Deferoxamine for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury (DEFEAT-AKI)

Multiple lines of evidence support a central role of iron in causing acute kidney injury (AKI), including the finding that prophylactic administration of iron chelators attenuates AKI in animal models. Patients undergoing cardiac surgery may be particularly susceptible to iron-mediated kidney injury due to the profound hemolysis that often occurs from cardiopulmonary bypass. The investigators will test in a phase 2, randomized, double-blind, placebo-controlled trial whether prophylactic administration of deferoxamine decreases the incidence of AKI following cardiac surgery.

Study Overview

• Status: Recruiting
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Drug: Deferoxamine; Drug: Normal saline

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David E. Leaf, MD, MMSc; Phone Number: 9144190622; Email: deleaf@bwh.harvard.edu
• Study Contact Backup: Name: Shahzad Shaefi, MD, MPH; Phone Number: 6178203570; Email: sshaefi@bidmc.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: David E. Leaf, MD, MMSc; Phone Number: 914-419-0622; Email: deleaf@bwh.harvard.edu
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Aranya Bagchi, MBBS; Email: abagchi@mgh.harvard.edu
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Shahzad Shaefi, MD, MPH; Email: sshaefi@bidmc.harvard.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥18 years
2. Undergoing coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass
3. AKI risk score ≥6 at the time of screening
4. Written informed consent from the patient or surrogate

Exclusion Criteria:

1. AKI, defined as any of the following:

   • Increase in serum creatinine ≥0.3 mg/dl in 48h
   • Increase in serum creatinine ≥50% in 7d (if no value available in last 7d, use most recent value in last 3 months)
   • Urine output ≤0.5 ml/kg/h x 6 consecutive hours (only assessed in patients with hourly monitoring via Foley catheter)
   • Receipt of renal replacement therapy (RRT) within 7d
2. Advanced chronic kidney disease (eGFR <15 ml/min/1.73m2 or end-stage kidney disease receiving RRT)
3. Hemoglobin <8 g/dL (closest value in the prior 3 months)
4. Fever (temperature ≥38⁰C) in the last 48h
5. Suspected or confirmed bacteremia, endocarditis, or pyelonephritis
6. Pneumonia, aspiration, or bilateral pulmonary infiltrates from an infectious etiology reported on chest x-ray or CT scan in the last 7d
7. Positive COVID-19 test within previous 10d
8. Chronic iron overload (including conditions such as hemochromatosis and beta thalassemia major) or previous iron chelation therapy (including prior participation in DEFEAT-AKI)
9. Known hypersensitivity to deferoxamine
10. Taking prochlorperazine
11. Severe hearing loss
12. Pregnant or breastfeeding
13. Prisoner
14. Concurrent participation in another interventional research study in which the intervention has potential interaction with deferoxamine
15. Surgery to be performed under conditions of circulatory arrest
16. Receiving extracorporeal membrane oxygenation
17. Durable ventricular assist device (VAD) prior to surgery (does not include Impella device or intra-aortic balloon pump)
18. Any condition which, in the judgement of the investigator, might increase the risk to the patient
19. Conflict with other research studies

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: Deferoxamine; Deferoxamine 30mg/kg (max dose, 6g) intravenous infusion (diluted in 240mL normal saline) administered over 12 hours	Drug: Deferoxamine; Deferoxamine 30mg/kg (max dose, 6g) intravenous infusion (diluted in 240mL normal saline) administered over 12 hours
Placebo Comparator: Placebo; Normal saline (240mL) intravenous infusion over 12 hours	Drug: Normal saline; Normal saline (240mL) intravenous infusion over 12 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute Kidney Injury	Composite outcome that includes any of the following: Urine output <0.5 ml/kg/h for ≥6 consecutive hours within the first 48h or until the Foley catheter is removed, whichever occurs first; Increase in serum creatinine ≥0.3 mg/dl within the first 48h; Increase in serum creatinine ≥50% within 7 days; Receipt of renal replacement therapy within 7 days	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal tubular injury	Urine levels of NGAL and KIM-1	3 days
Major Adverse Kidney Events	Increase in serum creatinine ≥100%, receipt of renal replacement therapy, or death within 7 days	7 days
Postoperative myocardial injury	Peak postoperative troponin I elevation >10 times the 99th percentile upper reference limit	2 days
Atrial fibrillation or atrial flutter	New onset postoperative atrial fibrillation or atrial flutter (patients with atrial fibrillation or atrial flutter at baseline will be excluded)	7 days
Prolonged mechanical ventilation	Requirement for mechanical ventilation >24h postoperatively	24 hours
Vasoactive-Inotropic Score	Validated method for integrating all IV vasoactive medications and their doses on an hourly basis into a single measure	24 hours
Time to liberation from vasoactive medications	Number of hours from time of incision to liberation from all IV vasoactive medications	7 days
Sepsis	Life-threatening organ dysfunction caused by a dysregulated host response to infection. Organ dysfunction is defined as an acute increase in the total SOFA score ≥2 points consequent to the infection.	7 days
Ventilator-free days	28 minus the number of days ventilated. Patients who die within 28 days will be assigned 0 ventilator-free days.	28 days
ICU-free days	28 minus the number of days in the ICU. Patients who die within 28 days will be assigned 0 ICU-free days.	28 days
Hospital-free days	28 minus the number of days hospitalized. Patients who die within 28 days will be assigned 0 hospital-free days.	28 days

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Massachusetts General Hospital; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: David E. Leaf, MD, MMSc, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Sharma S, Leaf DE. Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention. J Am Soc Nephrol. 2019 Nov;30(11):2060-2071. doi: 10.1681/ASN.2019060595. Epub 2019 Sep 25.

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2021
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: November 12, 2020
• First Submitted That Met QC Criteria: November 12, 2020
• First Posted (Actual): November 18, 2020

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• 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; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Siderophores; Deferoxamine
• Other Study ID Numbers: 2020P003605; R01DK125786 (U.S. NIH Grant/Contract)

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