Chronic Kidney Deseas MedDRA version: 21.1 Level: LLT Classification code 10050441 Term: Chronic renal insufficiency System Organ Class: 100000004857
Conditions
Interventions
Product Name: Dapagliflozin
Product Code: [SGLT2i]
Pharmaceutical Form: Gastro-resistant tablet
INN or Proposed INN: DAPAGLIFLOZIN
CAS Number: 461432-26-8
Current Sponsor code: BMS-512148-05
Concentra
Sponsors
IRCCS-A.O.U. SAN MARTINO-IST
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Adult (age 18-75 years) - Albuminuria defined as urinary albumin ratio: creatinine = 25 mg / g (or protein ratio: creatinine = 30 mg / g) or albuminuria> 30 mg / 24h - eGFR> 25 and 1g / 24h (only for the subgroup of patients candidates for the second renal biopsy) - Hemoglobin A1c (HbA1c) value> 6.5% (only for patients candidates for the second renal biopsy) CKD WITHOUT T2DM diagnosed with hypertension for at least 5 years Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 19 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 19
Exclusion criteria
Exclusion criteria: • Type 1 Diabetes • Hemoglobin A1c (HbA1c) value of > 9.5% during the Screening period (based on central laboratory measurement). • need for an adjunctive drugs on top on metformin and repaglinide • Hemoglobin A1c (HbA1c) value of 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 • 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Evaluate the role of dapagliflozin in confront to placebo on changes in markers of inflammation, on the activation of innate immunity and tubulointerstitial fibrosis in the kidney of patients with CKD.;Secondary Objective: The secondary objective is to describe changes from baseline in albuminuria, eGFR, blood pressure, body volume status, body weight, serum uric acid, lipids, glucose and HbA1c levels, after 6 months of treatment with dapagliflozin or placebo and to define their relationship with the changes in the markers of renal senescence, inflammation and tubulointerstitial damage.;Primary end point(s): 1) In the proximal tubule cells of the whole study population, changes in: a)protein expression of target inflammatory genes (such as p16ink4a, TLR-4, phospho-p65, DKK3, Myostatin, TGFß, SMAD 2,3 and MAPK pathways) and in epithelial-mesenchymal transition (EMT). b)target genes of inflammation, apoptosis, senescence such as type IV collagen fibronectin, TGF-ß, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A responses. 2)In the first six patients with T2DM, proteinuria > 1 g/day and biopsy proven diabetic kidney disese allocated to the treatment with dapagliflozin, changes in the protocol kidney biopsy at the end of the treatment period will be evaluated as follows: a)expression and location of senescence (p16inkA, SA-beta-galactosidase), and apoptosis markers (TNF receptor 1, EMF cadherin NF-kB). b)target inflammatory gene responses (of inflammation, apoptosis, senescence such as type IV collagen fibronectin, TGF-ß, TNF receptor 1, EMF cadherin production, NF-kB, MCP-1 , DKK3, myostatin and Activin A activation) c)expression and location of pro-inflammatory cytokine expression in kidney biopsies (for pro-inflammatory and pro-fibrotic cytokines expression such as MCP-1, DKK3, TLR-4, CCR-2, Myostatin, TGFß and Activin A will be evaluated by immunohistochemistry);Timepoint(s) of evaluation of this end point: | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): a) Changes in global and segmental renal oxygenation estimated by BOLD MRI (changes in R2* value defined as 1/T2*) b) Changes in urinary markers of a proxy of interstitial fibrosis in patients with CKD (Mir 20) c) Changes in urinary albumin excretion, eGFR, serum uric acid, HbA1c, lipid profile and body weight, blood pressure levels measured by ABPM and in the need of antihypertensive drugs;Timepoint(s) of evaluation of this end point: 12 and 24 weeks | — |
Countries
Italy
Contacts
Public ContactCentro Clinical Trials
IRCCS Ospedale Policlinico San Martino
Outcome results
None listed