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 magnetic resonance imaging (MRI) sub-study 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.
Description
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 (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 1750-2000 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:
Cardiac MRI sub-study The cardiac MRI sub-study will evaluate the effect of dapagliflozin on cardiac remodelling, as compared to placebo, measured with indexed left ventricular mass (LVMi), an intermediate cardiovascular outcome, in 250 participants across all three groups of the Renal Lifecycle Trial (i.e. advanced CKD, dialysis, kidney transplant recipients). This will provide robust evidence on the mechanisms under-pinning the cardioprotective effects of SGLT2 inhibitors in this high-risk patient population.
Primary outcome: Difference in LVMi after 12 months dapagliflozin compared to placebo.
Secondary outcomes: Differences between intervention groups in the following parameters at 12 months post-randomization: non-indexed LVM; indexed left atrial
Who can participate
Inclusion Criteria:
* Patients with advanced CKD i.e. an eGFR ≤25 mL/min/1.73m2
* Dialysis patients (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
* patients treated for a renal indication during the last 6 months with a course of systemic immunosuppressive agents or intensification of treatment with systemic immunosuppressive agents, such as patients with a kidney transplant and acute rejection or patients with GPA (Morbus 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.
* Pregnancy or breastfeeding
* Presence of other transplanted organ besides a kidney transplant
* Severe lactose intolerance
* Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with tolvaptan
БГ