteomics analyses in biopsies. Additionally, the study aims to assess if dapagliflozin can reduce overweight and abdominal fat mass, improve glucose tolerance, lower blood pressure, and decrease urinary protein excretion in kidney transplant recipients. These secondary outcomes are important for understanding the broader metabolic and structural benefits of dapagliflozin in this patient population.

The clinical trial involves participants who have undergone **kidney transplantation**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are required to be in a general health status that allows them to comply with medical treatment independently. The trial does not involve a vulnerable population. The selection criteria include renal transplant recipients who were transplanted 6 (±2) weeks earlier and have maintained calcineurin inhibitor trough concentrations within their individual therapeutic range, along with standard doses of prednisolone and mycophenolate mofetil over the last two weeks. Additionally, participants must have an estimated GFR of at least 25 mL/min/1.73 m². The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **dapagliflozin** in preserving renal function in patients who have undergone **kidney transplantation**. This is a randomized, double-blind, placebo-controlled trial, with participants receiving either dapagliflozin or a placebo. The trial is set to span a total duration of 36 months, with the primary endpoint being the difference in the estimated glomerular filtration rate (eGFR) slope between the two groups from before randomization to three years post-transplantation. Secondary endpoints include differences in urinary protein/creatinine ratio, blood pressure, glucose tolerance, and incidence of adverse events, among others.

Participants will be required to attend several study visits throughout the trial. The initial inclusion visit will serve as a screening to ensure eligibility, which includes criteria such as being a renal transplant recipient aged 18-75 years, having an estimated GFR of at least 25 mL/min/1.73 m², and being able to comply with medical treatment independently. Follow-up visits will occur regularly to monitor renal function, collect urine and blood samples, and assess any adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all collected data.

The expected length of participant involvement is approximately three years, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or any adverse events that may compromise participant safety. The trial aims to provide valuable insights into the potential benefits of dapagliflozin in maintaining kidney function post-transplantation, contributing to improved long-term outcomes for transplant recipients.

The clinical trial involves the administration of **DAPAGLIFLOZIN**, an SGLT2 inhibitor, to evaluate its efficacy in preserving renal function in transplanted kidneys. **DAPAGLIFLOZIN** is provided in the form of a film-coated tablet, with a chemical origin. The active substance is **DAPAGLIFLOZIN**, identified by the EU substance number SUB31650. The medication is administered orally, with a maximum daily dose of 10 mg and a total maximum dose of 12 mg per kilogram. The treatment period extends up to 36 months. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **Placebo** group to serve as a comparator for evaluating the effects of **DAPAGLIFLOZIN**. The **Placebo** is administered in a manner identical to the experimental medication, ensuring that the route and frequency of administration are consistent across both groups. The use of a **Placebo** allows for a controlled assessment of the drug's impact on renal function, as measured by the estimated glomerular filtration rate (eGFR) slope over time. The trial's main objective is to demonstrate a reduction in the yearly loss of renal function with **DAPAGLIFLOZIN** compared to the **Placebo**.

Efficacy in this clinical trial will be assessed primarily by evaluating the difference in the **eGFR slope** between the treatment groups from before randomization to three years post-transplantation. This primary endpoint will be determined using mixed model statistics, incorporating the estimated glomerular filtration rate (eGFR) calculated from at least four plasma creatinine measurements per year using the MDRD4 formula.

Secondary endpoints include several parameters to further assess efficacy. These include the difference in the slope of the urinary protein/creatinine ratio over the first 72 and 150 weeks of treatment, assessed from at least four urine samples per year using mixed model statistics. Additional secondary endpoints involve differences in blood pressure, changes in measured GFR (iohexol serum clearance), and changes in DXA-measured percent subcutaneous and visceral fat in relation to total fat mass from two weeks to 72 weeks of treatment. Other secondary endpoints include differences in glucose tolerance assessed by an oral glucose tolerance test, urinary metabolomic profile, and the number of patients with at least one biopsy-proven acute rejection episode up to 150 weeks of treatment.

Further secondary endpoints will evaluate differences in adverse events, such as genital candida infections, lower urinary tract infections, ketoacidosis, and Fournier's gangrene over the first 72 and 150 weeks of treatment. Differences in selected clinical chemistry markers (hemoglobin, hematocrit, sodium, potassium, magnesium, and uric acid) will be assessed before, at 72, and at 150 weeks of treatment. Additionally, changes in inflammation-score and fibrosis-score in protocol biopsies, changes in kidney graft mRNA and protein expression patterns, the 10-year extended eGFR slope, incidence of graft loss, and incidence and time to cardiovascular events will be evaluated.