Evaluation of Dapagliflozin on Endothelial Function in Patients with Chronic Kidney Disease: A Randomized, Placebo-Controlled Clinical Trial
- Trial ID
- 2024-514887-14-00
- Protocol
- 2021/0188/HP
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that a 12-week treatment with **dapagliflozin** improves endothelium-dependent flow-mediated dilatation of peripheral conduit arteries during a short-term increase in blood flow in patients with chronic kidney disease. This is clinically relevant as it may indicate potential cardiovascular benefits in this patient population, who are at increased risk for vascular complications.
Secondary objectives include:
- Demonstrating that 12-week treatment with dapagliflozin improves endothelium-dependent flow-mediated dilatation of peripheral conduit arteries during sustained increase in blood flow.
- Improving the bioavailability of endothelial vasodilating factors.
- Reducing oxidative stress and inflammation.
- Improving arterial stiffness and cardiovascular coupling.
- Enhancing cardiac function in chronic kidney disease patients.
Participants
The clinical trial involves **chronic kidney disease** patients, with an age range of 18 years and older. Both male and female participants are included in the study, and the trial population is considered vulnerable. The sponsor has not provided the total number of participants. Participants were selected based on specific criteria, including having an estimated glomerular filtration rate (eGFR) between 25 and 60 mL/min/1.73m², and receiving a stable dose of an ACE inhibitor or ARB for at least 12 weeks prior to screening, or being documented as unable to take these medications. Lifestyle considerations such as effective contraception for women of childbearing potential are required, and participants must be able to comply with the study protocol. The trial aims to assess the effects of a 12-week treatment with dapagliflozin on endothelium-dependent flow-mediated dilatation of peripheral conduit arteries in this patient population.
Plans and Procedures
The clinical trial is designed to evaluate the impact of **dapagliflozin** on vascular function in patients with **chronic kidney disease**. This study is a randomized, double-blind, placebo-controlled trial, conducted over a period of 12 weeks. The primary objective is to assess the change in brachial artery flow-mediated dilatation in response to reactive hyperemia after treatment with dapagliflozin or placebo. Secondary endpoints include changes in radial artery flow-mediated dilatation, plasma levels of nitric oxide, pro-oxidant and pro-inflammatory lipid mediators, carotid artery elastic modulus, and cardiac output parameters.
Participants will be involved in the study for a total duration of 12 weeks, with the trial estimated to conclude by March 2025. The study will commence with an inclusion visit, where eligibility criteria such as age, kidney function, and medication history will be assessed. Participants must have an estimated glomerular filtration rate (eGFR) between 25 and 60 mL/min/1.73m² and be on a stable dose of an ACE inhibitor or ARB, or be documented as unable to take these medications. Women of childbearing potential must adhere to effective contraception guidelines.
Following the inclusion visit, participants will be randomized to receive either dapagliflozin or a placebo, administered orally. Study visits will occur at regular intervals to monitor the participants' health status, adherence to the study protocol, and to collect data on the primary and secondary endpoints. The end-of-study visit will involve a comprehensive assessment to evaluate the outcomes of the treatment. Participants may be withdrawn from the study if they are unable to comply with the protocol, experience adverse effects, or if the investigator deems it necessary for their safety.
Treatment
The clinical trial involves the administration of **DAPAGLIFLOZIN**, an antidiabetic medication, in the form of film-coated tablets. Each tablet contains the active substance **dapagliflozin**, which is chemically derived. The pharmaceutical form is specified as a film-coated tablet, and the route of administration is oral. The dosage regimen for this trial is a maximum daily dose of 10 mg, with a total maximum dose of 900 mg over the course of the study. The treatment period is set for 90 days. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.
In addition to the experimental treatment, the study includes a placebo group. The placebo consists of film-coated tablets that contain the same excipients as FORXIGA® 10 mg tablets, but without the active ingredient dapagliflozin. The placebo is administered orally, mirroring the administration route of the experimental medication. The placebo serves as a comparator to evaluate the efficacy of dapagliflozin in improving vascular function in patients with chronic kidney disease. The placebo tablets are designed to be indistinguishable from the active medication to maintain the integrity of the double-blind study design.
