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

Sponsor

University Medical Center Groningen (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05374291

Collaborator

AstraZeneca (Industry)

1,500

Enrollment

Locations

Arms

Anticipated Duration (Months)

46.9

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Kidney Disease, Chronic Renal Transplant Failure Heart Failure Kidney Failure Death	Drug: Dapagliflozin 10 mg/day (oral) Drug: Placebo	Phase 3

Detailed 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 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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.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.

Masking:

Double (Participant, Investigator)

Masking Description:

double blinded

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2026

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin Dapagliflozin 10 mg/day (oral)	Drug: Dapagliflozin 10 mg/day (oral) Patients take 10 mg dapagliflozin or matching placebo once daily in the morning Other Names: Forxiga
Placebo Comparator: Placebo Placebo 10 mg/day (oral)	Drug: Placebo Patients take 10 mg dapagliflozin or matching placebo once daily in the morning

Arm

Intervention/Treatment

Experimental: Dapagliflozin

Dapagliflozin 10 mg/day (oral)

Drug: Dapagliflozin 10 mg/day (oral)

Patients take 10 mg dapagliflozin or matching placebo once daily in the morning

Other Names:

Forxiga

Placebo Comparator: Placebo

Placebo 10 mg/day (oral)

Drug: Placebo

Patients take 10 mg dapagliflozin or matching placebo once daily in the morning

Outcome Measures

Primary Outcome Measures

Number of partipants with all-cause mortality, kidney failure, and hospitalization for heart failure [Total study duration intended to last 48 months]
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

Secondary Outcome Measures

Number of participants to reach all-cause mortality [Total study duration intended to last 48 months]
To determine if dapagliflozin is superior to placebo in reducing the incidence of all-cause mortality
Incidence of hospitalization for heart failure [Total study duration intended to last 48 months]
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) [Total study duration intended to last 48 months]
To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure
incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups [Total study duration intended to last 48 months]
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

Other Outcome Measures

measuring Quality of life with the EQ-5D questionnaire [Total study duration intended to last 48 months]
To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based on the EQ-5D questionnaire
measuring Quality of life with the SF12 questionnaire [Total study duration intended to last 48 months]
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 [Total study duration intended to last 48 months]
cost-effectiveness of SGLT2-inhibition in the overall study population as well as in the three subpopulations
incidence of de-novo type 2 diabetes in patients without diabetes [Total study duration intended to last 48 months]
To determine whether dapagliflozin is superior to placebo in reducing the incidence of de-novo type 2 diabetes
Change in the eGFR slope [Total study duration intended to last 48 months]
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
incidence of diuresis <200 ml/24hr in the dialysis subgroup [Total study duration intended to last 48 months]
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 [Total study duration intended to last 48 months]
To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure with and without type 2 diabetes separately

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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≤30 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

Contacts and Locations

Locations

	Site	City	State	Country
1	Amphia Ziekenhuis	Breda	Noord-brabant	Netherlands
2	Amsterdam UMC	Amsterdam	Noord-Holland	Netherlands
3	Albert Schweitzer ziekenhuis	Dordrecht	Zuid-Holland	Netherlands
4	Noordwest Ziekenhuisgroep Alkmaar	Alkmaar		Netherlands
5	Meander Medisch Centrum	Amersfoort		Netherlands
6	Niercentrum aan de Amstel	Amstelveen		Netherlands
7	Dialysecentrum Dianet (Amsterdam)	Amsterdam		Netherlands
8	Gelre Ziekenhuizen	Apeldoorn		Netherlands
9	Reinier de Graaf Ziekenhuis	Delft		Netherlands
10	Jeroen Bosch Ziekenhuis	Den Bosch		Netherlands
11	Deventer Ziekenhuis	Deventer		Netherlands
12	Catharina Ziekenhuis Eindhoven	Eindhoven		Netherlands
13	Maxima Medisch Centrum	Eindhoven		Netherlands
14	Martini Ziekenhuis	Groningen		Netherlands
15	UMCG	Groningen		Netherlands
16	Dialysecentrum Tergooi	Hilversum		Netherlands
17	Spaarne Gasthuis	Hoofddorp		Netherlands
18	Elyse klinieken voor nierzorg	Kerkrade		Netherlands
19	Medisch Centrum Leeuwarden	Leeuwarden		Netherlands
20	Leiden UMC	Leiden		Netherlands
21	St. Jansdal ziekenhuis	Lelystad		Netherlands
22	Maastricht UMC+	Maastricht		Netherlands
23	St. Antonius Ziekenhuis	Nieuwegein		Netherlands
24	Radboud UMC	Nijmegen		Netherlands
25	Bravis ziekenhuis	Roosendaal		Netherlands
26	Franciscus Gasthuis en Vlietland	Rotterdam		Netherlands
27	Bernhoven	Uden		Netherlands
28	Diakonessenhuis Utrecht	Utrecht		Netherlands
29	Dialysecentrum Dianet (Utrecht)	Utrecht		Netherlands
30	UMC Utrecht	Utrecht		Netherlands
31	VieCuri Medisch Centrum	Venlo		Netherlands
32	Isala Ziekenhuis	Zwolle		Netherlands