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

Heart Failure Clinical Trial

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05374291
• Other study ID #: 202100617
• Secondary ID: 2021-005446-1520
• Status: Enrolling by invitation
• Phase: Phase 3
• Start date: November 8, 2022
• Est. completion date: January 2027

Study information

• Verified date: May 2024
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

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 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:

Cardiac 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.

Cognitive sub-study Patients with chronic kidney disease (CKD) are at a much higher risk for developing cognitive impairment compared with the general population and both lower glomerular filtration rate and the presence of albuminuria are associated with its development. SGLT-2 inhibitor use is associated with better preservation of cognitive function in patients with CKD including those on hemodialysis and after kidney transplantation compared to placebo.Patients will be requested to perform the symbol digit modalities test at the same time as the questionnaires, i.e. at baseline (visit 2), visit 5 and visit 6, once every year after visit 6 and at EoT/EET.The primary outcome of the cognition sub study is the change over time in the number of correct answers in the symbol digit modalities test within 90 seconds.

kidney metabolism substudy The primary aim of this substudy is to evaluate the effect of dapagliflozin 10 mg compared to a placebo on energy metabolism assessed by changes in the renal mitochondrial oxidative phosphorylation capacity in kidney transplant recipients participating in the RENAL LIFECYCLE Trial at the 3-month Follow-up Visit. Further aims of this substudy are to evaluate the differences in metabolic substrate preferences by measuring ketone body or acylcarnitine substrate-driven mitochondrial respiration following the randomization to dapagliflozin or placebo.

Differences in mitochondrial architecture including mitochondrial quantity and morphology will be assessed using electron microscopy.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 1500
• Est. completion date: January 2027
• Est. primary completion date: January 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Death
• Heart Failure
• Kidney Disease, Chronic
• Kidney Diseases
• Kidney Failure
• Renal Insufficiency
• Renal Insufficiency, Chronic
• Renal Transplant Failure

Intervention

Drug:
• Dapagliflozin 10 mg/day (oral)
Patients take 10 mg dapagliflozin or matching placebo once daily in the morning
• Placebo
Patients take 10 mg dapagliflozin or matching placebo once daily in the morning

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Sunshine Coast Hospital and Health Services	Birtinya	Queensland
Australia	Royal Brisbane and Womens Hospital	Brisbane	Queensland
Australia	Canberra Health Services	Canberra	Australian Capital Teritory
Australia	Townsville University hospital	Douglas	Queensland
Australia	Box Hill Hospital (Eastern Health)	Melbourne
Australia	Western Health	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	East Metro Health Services (Royal Perth Hospital and Armadale Health Services)	Perth	Western Australia
Australia	Concord Repatriation General Hospital	Sydney	New South Wales
Australia	Liverpool Hospital	Sydney	New South Wales
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	Royal North Shore Hospital	Sydney	New South Wales
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales
Australia	St George Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Sydney	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Germany	Charité	Berlin
Germany	Praxis für Dialyse und Nierenkrankheiten	Berlin
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsklinikum Halle (Saale) Innere Medizin 2	Halle
Germany	Zentrum fuer Nieren-, Hochdruck- und Stoffwechselerkrankungen Hannover	Hannover
Germany	Nierenzentrum Heidelberg	Heidelberg
Germany	Dialysezentrum Heilbronn - Überörtliche Berufsausübungsgemeinschaft für Nephro und Dialyse (ÜBAG)	Heilbronn
Germany	Universitätsklinikum JenaKlinik für Innere Medizin III	Jena
Germany	Universitätsmedizin Mainz	Mainz
Germany	Universitätsklinikum RegensburgAbteilung für Nephrologie	Regensburg
Germany	Universitätsklinikum Tübingen Medizinische Klinik IV	Tübingen
Germany	Universitätsklinikum Ulm, Klinik für Innere Medizin I, Nephrologie	Ulm
Germany	Nephrologisches Zentrum Villingen/Schwenningen	Villingen-Schwenningen
Germany	Nierenzentrum Wiesbaden	Wiesbaden
Germany	Medizinische Klinik und Poliklinik I der Universitätsklinik WürzburgSchwerpunkt Nephrologie	Würzburg
Netherlands	Noordwest Ziekenhuisgroep Alkmaar	Alkmaar
Netherlands	Meander Medisch Centrum	Amersfoort
Netherlands	Niercentrum aan de Amstel	Amstelveen
Netherlands	Amsterdam UMC	Amsterdam	Noord-Holland
Netherlands	Dialysecentrum Dianet (Amsterdam)	Amsterdam
Netherlands	Gelre Ziekenhuizen	Apeldoorn
Netherlands	Amphia Ziekenhuis	Breda	Noord-brabant
Netherlands	Reinier de Graaf Ziekenhuis	Delft
Netherlands	Jeroen Bosch Ziekenhuis	Den Bosch
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Albert Schweitzer ziekenhuis	Dordrecht	Zuid-Holland
Netherlands	Catharina Ziekenhuis Eindhoven	Eindhoven
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	UMCG	Groningen
Netherlands	Dialysecentrum Tergooi	Hilversum
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	Elyse klinieken voor nierzorg	Kerkrade
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden
Netherlands	Leiden UMC	Leiden
Netherlands	St. Jansdal ziekenhuis	Lelystad
Netherlands	Maastricht UMC+	Maastricht
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Netherlands	Radboud UMC	Nijmegen
Netherlands	Bravis ziekenhuis	Roosendaal
Netherlands	Franciscus Gasthuis en Vlietland	Rotterdam
Netherlands	Bernhoven	Uden
Netherlands	Diakonessenhuis Utrecht	Utrecht
Netherlands	Dialysecentrum Dianet (Utrecht)	Utrecht
Netherlands	UMC Utrecht	Utrecht
Netherlands	VieCuri Medisch Centrum	Venlo
Netherlands	Isala Ziekenhuis	Zwolle

