DAPARHT: DAPAgliflozin for Renal protection in Heart Transplant recipients

Kidney failure is common in heart transplant recipients and is a major cause of
morbidity and mortality. Sodium glucose transporter 2 (SGLT2) inhibitors were
developed as antidiabetics but were subsequently shown to reduce the incidence
of adverse cardiovascular outcomes and protect renal function in non-diabetics
as well as diabetics. However, SGLT2 inhibitors have not been tested in
clinical trials in heart transplant recipients.

The DAPARHT trial is designed to assess effect of the SGLT2 inhibitor
dapagliflozin to prevent deteriorating renal function in heart transplant
recipients. Secondary objectives are to assess the impact of treatment on: i)
weight, ii) glucose homeostasis, and iii) proteinuria, iv) the number of
rejections, and (v) safety and tolerability. As exploratory outcomes, we will
assess the effect of treatment on renal outcomes, clinical events (death,
myocardial infarction, cerebral stroke, cancer, and end-stage renal disease),
cardiac function, quality of life, and new-onset diabetes.

This is a phase 3, double-blind, randomised, placebo-controlled trial.
Participants will be randomised in a 1:1 fashion to receive 10 mg of oral
dapagliflozin or a matching placebo once daily for one year. The study is
designed to show superiority regarding the primary endpoint in patients
assigned to active treatment versus patients allocated to the placebo arm. In
the open-label phase, patients who were originally assigned to active treatment
will receive open-label dapagliflozin, whereas patients originally assigned to
placebo will not receive study-specific treatment.

Study Period
Estimated date of first patient enrolled (study start) January 1st, 2022
Anticipated recruitment period: January 1st, 2022 - June 30th, 2023
Estimated date of last patient completed blinded treatment phase: June 30th,
2024
Estimated date of last patient completed open-label treatment phase: June 30th,
2026
Estimated date of last patient completed (last patient, last visit: Study end):
July 31st, 2026
Treatment Duration: 12 months blinded treatment + 24 months open label
Follow-up: 37 months

After the participant has provided informed consent, he or she will be
randomised to receive oral dapagliflozin or a matching placebo. The
randomisation process will be performed online via the commercially available
electronic case report form (eCRF) system called Viedoc®. The investigational
drug, dapagliflozin 10 mg/placebo is taken orally, once daily, for the duration
of the blinded treatment phase (12 months). There will be no dose titration. At
the end of the blinded treatment phase, the efficacy measurements will be
performed, stored, and locked, and all adverse events will be recorded before
the study drug allocation is revealed in the eCRF. Patients allocated to
dapagliflozin will be invited to continue treatment throughout the open-label
phase (24 months); whereas patients allocated to placebo will enter the
open-label phase without treatment beyond the standard of care. Both groups
will be followed-up for safety and efficacy as specified in the study procedure
overview.

The investigational medicinal products will be administered once daily for one
year. No other study-specific intervention will be provided. Beyond the first
year, the patients are invited to enter the open-label follow-up phase, where
the code for the individual patient is opened, and patients who were originally
allocated to dapagliflozin will be encouraged to continue treatment; whereas
patients assigned to placebo will continue standard-of-care treatment.

The patients will self-administer the investigational drug.

There are several studies on diabetes, chronic kidney disease and chronic heart
failure using the study medication without major risks being reported. In
addition, urinary tract infections, genital infections and ketoacidosis
(diabetic patients only) are increased have been reported, but the figures are
low and not a major clinical issue for not using it.