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    Summary
    EudraCT Number:2021-005446-15
    Sponsor's Protocol Code Number:202100617
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-03-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-005446-15
    A.3Full title of the trial
    A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients with Severe Chronic Kidney Disease
    Een placebo gecontroleerde studie om het effect van dapagliflozine op nier- en hartfalen te onderzoeken bij nierpatiënten
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients with Severe Chronic Kidney Disease
    Een placebo gecontroleerde studie om het effect van dapagliflozine op nier- en hartfalen te onderzoeken bij nierpatiënten
    A.3.2Name or abbreviated title of the trial where available
    The RENAL LIFECYCLE trial
    De RENAL LIFECYCLE studie
    A.4.1Sponsor's protocol code number202100617
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05374291
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportDutch Kidney Foundation
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointProf. Dr. R.T. Gansevoort
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9700 RB
    B.5.3.4CountryNetherlands
    B.5.6E-mailr.t.gansevoort@umcg.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Forxiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDapagliflozin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population
    E.1.1.1Medical condition in easily understood language
    Combined endpoint of all-cause mortality, kidney failure, and hospitalization for heart failure in the overall study population
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether dapagliflozin is superior to placebo in reducing the incidence of the primary composite endpoint of all-cause mortality, kidney failure, hospitalization for heart failure, and all-cause mortality in patients with eGFR ≤25 mL/min/1.73m2, dialysis patients with residual diuresis ≥ 500 mL/24hr , and kidney transplant recipients with eGFR ≤45 mL/min/1.73m2.
    Het beschermende effect op hart- en nierfalen en de veiligheid van dapagliflozine op lange termijn onderzoeken bij patiënten met ernstige chronische nierschade, inclusief dialyse en niertransplantatie patiënten.
    E.2.2Secondary objectives of the trial
    1. To determine if dapagliflozin is superior to placebo in reducing the incidence of:
    • All-cause mortality
    • Kidney failure (chronic dialysis, kidney transplantation or mortality due to kidney failure)1
    • Hospitalization for heart failure

    2. To determine whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome of all-cause mortality, kidney failure, or heart failure hospitalization in
    • Patients with advanced CKD i.e. an eGFR ≤25 mL/min/1.73m2
    • Dialysis patients with residual diuresis ≥500 mL/24h
    • Transplant patients with an eGFR ≤45 mL/min/1.73m2
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Cardiac sub study: There are two cardiac sub-studies proposed. The Renal Lifecycle Trial 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 Renal Lifecycle Trial 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.
    E.3Principal inclusion criteria
    In order to be eligible to participate in the randomized controlled double blind trial subject must meet the criteria for one of the three strata:
    • 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.
    E.4Principal 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
    • Patients treated during the last 6 months with a course of immunosuppresive agents or intensification of treatment with immunosupressive agents, such as patients with a kidney transplant and acute rejection or patients with GPA (orbus 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.
    • Current pregnancy, lactation or women of child-bearing potential (WOCBP) unless using highly-effective contraceptive measurements7 until 4 weeks after last intake of the study medication
    • Presence of other transplanted organ besides a kidney transplant
    • Severe lactose intolerance
    Autosomal Dominant Polycystic Kidney Disease (ADPKD) treated with tolvaptan
    E.5 End points
    E.5.1Primary end point(s)
    Main study endpoint: Time to the composite endpoint of all-cause mortality, kidney failure (chronic dialysis, kidney transplantation or death due to kidney failure), and hospitalization for heart failure.

    Potential endpoints will be identified when questioning the patient about his/her overall health and through information received through standard medical practice. Investigators will be encouraged to inquire about events that might represent an endpoint.
    Heart failure hospitalization and death due to kidney failure endpoints will be recorded in the eCRF and submitted for central adjudication. The source documents and relevant eCRF data will be sent for adjudication. Detailed instructions regarding endpoint reporting will be provided to the study sites. Additional details about the evaluation of heart failure hospitalizations and death due to kidney failure will be described in the Clinical Endpoint Adjudication Committee charter.

    Patients will continue double blind study medication after reaching a primary endpoint (except all-cause mortality).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Per protocol in-patient follow-up visits are scheduled after 2 weeks, 3 months, 6 months (after randomization visit) and every 6 months thereafter.
    E.5.2Secondary end point(s)
    Secondary study parameters/endpoints
    • Time to kidney failure (in advanced CKD and transplant patients only)
    • Time to the first occurrence of heart failure hospitalization
    • Time to all-cause death

    Each of these study endpoints will be investigated in the overall study population.

    In addition, it will be investigated whether dapagliflozin is superior to placebo in reducing the incidence of the composite outcome of all-cause mortality, kidney failure, or heart failure hospitalization in each of the three subpopulations.

    Exploratory Endpoints
    • Time to new onset type 2 diabetes in patients without diabetes
    • Time to diuresis <200ml/24h in the dialysis subgroup
    • Rate of change in eGFR over time
    • Quality of life
    • Cost-effectiveness of intervention

    New onset of type 2 diabetes, post randomisation, is defined according to the following criteria:
    • Reporting of new onset of T2D necessitating initiation of anti-diabetic medication OR
    • HbA1c >6.5% (48 mmol/mol) measured by local laboratory at two consecutive study visits

    eGFR will be calculated with the CKD-EPI equation. For the dialysis subgroup eGFR will be calculated using the average of 24hr urinary creatinine and urea clearance values.

    Quality of life will be assessed by the validated EQ-5D questionnaire

    Safety Endpoints
    • Serious adverse events
    • Adverse events leading to drug discontinuation
    • Adverse events of special interest: clinically significant hypoglycemia (as defined as glucose concentration <3.0 mol/L, i.e. 54 mg/dL), diabetic ketoacidosis, urinary tract infections, and genital infections
    E.5.2.1Timepoint(s) of evaluation of this end point
    Per protocol in-patient follow-up visits are scheduled after 2 weeks, 3 months, 6 months (after randomization visit) and every 6 months thereafter.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned50
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Germany
    Netherlands
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    After 48 months, when the estimated 468 events have occurred, an End of Study visit will be scheduled. When patients opt to withdraw early from the study, an EET visit will be scheduled.

    Renal Lifecycle is designed as an endpoint driven trial and will finish when 468 primary study outcomes have occurred. The exact trial duration may be shorter or longer than the intended 48 months.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 500
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1000
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1250
    F.4.2.2In the whole clinical trial 1500
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    We will try to make the study medication available via compassionate use after EoT
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-03-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-30
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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