GLUcose Transport and REnalPROtection in Chronic Kidney Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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In the run-in phase, clinical parameters will be optimized by the use of metformin/repaglinide and or RAAS-I on the basis of the presence/absence of a diagnosis of diabetes. Subsequently, patients will be randomly assigned to start with standard therapy and placebo or dapagliflozin at the dose of 10 mg and will continue the assigned treatment for 24 weeks in double-blind and with dapagliflozin at the dose of 10 mg for an additional 48 weeks in open-label/Extended treatment. Urine samples will be collected at T0, T1, T2, T3 and T4 and used as a source of PTECs in order to study the expression of mediators of senescence, fibrosis and inflammation in the kidney. 24-hour ambulatory blood pressure monitoring, Bio-impedancemetry will be evaluated at T0, and T2 and the assessment of tubular oxygen consumption by MRI with BOLD method will be performed at baseline (T0) and after 12 weeks of treatment (T1). This timeline seems to be more appropriate for investigating chances in functional parameters such as blood pressure behaviour, distribution of body water and tubular oxigen consumption. Based on health claims data published in scientific journals, the treatment extension with Dapaglifozin will be proposed to patients of both arms of the Study at the end of 24 Weeks of treatment (T2) for additional 48 Weeks (T3, T4).

Official Title
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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

Conditions
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Chronic Kidney Disease, Diabetes Mellitus, Type 2, Hypertension

Intervention / Treatment
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* Drug: Dapagliflozin 10mg Tab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Allocation to treatment group will be done by stratified randomization for diabetics and non-diabetics. The randomization list will be generated with a designed computer program.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Type 2 Diabetes Dapagliflozin 10 mg<br>Patients with Type 2 Diabetes allocated to Dapagliflozin 10 mg | Drug: Dapagliflozin 10mg Tab<br>* Dapagliflozin will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide<br>|
| Placebo Comparator: Type 2 Diabetes Placebo<br>Patients with Type 2 Diabetes allocated to Placebo | Drug: Placebo<br>* Placebo will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide<br>|
| Active Comparator: Without Diabetes Dapagliflozin 10 mg<br>Patients without Type 2 Diabetes allocated to Dapagliflozin 10 mg | Drug: Dapagliflozin 10mg Tab<br>* Dapagliflozin will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide<br>|
| Placebo Comparator: Without Diabetes Placebo<br>Patients without Type 2 Diabetes allocated to Placebo | Drug: Placebo<br>* Placebo will be add on RAAS-i titrated with the aim to reach optimal blood pressure control as defined by European Society of Hypertension (i.e., 120-130/70-80 mmHg) in all subject. Prior to randomization all the patient with Type 2 Diabetes must have undergone at least 4 weeks of therapy with metformin and/or repaglinide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary proximal tubule cells changes in protein expression of inflammatory genes such as p16ink4a, TLR-4, phospho-p65, DKK3, Myostatin, TGFβ, SMAD 2,3 and MAPK pathways. |  | baseline and every 3 months up to 18 month | 
| Urinary proximal tubule cells changes in genes such as type IV collagen fibronectin, TGF-β, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A |  | baseline and every 3 months up to 18 month | 
| Biopsy changes in the expression and location of senescence markers by immunohistochemistry | In the first six patients with T2DM, proteinuria > 1 g/day and biopsy proven diabetic kidney disese allocated to the treatment with dapagliflozin, we will investigate the following changes in expression and location of p16inkA, SA-beta-galactosidase, TNF receptor 1, EMF cadherin NF-kB. | Baseline and after 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in BOLD MRI | Changes in global and segmental renal oxygenation estimated by BOLD MRI (changes in R2* value defined as 1/T2*) at 12 and 24 weeks | Baseline and after 3 month | 
| Urinary markers of interstitial fibrosis | Changes in urinary markers of a proxy of interstitial fibrosis in patients with CKD (Mir 20) | Baseline and every 3 months up to 18 month | 
| Changes in urinary albumin excretion | Changes in urinary albumin excretion | Baseline and every 3 months up to 18 month | 
| Changes in eGFR | decrease of eGFR ml/min > 30% | Baseline and every 3 months up to 18 month | 
| Outcomes of blood presssure control | changes in blood pressure values and in the need of antihypertensive drugs | Baseline and every 6 months up to 18 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gliflozine, senescence, BOLD MRI, Blood pressure variability