Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population
Conditions
Sponsors
University Medical Center Groningen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: In order to be eligible to participate in the randomized controlled double blind trial subject must meet the criteria for one of the three strata: • Patients with advanced CKD i.e. an eGFR =25 mL/min/1.73m2 • Dialysis patients with a residual diuresis=500 mL/24h (at least 3 months after start of dialysis) • Transplant patients with an eGFR =45 mL/min/1.73m2 (at least 6 months after transplantation) In addition, to be eligible all subjects must meet all criteria below • Age >18 years • Willing to sign informed consent • Pre-dialysis patients with eGFR =25 mL/min/1.73m2 have to be on a stable dose (no changes in dose or type of drug) of ACEis or ARBs for at least 4 weeks prior to the screening visit to be eligible to proceed to the randomization visit unless there is documented evidence that the patient does not tolerate an ACEi or ARB. These subjects will maintain their stable doses of ACEis or ARBs throughout the trial (when possible and tolerated by the patient). ACEi or ARBs are not required for patients on maintenance dialysis or kidney transplant recipients. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 1000 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 500
Exclusion criteria
Exclusion criteria: • Mentally incapacitated subjects (i.e. not able to sign informed consent) • Diagnosis of type 1 diabetes mellitus • Concurrent treatment with SGLT2 inhibitor • History of =2 urinary tract / genital infections during the last six months • Life expectancy <6 months in the opinion of the treating physician. • Scheduled start of dialysis within 3 months or kidney transplantation within 6 months • In patients with an eGFR =25 mL/min/1.73m2: kidney disease treated with immunosuppressive agents during the last 6 months • Patients treated during the last 6 months with a course of immunosuppresive agents or intensification of treatment with immunosupressive agents, such as patients with a kidney transplant and acute rejection or patients with GPA (orbus Wegener) and a recent flare. • Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin. • History of severe hypersensitivity or known severe hepatic impairment (Child-Pugh class C) • History of severe noncompliance to medical regimens or unwillingness to comply with the study protocol. • Current pregnancy, lactation or women of child-bearing potential (WOCBP) unless using highly-effective contraceptive measurements7 until 4 weeks after last intake of the study medication • Presence of other transplanted organ besides a kidney transplant • Severe lactose intolerance Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with tolvaptan
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine whether dapagliflozin is superior to placebo in reducing the incidence of the primary composite endpoint of all-cause mortality, kidney failure, hospitalization for heart failure, and all-cause mortality in patients with eGFR =25 mL/min/1.73m2, dialysis patients with residual diuresis = 500 mL/24hr , and kidney transplant recipients with eGFR =45 mL/min/1.73m2.;Secondary Objective: 1.To determine if dapagliflozin is superior to placebo in reducing the incidence of: •All-cause mortality •Kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)1 •Hospitalization for heart failure 2.To determine whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome of all-cause mortality, kidney failure, or heart failure hospitalization in •Patients with advanced CKD i.e. an eGFR =25 mL/min/1.73m2 •Dialysis patients with residual diuresis =500 mL/24h •Transplant patients with an eGFR =45 mL/min/1.73m2;Primary end point(s): Main study endpoint: Time to the composite endpoint of all-cause mortality, kidney failure (chronic dialysis, kidney transplantation or death due to kidney failure), and hospitalization for heart failure. Potential endpoints will be identified when questioning the patient about his/her overall health and through information received through standard medical practice. Investigators will be encouraged to inquire about events that might represent an endpoint. Heart failure hospitalization and death due to kidney failure endpoints will be recorded in the eCRF and submitted for central adjudication. The source documents and relevant eCRF data will be sent for adjudication. Detailed instructions regarding endpoint reporting will be provided to the study sites. Additional details about the evaluation of heart failure hospitalizations and death due to kidney failure will be described in the Clinical Endpoint Adjudication Committee charter. Patients will continue d | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary study parameters/endpoints • Time to kidney failure (in advanced CKD and transplant patients only) • Time to the first occurrence of heart failure hospitalization • Time to all-cause death Each of these study endpoints will be investigated in the overall study population. In addition, it will be investigated whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome of all-cause mortality, kidney failure, or heart failure hospitalization in each of the three subpopulations. Exploratory Endpoints • Time to new onset type 2 diabetes in patients without diabetes • Time to diuresis 6.5% (48 mmol/mol) measured by local laboratory at two consecutive study visits eGFR will be calculated with the CKD-EPI equation. For the dialysis subgroup eGFR will be calculated using the average of 24hr urinary creatinine and urea clearance values. Quality of life will be assessed by the validated EQ-5D questionnaire Safety Endpoints • Serious adverse events • Adverse events leading to drug discontinuation • Adverse events of special interest: clinically significant hypoglycemia (as defined as glucose concentration <3.0 mol/L, i.e. 54 mg/dL), diabetic ketoacidosis, urinary tract infections, and genital infections;Timepoint(s) of evaluation of this end point: Per protocol in-patient follow-up visits are scheduled after 2 weeks, 3 months, 6 months (after randomization visit) and every 6 months thereafter. | — |
Countries
Australia, Belgium, Germany, Netherlands
Contacts
Public ContactProf. Dr. R.T. Gansevoort
University Medical Center Groningen
Outcome results
None listed