Efficacy
Efficacy in the clinical trial titled "Impact of dapagliflozin on vascular function in chronic kidney disease patients - (DAPA-VASC)" will be assessed through both primary and secondary endpoints. The primary endpoint is the change in the magnitude of brachial artery flow-mediated dilatation in response to reactive hyperemia after a 12-week treatment with **dapagliflozin** or placebo. This measurement will evaluate the improvement in endothelium-dependent flow-mediated dilatation of peripheral conduit arteries.
Secondary endpoints include several parameters: the change in the magnitude of radial artery flow-mediated dilatation in response to hand skin heating, the change in plasma release of nitric oxide and epoxyeicosatrienoic acids induced by hand skin heating, and the change in plasma levels of pro-oxidant and pro-inflammatory lipid mediators after the 12-week treatment. Additionally, changes in carotid artery elastic modulus, carotid-to-femoral pulse wave velocity, aortic augmentation index, cardiac output, stroke volume, ejection fraction, and left ventricular end-systolic elastance will also be assessed. These endpoints will provide a comprehensive evaluation of the vascular and cardiac effects of dapagliflozin in patients with chronic kidney disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Chronic kidney disease (eGFR ≥ 25 and ≤ 60 mL/min/1.73m² by CKD-EPI)
- Age ≥ 18 years
- Receiving a stable dose of an ACE inhibitor or ARB for at least 12 weeks before screening or patients who were documented to be unable to take angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
- Patient having read and understood the information letter and signed the Informed Consent Form
- For women: a. Women of childbearing potential : i. Effective contraception according to CTFG contraception recommendations (V1.1 21/09/2020) since at least 4 weeks before randomization and during treatment, and; ii. Negative blood pregnancy test; b. Women surgically sterile (absence of ovaries and/or uterus); c. Postmenopausal women (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit). Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Barrier methods must always be supplemented with the use of a spermicide.
- Patient able to comply with the study protocol, in the investigator's judgment
- Patient affiliated with, or beneficiary of a social security (health insurance) category.
Exclusion Criteria
- Type 1 and type 2 diabetes (fasting glycemia ≥ 126 mg/dL or use of oral hypoglycemic agents or insulin)
- Patients whose conditions lead to reduced food absorption or severe dehydration
- Patients with reduced insulin levels
- Patients with increased insulin requirements due to an acute medical condition, surgery or excessive alcohol consumption
- Recessive or autosomal dominant polycystic kidney disease
- Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
- Lupus nephritis
- Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment
- History of organ transplantation
- Body weight > 35 kg/m²
- Receiving therapy with a sodium glucose co-transporter 2 (SGLT2) inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor
- Receiving phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil or other) or riociguat (due to the risk of hypotension potentiation with GTN spray).
- Patients with NYHA class IV congestive heart failure at the time of enrolment
- Myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment
- Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment or is planned to undergo any of these procedures after randomization
- Active malignancy requiring treatment at the time of enrolment or is planned to undergo any treatment after randomization
- Severe hepatic impairment (Child-Pugh class C)
- History of pancreatitis
- History of frequent genital mycotic infections (> 2 during the last 12 months)
- Current pregnancy OR women who are breast-feeding
- Contraindications to NATISPRAY® 0.30mg/dose, solution for oral spray : - Hypersensitivity to nitrates or to any of the excipients, - State of shock, severe hypotension, - In combination with sildenafil, taladafil, vardenafil, avanafil and riociguat - Obstructive cardiomyopathy, - Inferior site myocardial infarction with extension to the right ventricle, acute phase, except when there is a sign of left ventricular failure, - Intracranial hypertension
- Contra-indication to FORXIGA 10 mg film-coated tablets: hypersensitivity to dapagliflozin or to any of the excipients
- Participation in another clinical study with an investigational product during the last 4 weeks prior to enrolment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 18 Oct 2022 | 54 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Film-coated tablets containing the same excipients than FORXIGA® 10 mg excipientsbut not dapagliflozin | Placebo | N/A | — | — | — | N/A |
DAPAGLIFLOZIN | Test | — | ORAL USE | 10 | 90 | SUB31650 |