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

Phase 2

Withdrawn

• Conditions: Cardiovascular Diseases; End Stage Renal Disease
• Interventions: Drug: Dapagliflozin; Drug: Placebo

• Registration Number: NCT04764097
• Lead Sponsor: Tan Tock Seng Hospital

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-02-18
• Study First Submitted QC: 2021-02-19
• Study First Posted: 2021-02-21
• Study Start: 2021-06
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-13
• Last Update Posted: 2021-10-21
• Primary Completion: 2025-06
• Study Completion: 2026-06

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin	Dapagliflozin	Dapagliflozin, Oral Tablet,10mg, od, 24 months.
Placebo	Placebo	Placebo, Oral Tablet, od, 24 months.

Primary Outcome Measures

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

Secondary Outcome Measures

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