GLUcose Transport and REnalPROtection in Chronic Kidney Disease

NCT05998837 | Completed Phase 2

• 1 other identifier: D169AL00005
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Chronic Kidney Disease; Diabetes Mellitus, Type 2; Hypertension

Keywords

gliflozine; senescence; BOLD MRI; Blood pressure variability

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (5)

• Changes in BOLD MRI

  Baseline and after 3 month

• Urinary markers of interstitial fibrosis

  Baseline and every 3 months up to 18 month

• Changes in urinary albumin excretion

  Baseline and every 3 months up to 18 month

• Changes in eGFR

  Baseline and every 3 months up to 18 month

• Outcomes of blood presssure control

  Baseline and every 6 months up to 18 month

Study Arms (4)

Type 2 Diabetes Dapagliflozin 10 mg

ACTIVE COMPARATOR

Patients with Type 2 Diabetes allocated to Dapagliflozin 10 mg

Drug: Dapagliflozin 10mg Tab

Type 2 Diabetes Placebo

PLACEBO COMPARATOR

Patients with Type 2 Diabetes allocated to Placebo

Drug: Placebo

Without Diabetes Dapagliflozin 10 mg

ACTIVE COMPARATOR

Patients without Type 2 Diabetes allocated to Dapagliflozin 10 mg

Drug: Dapagliflozin 10mg Tab

Without Diabetes Placebo

PLACEBO COMPARATOR

Patients without Type 2 Diabetes allocated to Placebo

Drug: Placebo

Interventions

Dapagliflozin 10mg Tab DRUG

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

Type 2 Diabetes Dapagliflozin 10 mg; Without Diabetes Dapagliflozin 10 mg

Placebo DRUG

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

Type 2 Diabetes Placebo; Without Diabetes Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.)

Sponsors & Collaborators

• IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy: lead
• AstraZeneca: collaborator

Study Sites (1)

IRCCS Ospedale Policlinico San Martino

Genova, GE, 16132, Italy

Location

Related Publications (1)

• Russo E, Cappadona F, Maccio L, Di Vincenzo J, Piaggio M, Verzola D, Chirco G, Garibotto G, Esposito P, Viazzi F. Dapagliflozin Reduces Ambulatory Arterial Stiffness Index in CKD Patients with and Without Diabetes Independently of Blood Pressure Control: Results from the GLUcose Transport and Renal PROtection in Chronic Kidney Disease (GLUTREPRO) Trial. High Blood Press Cardiovasc Prev. 2025 Dec 9. doi: 10.1007/s40292-025-00764-3. Online ahead of print.

  PMID: 41366613 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Diabetes Mellitus, Type 2; Hypertension

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: April 16, 2023
• First Posted: August 21, 2023
• Study Start: April 13, 2021
• Primary Completion: September 30, 2024
• Study Completion: September 30, 2024
• Last Updated: March 28, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)