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

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Cardiovascular Diseases; End Stage Renal Disease
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin

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 Type: Interventional
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapagliflozin, Oral Tablet,10mg, od, 24 months.	Drug: Dapagliflozin; SGTL2 Inhibitor
Placebo Comparator: Placebo; Placebo, Oral Tablet, od, 24 months.	Drug: Placebo; Placebo

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability will be assessed from overall adverse events, serious adverse events, adverse events of special interest	The assessment will include an evaluation of the incidence of adjudicated hyperkalemia, diabetic ketoacidosis, thromboembolic event, genital infections, bone fractures,amputation, liver injury etc.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

Collaborators and Investigators

• Sponsor: Tan Tock Seng Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2021
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): June 1, 2026

Study Registration Dates

• First Submitted: February 18, 2021
• First Submitted That Met QC Criteria: February 19, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): October 21, 2021
• Last Update Submitted That Met QC Criteria: October 13, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Dapagliflozin; Renal Disease; Cardiovascular Outcomes; SGLT2 Inhibitor
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Cardiovascular Diseases; Kidney Diseases; Kidney Failure, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: TTSH-DECODED

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No