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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05374291




Registration number
NCT05374291
Ethics application status
Date submitted
22/04/2022
Date registered
16/05/2022
Date last updated
3/06/2024

Titles & IDs
Public title
The RENAL LIFECYCLE Trial: A RCT to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe CKD
Scientific title
A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe Chronic Kidney Disease
Secondary ID [1] 0 0
2021-005446-15
Secondary ID [2] 0 0
202100617
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Kidney Disease, Chronic 0 0
Renal Transplant Failure 0 0
Heart Failure 0 0
Kidney Failure 0 0
Death 0 0
Condition category
Condition code
Renal and Urogenital 0 0 0 0
Kidney disease
Renal and Urogenital 0 0 0 0
Other renal and urogenital disorders
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dapagliflozin 10 mg/day (oral)
Treatment: Drugs - Placebo

Experimental: Dapagliflozin - Dapagliflozin 10 mg/day (oral)

Placebo comparator: Placebo - Placebo 10 mg/day (oral)


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

Treatment: Drugs: Placebo
Patients take 10 mg dapagliflozin or matching placebo once daily in the morning
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of partipants with all-cause mortality, kidney failure, and hospitalization for heart failure
Timepoint [1] 0 0
Total study duration intended to last 48 months
Secondary outcome [1] 0 0
Number of participants to reach all-cause mortality
Timepoint [1] 0 0
Total study duration intended to last 48 months
Secondary outcome [2] 0 0
Incidence of hospitalization for heart failure
Timepoint [2] 0 0
Total study duration intended to last 48 months
Secondary outcome [3] 0 0
Incidence of kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)
Timepoint [3] 0 0
Total study duration intended to last 48 months
Secondary outcome [4] 0 0
incidence of the composite outcome (kidney failure, hospitalization for heart failure, and all-cause mortality) in subgroups
Timepoint [4] 0 0
Total study duration intended to last 48 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/11/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/01/2027
Actual
Sample size
Target
1500
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Australian Capital TeritoryNSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Canberra Health Services - Canberra
Recruitment hospital [2] 0 0
Concord Repatriation General Hospital - Sydney
Recruitment hospital [3] 0 0
Liverpool Hospital - Sydney
Recruitment hospital [4] 0 0
Prince of Wales Hospital - Sydney
Recruitment hospital [5] 0 0
Royal North Shore Hospital - Sydney
Recruitment hospital [6] 0 0
Royal Prince Alfred Hospital - Sydney
Recruitment hospital [7] 0 0
St George Hospital - Sydney
Recruitment hospital [8] 0 0
Westmead Hospital - Sydney
Recruitment hospital [9] 0 0
Wollongong Hospital - Wollongong
Recruitment hospital [10] 0 0
Sunshine Coast Hospital and Health Services - Birtinya
Recruitment hospital [11] 0 0
Royal Brisbane and Womens Hospital - Brisbane
Recruitment hospital [12] 0 0
Townsville University hospital - Douglas
Recruitment hospital [13] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [14] 0 0
Western Health - Melbourne
Recruitment hospital [15] 0 0
Royal Melbourne Hospital - Parkville
Recruitment hospital [16] 0 0
East Metro Health Services (Royal Perth Hospital and Armadale Health Services) - Perth
Recruitment hospital [17] 0 0
Box Hill Hospital (Eastern Health) - Melbourne
Recruitment postcode(s) [1] 0 0
- Canberra
Recruitment postcode(s) [2] 0 0
- Sydney
Recruitment postcode(s) [3] 0 0
- Wollongong