Sponsors (3)

Lead Sponsor	Collaborator
University Medical Center Groningen	AstraZeneca, Dutch Kidney Foundation

Countries where clinical trial is conducted

Australia,  Germany,  Netherlands, 

References & Publications (4)

Chertow GM, Vart P, Jongs N, Toto RD, Gorriz JL, Hou FF, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Langkilde AM, Wheeler DC, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease. J Am Soc Nephrol. 2021 Sep;32(9):2352-2361. doi: 10.1681/ASN.2021020167. Epub 2021 Jul 16. — View Citation

Chewcharat A, Prasitlumkum N, Thongprayoon C, Bathini T, Medaura J, Vallabhajosyula S, Cheungpasitporn W. Efficacy and Safety of SGLT-2 Inhibitors for Treatment of Diabetes Mellitus among Kidney Transplant Patients: A Systematic Review and Meta-Analysis. Med Sci (Basel). 2020 Nov 17;8(4):47. doi: 10.3390/medsci8040047. — View Citation

Heerspink HJL, Jongs N, Chertow GM, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjostrom CD, Stefansson BV, Toto RD, Wheeler DC, Greene T; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):743-754. doi: 10.1016/S2213-8587(21)00242-4. Epub 2021 Oct 4. Erratum In: Lancet Diabetes Endocrinol. 2022 Oct;10(10):e10. — View Citation

Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	measuring Quality of life with the EQ-5D questionnaire	To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based on the EQ-5D questionnaire	Total study duration intended to last 48 months
Other	measuring Quality of life with the SF12 questionnaire	To determine whether dapagliflozin is superior to placebo in comparing the Quality of Life for all subgroups based onthe SF12 questionnaire	Total study duration intended to last 48 months
Other	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	Total study duration intended to last 48 months
Other	incidence of de-novo type 2 diabetes in patients without diabetes	To determine whether dapagliflozin is superior to placebo in reducing the incidence of de-novo type 2 diabetes	Total study duration intended to last 48 months
Other	Change in the eGFR slope	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	Total study duration intended to last 48 months
Other	incidence of diuresis <200 ml/24hr in the dialysis subgroup	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	Total study duration intended to last 48 months
Other	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	Total study duration intended to last 48 months
Primary	Number of partipants with all-cause mortality, kidney failure, and hospitalization for heart failure	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	Total study duration intended to last 48 months
Secondary	Number of participants to reach all-cause mortality	To determine if dapagliflozin is superior to placebo in reducing the incidence of all-cause mortality	Total study duration intended to last 48 months
Secondary	Incidence of hospitalization for heart failure	Incidence of hospitalization for heart failureTo determine if dapagliflozin is superior to placebo in reducing the incidence of heart failure	Total study duration intended to last 48 months
Secondary	Incidence of kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)	To determine if dapagliflozin is superior to placebo in reducing the incidence of kidney failure	Total study duration intended to last 48 months
Secondary	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	Total study duration intended to last 48 months