PREVENTion With Sglt-2 Inhibition of Acute Kidney Injury in Intensive Care (PREVENTS-AKI)

Background Acute Kidney Injury (AKI) is a potentially life-threatening condition caused by unsafe levels of fluid and waste products accumulating in the body. Often, patients with AKI need treatment with an artificial kidney (called renal replacement therapy or dialysis) to do the work of their kidneys and remove these dangerous levels of fluid and waste from the body. If left untreated, AKI can become a chronic (long-term) condition that may require treatment for life.

Dapagliflozin is a medication used to treat patients with diabetes, heart disease and long-term (chronic) kidney disease. Recently, Dapagliflozin has been shown to slow the progression of other kidney related complications, however this has not yet been studied in critically ill patients.

Aim To determine if giving Dapagliflozin (one tablet a day) compared to placebo (a tablet that looks identical but has no active ingredients), decreases injury to the kidneys in patients admitted to the Intensive Care Unit.

Design This study will enrol 3000 patients from 45-50 hospitals worldwide. It is a 'randomised controlled trial' meaning patients will be randomly assigned (like tossing a coin) by a computer to receive either Dapagliflozin or placebo for a maximum of 30 days whilst in the ICU. The study is also a 'double blinded trial' meaning that neither the doctor, the intensive care staff or the patient will know which study treatment they are receiving.

Study Overview

• Status: Recruiting
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Drug: Dapagliflozin 10mg Tab; Drug: Placebo

Detailed Description

Acute kidney injury (AKI) is an increasingly common complication of hospitalisation globally, and a major driver of poor patient outcomes, including higher mortality and reduced quality of life. While numerous studies, including several led by investigators in this grant team, have tested treatments to reduce the impact of AKI, none have been shown to improve outcomes. The absence of any proven therapy highlights a critical unmet need.

A novel class of medicines, inhibitors of the sodium-glucose co-transporter II (SGLT-2 inhibitors), have been shown in recent years to have dramatic effects upon cardiovascular and renal outcomes in patients with heart failure at high risk for renal failure. The evidence suggests that these drugs might prevent AKI from occurring, but this has not been intentionally tested in adequately powered trials. A recently published randomised controlled trial evaluated the use of these drugs in acutely unwell COVID-19 patients and did not raise any safety concern in this acute setting. The trial also showed a numerically lower rate of AKI in those that received the SGLT-2 inhibitor dapagliflozin compared to placebo, but the trial was not sufficiently powered for this outcome.

The PREVENTion with Sglt2 inhibition of Acute Kidney Injury in intensive care (PREVENTS-AKI) trial, will test the effect of dapagliflozin versus placebo upon patients' risk of developing severe AKI in a population admitted to intensive care. This global trial will test the most promising treatment for mitigating the increased risk of AKI. The results will provide the first definitive insight into the prevention of AKI with these agents and will shape global clinical practice in an area where treatments are profoundly lacking.

• Study Type: Interventional
• Enrollment (Estimated): 3000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sarah Coggan, BSc, MPH; Phone Number: 02 9993 4566; Email: scoggan@georgeinstitute.org.au
• Study Contact Backup: Name: Sharon Micallef, BN; Email: smicallef@georgeinstitute.org.au

Study Locations

• Australia
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • Not yet recruiting
      • Grampians Health
      • Contact: Khaled El-Khawas, Dr
      • Principal Investigator: Khaled El-Khawas
    • Heidelberg, Victoria, Australia, 3084
      • Recruiting
      • Austin Health
      • Contact: Rinaldo Bellomo, Prof
      • Principal Investigator: Rinaldo Bellomo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 years or more
• Admitted to ICU within the last 7 days
• Expected to be in the ICU the day after tomorrow
• An arterial or central venous catheter is in situ, or placement is planned for routine management
• Able to receive study treatment orally or via enteral route

• At least one of the following risk factors for AKI:

  • Required fluid resuscitation, defined as a bolus of fluid prescribed to be given over ≤1 hour to increase or maintain intravascular volume that is in addition to maintenance fluids
  • Being treated with continuous vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial blood pressure > 60mmHg or a MAP target set by the treating clinician for maintaining perfusion

• At least one of the following pre-morbid risk factors:

  • Treatment for high blood pressure
  • Treatment for type 2 diabetes (minimum diet therapy)
  • Atherosclerotic cardiovascular disease
  • History of heart failure
  • Impaired renal function, defined as an eGFR between 20 - 60 mL/min/1.73m2
  • Estimated BMI 30 kg/m2 or more
  • Age 60 years or more

Exclusion Criteria:

• Met all inclusion criteria more than 24 hours ago
• History of type 1 diabetes mellitus or diabetic ketoacidosis
• COVID-19 infection as the reason for ICU admission
• Requiring renal replacement therapy for intoxication
• eGFR less than 20 mL/min/1.73m2
• Known hypersensitivity to any SGLT-2 inhibitor e.g. dapagliflozin, canagliflozin, empagliflozin, ertugliflozin
• Solid organ transplantation within the last 12 months
• Likely to be transferred to another hospital in the next 3 days
• Known or suspected pregnancy
• Death is deemed imminent or inevitable
• Life expectancy is estimated to be less than 90 days
• Patient or the treating clinician declines to participate
• Enrolled in another interventional trial for which co-enrolment is not approved
• Patient has previously been enrolled in the PREVENTS-AKI Study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapaliflozin 10mg tablet administered once daily while in ICU for up to 30 days	Drug: Dapagliflozin 10mg Tab; Patients will be randomly assigned to receive either dapagliflozin 10 mg or placebo daily while in ICU for up to 30 days; Other Names: SGLT2 inhibitor
Placebo Comparator: Matched Placebo; Matched placebo tablet administered once daily while in ICU for up to 30 days	Drug: Placebo; Patients will be randomly assigned to receive either dapagliflozin 10 mg or placebo daily while in ICU for up to 30 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite outcome: Doubling of serum creatinine from baseline, initiation of renal replacement therapy or death	Proportion of patients experiencing a component of the composite outcome, defined as a doubling of serum creatinine from the study baseline value, initiation of RRT or death	Within 30 days of randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Doubling of Serum Creatinine	Proportion of patients with a doubling of serum creatinine from baseline value	Within 30 days of randomisation
Requirement of Renal Replacement Therapy (RRT)	Proportion of patients requiring RRT	Within 30 days of randomisation
All-cause mortality	Proportion of patients who have died from any cause	Within 30 days of randomisation
Vasoactive drug therapy	Proportion of patients who were treated with vasoactive drugs	Within 30 days of randomisation
Mechanical ventilation	Proportion of patients who required mechanical ventilation	Within 30 days of randomisation
Ventricular tachycardia or ventricular fibrillation	Proportion of patients who experienced ventricular tachycardia or ventricular fibrillation lasting at least 30 seconds whilst in intensive care	Within 30 days of randomisation

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: University Medical Center Groningen; Australian and New Zealand Intensive Care Society Clinical Trials Group
• Investigators: Study Director: Martin P Gallagher, MBBS, FRACP, The George Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2023
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: ICU; Kidney failure; Critical Care; Critically ill; Sodium Glucose cotransporter-2 inhibitors
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Wounds and Injuries; Acute Kidney Injury; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: GI-RM-7738

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No