Single-center, Randomized, Controlled Study to Evaluate the Effects of a Six-month Treatment With Renal Glucose Transport Inhibitor (SGLT2i) Drugs on Markers of Senescence, Inflammation and Tubulointerstitial Damage in the Kidney of Patients With Chronic Kidney Disease With or Without Type 2 Diabetes

D169AL00005

This is a single-center, double blind, randomized, parallel-arms study designed to investigate the effects of a six-month treatment with the SGLT2i dapagliflozin on markers of kidney senescence, inflammation and tubulointerstitial damage compared to placebo. These mechanisms of renal damage will be investigated in proximal tubular epithelial cells (PTECs) isolated from urine from patients with CKD with or without T2DM and in renal biopsy specimens in a subgroup of patients with diabetic kidney disease.

2021-04-13

2024-09-30

2024-09-30

Recruiting

Early phase I

34

Inclusion Criteria: * Albuminuria defined as urinary albumin:creatinine ratio ≥ 25 mg/g (or protein:creatinine ratio ≥ 30 mg/g) or albuminuria \> 30 mg/24h * eGFR \> 25 and \< 75 ml/minute 1.73m2 * BMI between 19 kg/m2 and 30 kg/m2 * Treatment with an ACE inhibitor and/or ARB at the maximum tolerated (for the individual subject) dose. The maximum tolerated dose for an individual subject may be less than the maximum labeled dose or may be zero if the medical reason is documented. * Mean systolic and diastolic blood pressure (determined as the average of three replicates) must be \< 180/90mmHg * Pre-menopausal women of child-bearing potential 1 must have a negative pregnancy test performed before the inclusion in the study V e r s i o n 6 . 0 - P a g . 10 \| 32 * Willingness to participate in the study (signed informed consent) IN PARTICIPANTS WITH Type 2 Diabetes * Clinical diagnosis of T2DM for at least 1 year * Hemoglobin A1c (HbA1c) value of \< 9.5% * Patients treated only with metformin and/or repaglinide * A diagnosis of Diabetic Nephropathy at renal biopsy made not more than 6 months before the screening visit (only for the subgroup of patients candidated to the second kidney biopsy) * Proteinuria \> 1g/24h (only for the subgroup of patients candidated to the second kidney biopsy) * Hemoglobin A1c (HbA1c) value of \> 6.5% (only for patients candidated to the second kidney biopsy) In PARTICIPANTS Without Type 2 Diabetes * diagnosis of hypertension for at least 5 years Exclusion Criteria: * Type 1 Diabetes * Hemoglobin A1c (HbA1c) value of \> 9.5% during the Screening period (based on central laboratory measurement). * The need for an adjunctive drugs on top on metformin and repaglinide * Hemoglobin A1c (HbA1c) value of \< 6.5% only for patients candidated to the second kidney biopsy * Estimated glomerular filtration rate \< 25 or \> 75 ml/min/1.73m2 (according to the CKD-EPI) at screening * Untreated urinary or genital infection at screening and follow-up * Clear signs of volume depletion * Symptomatic hypotension, or systolic blood pressure \< 90 or non-controlled hypertension * History of alcohol or drug abuse, anuria, dialysis, or acute kidney injury/acute renal failure in the 3 months prior to Screening Period * Heart, liver or kidney transplant V e r s i o n 6 . 0 - P a g . 11 \| 32 * Acute coronary syndrome, stroke, or transient ischemic attack within 3 months prior to informed consent * Liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening * Planned cardiac surgery or angioplasty within 3 months * Cancer or medical history of cancer (except for basal cell carcinoma) within the last 5 years * Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.) * SGLT2i treatment in the 10 weeks before the Screening Period * Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent * Any uncontrolled endocrine disorder except T2DM * Women who are pregnant or breastfeeding * Pre-menopausal women of child bearing potential who are not willing to employ effective contraception according to 2007 CTFG Recommendations related to contraception and pregnancy testing in clinical trials from screening for all the duration of the study * Patients with a known hypersensitivity to Dapagliflozin or other SGLT2- inhibitors, including hypersensitivity to excipients (e.g. lactose) * History of pancreatitis, or pancreatic surgery, diabetic ketoacidosis * Prior lower extremity amputation or current threat of amputation (eg, lower extremity ulcer and peripheral artery disease) * History of severe hypoglycaemia and hypoglycaemia unawareness. * Contraindication to MRI

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2', 'PHASE3'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Allocation to treatment group will be done by stratified randomization for diabetics and non-diabetics.\n\nThe randomization list will be generated with a designed computer program.', 'primaryPurpose': 'PREVENTION', 'maskingInfo': {'masking': 'DOUBLE', 'maskingDescription': 'Once eligibility is verified, the Investigator will randomize the subject contacting by e-mail the Secretarial Office of the Nephrologic Clinic of the Ospedale Policlinico San Martino The assigned randomization number will communicated via e-mail and recorded by the Investigator in the CRF. Therefore both investigators and participants will be blind', 'whoMasked': ['PARTICIPANT', 'INVESTIGATOR']}}, 'enrollmentInfo': {'count': 34, 'type': 'ESTIMATED'}}

2023-12-01