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

• ClinicalTrials.gov Identifier: NCT04633889
• Recruitment Status: Recruiting
• First Posted: November 18, 2020
• Last Update Posted: May 21, 2021
• Sponsor: Brigham and Women's Hospital
• Collaborators: Massachusetts General Hospital; Beth Israel Deaconess Medical Center; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): David Leaf, Brigham and Women's Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Kidney Injury	Drug: Deferoxamine; Drug: Normal saline	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Deferoxamine for the Prevention of Cardiac Surgery-Associated Acute Kidney Injury
• Actual Study Start Date: April 13, 2021
• Estimated Primary Completion Date: June 1, 2025
• Estimated Study Completion Date: August 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Acute Kidney Injury [ Time Frame: 7 days ]

   Composite outcome that includes any of the following:

   1. 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
   2. Increase in serum creatinine ≥0.3 mg/dl within the first 48h
   3. Increase in serum creatinine ≥50% within 7 days
   4. Receipt of renal replacement therapy within 7 days

Secondary Outcome Measures :

1. Renal tubular injury [ Time Frame: 3 days ]
   Urine levels of NGAL and KIM-1
2. Major Adverse Kidney Events [ Time Frame: 7 days ]
   Increase in serum creatinine ≥100%, receipt of renal replacement therapy, or death within 7 days
3. Postoperative myocardial injury [ Time Frame: 2 days ]
   Peak postoperative troponin I elevation >10 times the 99th percentile upper reference limit
4. Atrial fibrillation or atrial flutter [ Time Frame: 7 days ]
   New onset postoperative atrial fibrillation or atrial flutter (patients with atrial fibrillation or atrial flutter at baseline will be excluded)
5. Prolonged mechanical ventilation [ Time Frame: 24 hours ]
   Requirement for mechanical ventilation >24h postoperatively
6. Vasoactive-Inotropic Score [ Time Frame: 24 hours ]
   Validated method for integrating all IV vasoactive medications and their doses on an hourly basis into a single measure
7. Time to liberation from vasoactive medications [ Time Frame: 7 days ]
   Number of hours from time of incision to liberation from all IV vasoactive medications
8. Sepsis [ Time Frame: 7 days ]
   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.
9. Ventilator-free days [ Time Frame: 28 days ]
   28 minus the number of days ventilated. Patients who die within 28 days will be assigned 0 ventilator-free days.
10. ICU-free days [ Time Frame: 28 days ]
    28 minus the number of days in the ICU. Patients who die within 28 days will be assigned 0 ICU-free days.
11. Hospital-free days [ Time Frame: 28 days ]
    28 minus the number of days hospitalized. Patients who die within 28 days will be assigned 0 hospital-free days.

Eligibility Criteria

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

Criteria

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 3 weeks
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

Contacts and Locations

Contacts

Contact: David E. Leaf, MD, MMSc; 9144190622; deleaf@bwh.harvard.edu

Contact: Shahzad Shaefi, MD, MPH; 6178203570; sshaefi@bidmc.harvard.edu

Locations

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Aranya Bagchi, MBBS abagchi@mgh.harvard.edu

Brigham and Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: David E. Leaf, MD, MMSc 914-419-0622 deleaf@bwh.harvard.edu

Beth Israel Deaconess Medical Center; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Shahzad Shaefi, MD, MPH sshaefi@bidmc.harvard.edu

Sponsors and Collaborators

Brigham and Women's Hospital

Massachusetts General Hospital

Beth Israel Deaconess Medical Center

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: David E. Leaf, MD, MMSc; Brigham and Women's Hospital

More Information

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. Review.

• Responsible Party: David Leaf, Assistant Professor of Medicine, Harvard Medical School, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT04633889
• Other Study ID Numbers: 2020P003605; R01DK125786 ( U.S. NIH Grant/Contract )
• First Posted: November 18, 2020
• Last Update Posted: May 21, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Acute Kidney Injury; Wounds and Injuries; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Deferoxamine; Siderophores; Iron Chelating Agents; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action