Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery: Proposal for Pilot Investigation

July 24, 2018 updated by: Medical City Children's Hospital

Cardiopulmonary bypass and arrest of the heart during cardiac surgery are necessary to allow the surgeon to perform heart operations. However, these processes can cause injury to the heart which may worsen post-operative outcomes. In fact, the effects of these injuries may continue after surgery, and lead to a long-term decrease in heart function. Neonates and young infants are at particular risk for this occurrence.

While much research has been done in adults looking for medicines that might protect the heart during surgery, few studies have been conducted in neonates and young infants. The investigators are testing Dexrazoxane, which has proven to be cardio-protective in pediatric cancer patients, in the hope that it may lessen cardiac injury during and after congenital heart surgery, and thereby improve outcomes in the neonatal and young infant population.

In order to accomplish this, the investigators must first determine how Dexrazoxane can be safely administered to young children with congenital heart disease. Therefore, the investigators are performing a pilot study of 12 children to assess:

  1. how Dexrazoxane at 3 different doses is metabolized in the body of a child age 0-6 months during and after congenital heart surgery, and
  2. the safety of Dexrazoxane use in the neonatal and young infant population undergoing cardiac surgery.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Neonates and infants undergoing heart surgery with cardioplegic arrest experience both inflammation and myocardial ischemia-reperfusion [IR] injury. These processes provoke myocardial apoptosis and oxygen free radical formation which result in cardiac injury and dysfunction. Dexrazoxane is a derivative of EDTA that is approved for prevention of anthracycline-related cardiotoxicity. It provides cardioprotection through reduction of toxic reactive oxygen species [ROS], and suppression of apoptosis.

The deleterious effects of cardiopulmonary bypass [CPB] with cardioplegic arrest of the heart during congenital heart operations greatly influence postoperative morbidity and mortality. Neonates and infants undergoing cardiac surgery experience both a systemic inflammatory response, and myocardial IR injury as cardioplegic arrest is reversed. These processes provoke elaboration of cytokines and activation of the complement cascade, as well as oxygen free radical formation and induction of myocardial apoptosis (1, 2, 3). Frequently, myocardial injury and cardiac dysfunction ensue, leading to low cardiac output syndrome and multi-system organ failure. The irreversible component of these injuries, in addition to the abnormal workloads imposed on the myocardium from the anatomic defects themselves, may have consequences for long-term cardiac function, and may in part explain contractile dysfunction observed late after congenital heart

The investigators propose a pilot pharmacokinetic/safety trial of dexrazoxane in children 0-6 months of age, followed by a randomized, double-blind, clinical trial of dexrazoxane vs placebo during congenital heart surgery. The investigators will evaluate postoperative time to resolution of organ failure, development of low cardiac output syndrome, length of cardiac ICU and hospital stays, and echocardiographic indices of cardiac dysfunction. Results could establish the safety and clinical utility of dexrazoxane in ameliorating ischemia-reperfusion injury during congenital heart surgery.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75230
        • Medical City Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 day to 6 months (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age 6 months and under
  • open heart surgery requiring CPB and use of cardioplegia
  • parent/guardian consent for study obtained surgery planned Monday to Friday

Exclusion Criteria:

  • gestational age <36weeks
  • known syndrome or genetic abnormality, except Trisomy 21 single ventricle physiology
  • concurrent enrollment in another research protocol
  • no parental/guardian consent obtained
  • ECMO utilization prior to surgery or necessary at the time of ICU admission

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Dexrazoxane

Trial subjects will be assigned preoperatively to receive Dexrazoxane at one of three doses: low (200mg/m2/dose), medium (300mg/m2/dose), or high (400mg/m2/dose). Four patients will be assigned to each dosing regimen for a total of 12 patients.

The medication will be administered in the operating room 15-30 minutes prior to starting cardiopulmonary bypass (dose #1), after finishing cardiopulmonary bypass (dose #2), and on the morning after surgery in the cardiac intensive care unit (dose #3).
Drug: Dexrazoxane
Dose escalation every 4 subjects from 200mg/m2/dose; 300mg/m2/dose to 400mg/m2/dose
Other Names:
  • Zinecard

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Resolution of organ failure
Time Frame: 60 days postoperative
measured by number of days to the point of being off invasive mechanical ventilation, renal replacement therapy and inotropic support
60 days postoperative

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Postoperative low cardiac output syndrome
Time Frame: 60 days
observance of clinical signs or symptoms such as tachycardia, oliguria, poor perfusion and cardiac arrest.
60 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Myocardial injury
Time Frame: 60 days
determined by elevated serum cardiac troponin
60 days
Oxidative stress
Time Frame: 60 days
measured by lipoperoxidation (serum F2 isoprostane), plasma thiobarbituric acid reactive substance (TBARS), and plasma total antioxidant activity
60 days
Inflammatory activation (IL-6 and IL-10)
Time Frame: 60 days
60 days
Myocardial dysfunction (via echocardiogram)
Time Frame: 60 days
measured by Tei index, tissue doppler E/E ratio, and ventricular ejection fraction
60 days
Neurologic injury (activin A)
Time Frame: 60 days
measured by serum activin A concentration
60 days
ICU and hospital length of stay
Time Frame: 60 days
60 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical City Children's Hospital

Collaborators

Mylan Pharmaceuticals Inc

Investigators

  • Principal Investigator: Daniel Stromberg, MD, Medical City Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2014

Primary Completion (Actual)

March 1, 2017

Study Completion (Actual)

March 1, 2017

Study Registration Dates

First Submitted

May 14, 2015

First Submitted That Met QC Criteria

August 5, 2015

First Posted (Estimate)

August 10, 2015

Study Record Updates

Last Update Posted (Actual)

July 26, 2018

Last Update Submitted That Met QC Criteria

July 24, 2018

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCCH-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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