Recruitment postcode(s) [4] 0 0
- Birtinya
Recruitment postcode(s) [5] 0 0
- Brisbane
Recruitment postcode(s) [6] 0 0
- Douglas
Recruitment postcode(s) [7] 0 0
- Adelaide
Recruitment postcode(s) [8] 0 0
- Melbourne
Recruitment postcode(s) [9] 0 0
- Parkville
Recruitment postcode(s) [10] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Berlin
Country [2] 0 0
Germany
State/province [2] 0 0
Düsseldorf
Country [3] 0 0
Germany
State/province [3] 0 0
Erlangen
Country [4] 0 0
Germany
State/province [4] 0 0
Halle
Country [5] 0 0
Germany
State/province [5] 0 0
Hannover
Country [6] 0 0
Germany
State/province [6] 0 0
Heidelberg
Country [7] 0 0
Germany
State/province [7] 0 0
Heilbronn
Country [8] 0 0
Germany
State/province [8] 0 0
Jena
Country [9] 0 0
Germany
State/province [9] 0 0
Mainz
Country [10] 0 0
Germany
State/province [10] 0 0
Regensburg
Country [11] 0 0
Germany
State/province [11] 0 0
Tübingen
Country [12] 0 0
Germany
State/province [12] 0 0
Ulm
Country [13] 0 0
Germany
State/province [13] 0 0
Villingen-Schwenningen
Country [14] 0 0
Germany
State/province [14] 0 0
Wiesbaden
Country [15] 0 0
Germany
State/province [15] 0 0
Würzburg
Country [16] 0 0
Netherlands
State/province [16] 0 0
Noord-brabant
Country [17] 0 0
Netherlands
State/province [17] 0 0
Noord-Holland
Country [18] 0 0
Netherlands
State/province [18] 0 0
Zuid-Holland
Country [19] 0 0
Netherlands
State/province [19] 0 0
Alkmaar
Country [20] 0 0
Netherlands
State/province [20] 0 0
Amersfoort
Country [21] 0 0
Netherlands
State/province [21] 0 0
Amstelveen
Country [22] 0 0
Netherlands
State/province [22] 0 0
Amsterdam
Country [23] 0 0
Netherlands
State/province [23] 0 0
Apeldoorn
Country [24] 0 0
Netherlands
State/province [24] 0 0
Delft
Country [25] 0 0
Netherlands
State/province [25] 0 0
Den Bosch
Country [26] 0 0
Netherlands
State/province [26] 0 0
Deventer
Country [27] 0 0
Netherlands
State/province [27] 0 0
Eindhoven
Country [28] 0 0
Netherlands
State/province [28] 0 0
Groningen
Country [29] 0 0
Netherlands
State/province [29] 0 0
Hilversum
Country [30] 0 0
Netherlands
State/province [30] 0 0
Hoofddorp
Country [31] 0 0
Netherlands
State/province [31] 0 0
Kerkrade
Country [32] 0 0
Netherlands
State/province [32] 0 0
Leeuwarden
Country [33] 0 0
Netherlands
State/province [33] 0 0
Leiden
Country [34] 0 0
Netherlands
State/province [34] 0 0
Lelystad
Country [35] 0 0
Netherlands
State/province [35] 0 0
Maastricht
Country [36] 0 0
Netherlands
State/province [36] 0 0
Nieuwegein
Country [37] 0 0
Netherlands
State/province [37] 0 0
Nijmegen
Country [38] 0 0
Netherlands
State/province [38] 0 0
Roosendaal
Country [39] 0 0
Netherlands
State/province [39] 0 0
Rotterdam
Country [40] 0 0
Netherlands
State/province [40] 0 0
Uden
Country [41] 0 0
Netherlands
State/province [41] 0 0
Utrecht
Country [42] 0 0
Netherlands
State/province [42] 0 0
Venlo
Country [43] 0 0
Netherlands
State/province [43] 0 0
Zwolle

Funding & Sponsors
Primary sponsor type
Other
Name
University Medical Center Groningen
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
AstraZeneca
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Dutch Kidney Foundation
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.

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.
Trial website
https://clinicaltrials.gov/study/NCT05374291
Trial related presentations / publications
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.
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. doi: 10.1016/S2213-8587(22)00223-6.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Ron Gansevoort
Address 0 0
University Medical Center Groningen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05374291