Kidney transplanted patients. Looking at the effect of SGLT2 inhibitor on graft survival by repeated eGFR measurements, measured GFR, kidney graft biopsies to evaluate inflammation, fibrosis and vascular pathology. As secondary endpoints, we will look at the effect of visceral fat accumulation and blood pressure. MedDRA version: 20.0 Level: LLT Classification code 10023438 Term: Kidney transplant System Organ Class: 10042613 - Surgical and medical procedures
Conditions
Interventions
Trade Name: Forxiga (dapagliflozin)
Product Name: dapagliflozin
Pharmaceutical Form: Tablet
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use
Sponsors
Oslo Univeristy Hospital - Rikshospitalet
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Renal transplant recipients transplanted =65 years) yes F.1.3.1 Number of subjects for this age range 80
Exclusion criteria
Exclusion criteria: • Type 1 diabetes • Rejection episodes of the kidney graft prior to randomization. • Ongoing infectious disease or intermittent causes affecting renal function, e.g. obstructive lymphocele. • Malnutrition. • Urosepsis less than 1 year prior to randomization. • Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the product. • For WOCBP (women of childbearing potential) only – currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The overall objective of this study is to find a new way of prolonging kidney graft survival. We are looking at the effect of SGLT2i in three different ways: Can SGLT2i; 1) Preserve renal function (GFR) in kidney transplants over time? 2) Reduce interstitial fibrosis and protect cortical microvasculature in the kidney and 3) Improve metabolic risk factors for graft failure such as visceral obesity, glucose intolerance and high blood pressure? Primary objective: to show that the yearly loss of renal function measured by estimating GFR from blood sampling over time(eGFR slope) is reduced with the SGLT2 inhibitor dapagliflozin versus placebo.;Secondary Objective: Secondary objectives: to show that (1) Treatment with the SGLT2 inhibitor dapagliflozin may reduce the degree of inflammation, fibrosis and vasculopathy in renal kidney grafts, and change footprints of degenerative pathways visualized by mRNA sequencing and proteomics analyses in the biopsies. (2) Treatment with dapagliflozin will may reduce overweight and abdominal fat mass, together with improved glucose tolerance, blood pressure and urinary protein excretion in kidney transplant recipients. ;Primary end point(s): The primary endpoint is the difference in eGFR slope between groups from before randomization to 3 years after transplantation. The slope is to be determined by mixed model statistics including MDRD4 formula estimated GFR from at least 4 creatinine measurements per year.;Timepoint(s) of evaluation of this end point: Evaluation will be done at 1,5 years and 3 years after inclution. Furthermore, following the final study visit after 3 years of blinded treatment, all patients will be offered further treatment with SGLT2-inhibitors, and eGFR slope and cardiovascular events will be followed based on annual data from the Norwegian Renal Registry for up to 10 years after transplantation. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints: Main study: • Difference between groups in the slope of urinary protein/creatinine ratio over the first 72 and 150 weeks of treatment, respectively, assessed from at least 4 urine samples per year using mixed model statistics. • Difference between groups in blood pressure from before to 72 and 150 weeks of treatment • Difference between groups in changes of measured GFR (iohexol serum clearance) from 2 weeks to 72 weeks of treatment • Difference between groups in changes of DXA-measured percent subcutaneous and visceral fat in relation to total fat mass from 2 weeks to 72 weeks of treatment • Difference between groups in glucose tolerance assess by an oral glucose tolerance test before to 72 weeks of treatment • Difference between groups in urinary metabolomic profile from before to 72 weeks of treatment (explorative endpoint) • Difference between groups in number of patients with at least one biopsy proven acute rejection episode up to 150 weeks of treatment • Difference between groups in adverse events such as genital candida infections, lower urinary tract infections, ketoacidosis and Fourniers gangrene over the first 72 and 150 weeks of treatment, respectively • Difference between groups in selected clinical chemistry markers (hemoglobin, hematocrit, sodium, potassium, magnesium and uric acid) before, at 72 and at 150 weeks of treatment. Substudy – the first 140 included patients: • Difference between groups in degree of change in inflammation-score (Immunohistochemistry analysis with regards to amount of collagen and extracellular markers.) in protocol biopsies from before to 72 weeks of treatment • Difference between groups in degree of change in fibrosis-score (Semi-quantitative estimation of percent graft fibrosis in the renal cortex) in protocol biopsies from before to 72 weeks of treatment Substudy –the first 25 patients in each arm with protocol biopsies of good quality (two full biopsy cores for diagnostic p | — |
Countries
Norway
Contacts
Public ContactCharlotte Kongerud
Oslo Univeristy Hospital - Rikshospitalet
Outcome results
None listed