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    Summary
    EudraCT Number:2022-002428-10
    Sponsor's Protocol Code Number:KTxSGLT2i-22
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-04
    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 ConcernedNorway - NOMA
    A.2EudraCT number2022-002428-10
    A.3Full title of the trial
    CAN DAPAGLIFLOZIN PRESERVE STRUCTURE AND FUNCTION IN TRANSPLANTED KIDNEYS?
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CAN DAPAGLIFLOZIN PRESERVE STRUCTURE AND FUNCTION IN TRANSPLANTED KIDNEYS?
    A.3.2Name or abbreviated title of the trial where available
    KTxSGLT2i-22
    A.4.1Sponsor's protocol code numberKTxSGLT2i-22
    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 SponsorOslo Univeristy Hospital - Rikshospitalet
    B.1.3.4CountryNorway
    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.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOslo Univeristy Hospital - Rikshospitalet
    B.5.2Functional name of contact pointCharlotte Kongerud
    B.5.3 Address:
    B.5.3.1Street AddressSognsvannsveien 20
    B.5.3.2Town/ cityOslo
    B.5.3.3Post code0372
    B.5.3.4CountryNorway
    B.5.4Telephone number+4741451132
    B.5.5Fax number+4723073865
    B.5.6E-mailingkon@ous-hf.no
    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 (dapagliflozin)
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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
    Kidney transplanted patients. Looking at the effect of SGLT2 inhibitor on graft survival by repeated eGFR measurements, measured GFR, kidney graft biopsies to evaluate inflammation, fibrosis and vascular pathology. As secondary endpoints, we will look at the effect of visceral fat accumulation and blood pressure.
    E.1.1.1Medical condition in easily understood language
    Kidney transplanted patients. Looking at the effect of SGLT2 inhibitor on kidney graft survival and preserved function of the kidney.
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10023438
    E.1.2Term Kidney transplant
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The overall objective of this study is to find a new way of prolonging kidney graft survival. We are looking at the effect of SGLT2i in three different ways: Can SGLT2i; 1) Preserve renal function (GFR) in kidney transplants over time? 2) Reduce interstitial fibrosis and protect cortical microvasculature in the kidney and 3) Improve metabolic risk factors for graft failure such as visceral obesity, glucose intolerance and high blood pressure?

    Primary objective: to show that the yearly loss of renal function measured by estimating GFR from blood sampling over time(eGFR slope) is reduced with the SGLT2 inhibitor dapagliflozin versus placebo.
    E.2.2Secondary objectives of the trial
    Secondary objectives: to show that
    (1) Treatment with the SGLT2 inhibitor dapagliflozin may reduce the degree of inflammation, fibrosis and vasculopathy in renal kidney grafts, and change footprints of degenerative pathways visualized by mRNA sequencing and proteomics analyses in the biopsies.
    (2) Treatment with dapagliflozin will may reduce overweight and abdominal fat mass, together with improved glucose tolerance, blood pressure and urinary protein excretion in kidney transplant recipients.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Changes in renal graft fibrosis and protomic markers with SGLT2 inhibition in renal transplant recipients (Sub-study): First 140 kidney transplanted patients included from the main study will be assessed in an explorative analysis, looking at level of inflammation, fibrosis and vascular pathology as an effects of dapagliflozin on kidney grafts. Twentyfive from each group will get their biopsis visualized by protomic and mRNA analysis.

    Related objective: Treatment with the SGLT2 inhibitor dapagliflozin may reduce the degree of inflammation, fibrosis and vasculopathy in renal kidney grafts, and change footprints of degenerative pathways visualized by mRNA sequencing and proteomics analyses in the biopsies.
    E.3Principal inclusion criteria
    • Renal transplant recipients transplanted < 8 weeks earlier at OUH Rikshospitalet.
    • Age 18-75 years.
    • Able to comply with the medical treatment on their own.
    • Calcineurin inhibitor trough concentrations in accordance with individual therapeutic range and standard dose prednisolone and mycophenolate mofetil over the last 2 weeks.
    • Estimated GFR (MDRD4-formula) ≥25 mL/min/1.73 m2.
    E.4Principal exclusion criteria
    • Type 1 diabetes
    • Rejection episodes of the kidney graft prior to randomization.
    • Ongoing infectious disease or intermittent causes affecting renal function,
    e.g. obstructive lymphocele.
    • Malnutrition.
    • Urosepsis less than 1 year prior to randomization.
    • Participants with a known hypersensitivity to dapagliflozin or any of the excipients of the product.
    • For WOCBP (women of childbearing potential) only – currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the difference in eGFR slope between groups from before randomization to 3 years after transplantation. The slope is to be determined by mixed model statistics including MDRD4 formula estimated GFR from at least 4 creatinine measurements per year.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation will be done at 1,5 years and 3 years after inclution.

    Furthermore, following the final study visit after 3 years of blinded treatment, all patients will be offered further treatment with SGLT2-inhibitors, and eGFR slope and cardiovascular events will be followed based on annual data from the Norwegian Renal Registry for up to 10 years after transplantation.
    E.5.2Secondary end point(s)
    Secondary endpoints:
    Main study:
    • Difference between groups in the slope of urinary protein/creatinine ratio over the first 72 and 150 weeks of treatment, respectively, assessed from at least 4 urine samples per year using mixed model statistics.
    • Difference between groups in blood pressure from before to 72 and 150 weeks of treatment
    • Difference between groups in changes of measured GFR (iohexol serum clearance) from 2 weeks to 72 weeks of treatment
    • Difference between groups in changes of DXA-measured percent subcutaneous and visceral fat in relation to total fat mass from 2 weeks to 72 weeks of treatment
    • Difference between groups in glucose tolerance assess by an oral glucose tolerance test before to 72 weeks of treatment
    • Difference between groups in urinary metabolomic profile from before to 72 weeks of treatment (explorative endpoint)
    • Difference between groups in number of patients with at least one biopsy proven acute rejection episode up to 150 weeks of treatment
    • Difference between groups in adverse events such as genital candida infections, lower urinary tract infections, ketoacidosis and Fourniers gangrene over the first 72 and 150 weeks of treatment, respectively
    • Difference between groups in selected clinical chemistry markers (hemoglobin, hematocrit, sodium, potassium, magnesium and uric acid) before, at 72 and at 150 weeks of treatment.

    Substudy – the first 140 included patients:
    • Difference between groups in degree of change in inflammation-score (Immunohistochemistry analysis with regards to amount of collagen and extracellular markers.) in protocol biopsies from before to 72 weeks of treatment
    • Difference between groups in degree of change in fibrosis-score (Semi-quantitative estimation of percent graft fibrosis in the renal cortex) in protocol biopsies from before to 72 weeks of treatment
    Substudy –the first 25 patients in each arm with protocol biopsies of good quality (two full biopsy cores for diagnostic purpose) before and after 72 weeks of treatment:
    • Difference between groups in changes in kidney graft mRNA and protein expression patterns from before to 72 weeks of treatment (explorative endpoint)

    10-year open follow-up extension:
    • Difference between groups in the 10-year extended eGFR slope from annual plasma creatinine values reported to NRR after year 3
    • Difference between groups in incidence of graft loss (assessed from NRR) up to 10 years after transplantation
    • Difference between groups in incidence and time to cardiovascular events (from NRR, first of each type; coronary heart disease, cerebrovascular events, chronic heart failure) as assessed up to 10 years after transplantation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation at 1,5 years after inclution.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    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 concerned26
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years3
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    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 state330
    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)
    standard follow-up
    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 Decision2023-03-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-21
    P. End of Trial
    P.End of Trial StatusOngoing
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