Dapagliflozin Effect on Cardiovascular Outcomes in Haemodialysis for End Stage Renal Disease

Study Overview
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Brief Summary
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This study aims to study SGLT2 inhibitors in patients who are undergoing haemodialysis for end stage renal disease and established ASCVD, to examine the safety and clinical outcomes, consisting of a composite of non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death as the primary outcome. The key secondary composite outcome was all cause death or hospitalization for unstable angina.

Detailed Description
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Cardiovascular disease accounts for more than 50% of end-stage renal disease (ESRD) deaths. The reported cardiovascular death rates in patients receiving dialysis are substantially higher than in the general population. Cardiovascular mortality in ESRD is particularly high after acute myocardial infarction, but it is also elevated in ESRD patients with other forms of atherosclerotic vascular disease (eg, chronic coronary artery disease, strokes, transient ischemic attacks, and peripheral arterial disease). Left ventricular hypertrophy and dilation are associated with increased cardiovascular mortality, as is congestive heart failure. One of the major reasons for such high cardiovascular mortality in ESRD is the large burden of cardiovascular disease present in patients with chronic artery disease before renal replacement therapy. SGLT2 inhibitors have demonstrated benefits in reduction of major adverse cardiac events and heart failure hospitalisation in phase 3 randomised controlled trials. In addition, several recent clinical publications have also indicated renal benefits in patients with chronic renal impairment (eGFR >30ml/min). The primary SGLT2 inhibition predominantly occurs at the proximal tubules of kidneys. The mechanistic benefits postulated (other than serum glucose lowering) included SGL2i mediated naturesis and glucosuria. Independent of this class's effects at the renal level, SGL2i possibly affect cardiac metabolism (in animal studies), with reverse adverse cardiac remodelling by switching myocardial substrate utilization from glucose toward oxidation of fatty acids, ketone bodies and branch-chained amino acids. Such improvement in cardiac metabolism may attenuate myocardial ischemia, improve cardiac haemodynamics and reduce overall cardiac mortality, either independent of or synergistic with SGLT2 inhibition at the kidney level. Currently, there is a gap in knowledge and paucity of safety, efficacy and clinical outcomes data for the use of SGLT2 inhibitors in patients who are undergoing haemodialysis for end stage renal disease and established ASCVD. This study aims to study SGLT2 inhibitors in this population and examine the safety and clinical outcomes, consisting of a composite of non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death as the primary outcome. The key secondary composite outcome was all cause death or hospitalization for unstable angina.

Official Title
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A Multi-centre, Randomised, Double-blind, Placebo-controlled Trial to Determine the Effect of Dapagliflozin 10mg Once Daily on Cardiovascular Outcomes in Haemodialysis for Patients With End Stage Renal Disease (ESRD)

Conditions
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Cardiovascular Diseases, End Stage Renal Disease

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Female or male aged ≥ 21 years. Undergoing haemodialysis for end stage renal disease regardless of cause and previous cardiac events. Exclusion Criteria: Diagnosis of Type 1 diabetes mellitus. Pregnant or planning pregnancy or breast-feeding patients. Any clinical condition that would jeopardize patient safety while participating in this clinical trial. Intake of an investigational drug or participating in another clinical trial involving an investigational drug. Life limiting disease other than ESRD with life expectancy estimated to be less than 12 month.

Ages Eligible for Study
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Minimum Age: 21 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: Randomised (1:1) to either Dapaglifozin 10mg or placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin, Oral Tablet,10mg, od, 24 months. | Drug: Dapagliflozin<br>* SGTL2 Inhibitor<br>|
| Placebo Comparator: Placebo<br>Placebo, Oral Tablet, od, 24 months. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects included in the composite endpoint of cardiovascular death, myocardial infarction or ischemic stroke (time to first or recurrent event). | Data will be derived from 3 monthly telephone follow-up and 6monthly physical site visits and events are documented in eCRF | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects included in the composite endpoint of all-cause death or hospitalization for unstable angina (time to first or recurrent event). | Data will be derived from 3 monthly telephone follow-up and 6monthly physical site visits and events are documented in eCRF | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Outcomes, Renal Disease, Dapagliflozin, SGLT2 Inhibitor