The RENAL LIFECYCLE Trial: A RCT to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe CKD

The RENAL LIFECYCLE Trial: A RCT to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe CKD

A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe Chronic Kidney Disease

Rationale: Sodium glucose co transporter 2 (SGLT2) inhibitors are a relatively new class of agents, originally developed as oral antihyperglycemic drugs. SGLT2 inhibitors are clinically available since 2012 for the treatment of patients with diabetes mellitus type 2. Later, SGLT2 inhibitors appeared to have also specific reno- and cardioprotective effects. Remarkably, the trials that have been performed thus far excluded patients with an eGFR below 25 mL/min/1.73m2 at inclusion, prevalent dialysis patients, and kidney transplant recipients. This is unfortunate, because especially these patients are at high risk of reaching kidney failure requiring dialysis, cardiovascular complications and mortality, whereas there are only few proven effective therapies. There is emerging evidence from experimental studies and post hoc-analyses of randomized clinical trials that SGLT2 inhibitors may also be effective in preventing cardiovascular and mortality outcomes in these patients with severe CKD, including patients receiving dialysis or living with a kidney transplant. For instance, subgroup analysis of the DAPA-CKD trial comparing 624 patients with an eGFR<30 to the remainder of the trial population with better kidney function, demonstrated that the efficacy of the SGLT2 inhibitor dapagliflozin in reducing cardiovascular, heart failure and renal outcomes persisted in the population with impaired kidney function. Furthermore, in the DAPA-CKD trial patients continued to use dapagliflozin or placebo when dialysis was initiated. In the subgroup of patients who initiated dialysis, dapagliflozin was associated with a relative risk reduction for mortality of 21%. Finally, in kidney transplant recipients, SGLT2 inhibitors have been shown to be effective in lowering HbA1c, body weight, blood pressure and stabilize kidney function, and these agents were well tolerated and safe. Taken these findings together there is a sound rationale to study the long-term reno- and cardioprotective efficacy and safety of SGLT2 inhibitors in patients with severe CKD. There are two cardiac sub-studies: the cardiac MRI substudy and the echocardiography sub-study. The echocardiography sub-study is referred to as the "SGLT-2-inhibitors to Target Heart Failure in Peritoneal Dialysis" (STOP HF in PD) study. In STOP HF in PD the effect of dapagliflozin on cardiac function will be assessed in a subset of 100 patients treated with peritoneal dialysis.

Objective: To establish the reno- and cardioprotective efficacy and safety of dapagliflozin in patients with severe CKD Study design: Multicenter, randomized, controlled, double blinded, pragmatic, interventional trial Study population: Patients with advanced CKD, i.e. an eGFR ≤25 mL/min*1.73m2 Patients on dialysis with a residual diuresis >500 mL/24h (at least 3 months after start of dialysis) Patients with a kidney transplant and an eGFR ≤45 mL/min/1.73m2 (at least 6 months after transplantation) Intervention: Dapagliflozin 10 mg/day or matching placebo Primary outcome measure: Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population Study duration: 18 month recruitment phase, 30 month follow-up after enrollment of the last patient: Total study duration intended to last 48 months. It should be noted that the trial is event driven and will be terminated when 468 primary composite outcomes have occurred. The exact trial duration may therefore be shorter or longer than the intended 48 months. Study visits: Screening, baseline, week 2, month 3, month 6 and every 6 months thereafter. Information needed for the trial will be obtained as much as possible from visits taking place as part of routine clinical care. Sample size: Renal Lifecycle is designed as an endpoint driven trial and will finish when 468 primary study outcomes have occurred. The investigators have estimated a sample size of 1500 patients. Novel aspects: A unique patient population with severe chronic kidney disease at very high risk of adverse outcomes for whom very few proven effective therapies exist. The initiation and efficacy of SGLT2 inhibitors, including dapagliflozin, has not been studied before in this population. However, SGLT2 inhibitors have the potential to be very effective and well tolerated which would imply a major advance in the pharmacotherapy of these patients. When patients reach a renal endpoint, e.g. start or chronic dialysis or receiving a kidney transplantation, study medication will not be stopped as customary in many other trials in nephrology, but continued in the new phase of their "renal lifecycle", hence the name of the trial. Sub studies: The cardiac MRI sub-study will evaluate the effect of dapagliflozin, as compared to placebo, on left ventricular mass, an intermediate cardiovascular outcome, in 250 participants with advanced CKD. This will provide robust evidence on the mechanisms under-pinning the cardioprotective effects of SGLT2 inhibitors in this high-risk patient population. The cardiac echocardiography sub-study will evaluate the effect of dapagliflozin, as compared to placebo, on LV-GLS, in 100 participants with ESKD treated with peritoneal dialysis. This will provide additional evidence on the mechanisms underlying the cardio-protective effects of SGLT2i in patients with ESKD. Furthermore, the GLS-data will be related to measured CKD- and PD-associated mediators of heart failure (measured in serum, urine and peritoneal effluent. This will aid to determine their relevance in patients with ESKD, as well as to define if and to what extent SGLT2i affect these mediators in patients with ESKD. Finally, this sub-study allows prospective evaluation of LV-GLS as a predictor of adverse cardiovascular events in patients treated with PD.

advanced CKD, dialysis, kidney transplant, all-cause mortality, kidney failure, hospitalization for heart failure, Dapagliflozin

The RENAL LIFECYCLE trial consists of a screening period and a double blind treatment period with two arms. Participants will be randomly assigned in a 1:1 ratio to double blind treatment with dapagliflozin 10 mg/d or matching placebo. Randomization will be stratified by enrolment stratum (pre-dialysis, dialysis, kidney transplantation), centre and type 2 diabetes mellitus status yes/no) to ensure balanced distribution across the two treatment arms.

To determine whether dapagliflozin is superior to placebo in reducing the incidence of the primary composite endpoint Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population

To determine if dapagliflozin is superior to placebo in reducing the incidence of all-cause mortality

Incidence of hospitalization for heart failureTo determine if dapagliflozin is superior to placebo in reducing the incidence of heart failure

Incidence of kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)

incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups

To determine whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome in subgroups subgroups: advanced CKD i.e. an eGFR ≤30 mL/min/1.73m2, dialysis patients and transplant patients

To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based on the EQ-5D questionnaire

To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based onthe SF12 questionnaire

Cost-effectiveness of SGLT2-inhibition using the Quality of Life-data derived from the EQ-5D and SF-12 questionnaires

cost-effectiveness of SGLT2-inhibition in the overall study population as well as in the three subpopulations

To determine whether dapagliflozin is superior to placebo in reducing the incidence of de-novo type 2 diabetes

To determine whether dapagliflozin is superior to placebo in reducing the eGFR slope eGFR slope; for the dialysis subgroup slope residual kidney function will be calculated using the average of 24hr urinary creatinine and urea clearance values over time

To determine whether dapagliflozin is superior to placebo in the incidence of diuresis <200 ml/24hr in the dialysis subgroup for this purpose 24hr urine samples will be collected ≥2 times per year

incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups with and without type 2 diabetes separately

To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure with and without type 2 diabetes separately

Inclusion Criteria: 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. 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 In kidney transplant patients history of acute rejection during the last 6 months 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. Pregnancy or breastfeeding Presence of other transplanted organ besides a kidney transplant Severe lactose intolerance Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with tolvaptan

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