Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow (L-carn)

May 4, 2020 updated by: University of California, San Francisco

Phase 1 Study of the Safety and Pharmacokinetics of Perioperative IV L-carnitine Administration in Patients With Congenital Heart Disease With Increased Pulmonary Blood Flow

Infants with congenital heart disease and increased pulmonary blood flow have altered carnitine homeostasis that is associated with clinical outcomes; and L-carnitine treatment will attenuate these alterations and improve clinical outcomes.

The investigators will pilot a trial assessing the safety and pharmacokinetics of perioperative IV L-carnitine administration in these patients. To this end, a pilot clinical trial is proposed. Infants with ventricular septal defects or atrioventricular septal defects undergoing complete surgical repair will receive L-carnitine (25, 50, or 100 mg/kg, IV) just prior to cardiopulmonary bypass (CPB) and 2hr after CPB. Carnitine levels will be measured before CPB, and before and 0.5, 1.5, 3, 5, 9, 12, and 24h after the second dose. The safety, pharmacokinetic profile, feasibility, and effect of L-carnitine administration on biochemical parameters, as well as clinical outcomes will be determined. The investigators expect this pilot to provide the data needed to proceed with a placebo-based randomized, controlled, trial.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

AIM: To pilot a trial assessing the safety and pharmacokinetics (PK) of perioperative IV L-carnitine administration in these patients. To this end, a pilot clinical trial is proposed. Infants with VSD or AVSD undergoing complete repair will receive L-carnitine, in one of 3 doses (25, 50, or 100 mg/kg, IV), just prior to CPB, and again 2 hr after CPB. Serial blood samples will be obtained to determine free, total, and acylcarnitine levels, and plasma markers of mitochondrial function, oxidative stress, and bioavailable NO. Adverse events will be sought, and clinical outcomes will be assessed.

Study design: The inclusion and exclusion criteria are as described in Aim 3A except only infants with VSD or AVSD will be enrolled (no TOF). The safety profile of L-carnitine is outstanding, with no reports of toxicity from overdose reported113. In fact, the only adverse reactions reported are transient nausea and vomiting, and less commonly gastritis. However, although rare, seizures have been reported to occur in patients receiving L-carnitine. Therefore, the major adverse events that will be monitored include evidence of seizure activity and GI bleeding. As per routine, any patient suspected of having seizures is monitored with continuous EEG. Dosing is not well studied in children, particularly critically ill children67, 114-116117. In addition, the effect of CPB on L-carnitine clearance in children is not known. Therefore, a major goal of this sub-aim is to establish a pharmacokinetic profile of L-carnitine in this patient population undergoing surgery with CPB, in order to move forward with a larger randomized trial powered for efficacy in prevention of increased PVR post-bypass in at-risk infants. Plasma concentration profiles after IV bolus dosing in adults were described by a two-compartmental model67, 113, 114, 118. Usual pediatric dosing is not well delineated, but recommendations include a 50 mg/kg bolus followed by an infusion of 50mg/kg/day, that can be increased to 300 mg/kg/day113, 119. Therefore, we will begin at a lower dose (25 mg/kg), and escalate the dose after each group of 5. No intra-patient escalation will be allowed and the dose will not be escalated until all patients in the current dose level have been followed to hospital discharge or 30 days post-op and the safety and PK data have been analyzed. The DSMB will approve all dose escalations. The dosing goal will be to achieve normal or supra-normal free carnitine levels (~50 μmol/L) and low AC levels (~3 μmol/L) just before and for 24 hrs after CPB; the period with the greatest risk of pulmonary vascular morbidity.

Study Type

Interventional

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
    • California
      • San Francisco, California, United States, 94143-0106
        • University of California San Francisco

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

2 months to 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • have unrestrictive VSD, AVSD
  • are undergoing complete repair
  • are between 2-12 months of age
  • are corrected gestational age ≥34 weeks
  • will have an indwelling arterial or venous line
  • have not had enteral or parenteral nutrition for at least 6 hrs

Exclusion Criteria:

  • have body weight < 2.0 kg
  • pulmonary artery or vein abnormalities not being addressed surgically
  • suspected or proven in-born error of metabolism
  • have other major congenital abnormalities that affect the cardiopulmonary system
  • are taking carnitine supplementation

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: IV L-carnitine
L-carnitine (25, 50, or 100mg/kg IV) will be given, 30-60 minutes prior to the initiation of CPB, and a second dose ~2 hr. following separation from CPB (with a minimum of 4 hrs from initial dose). The first 5 subjects will receive 25 mg/kg, with an escalation of dose after each 5 subjects enrolled. The study drug will be brought to the operating room and administered over 5 minutes by the anesthesiologist after an IV has been placed. Prior to the administration of the study drug, and again 24 and 48 hrs after CPB, 3.0 ml of blood will be collected for determinations of carnitine levels (free, total, and acylcarnitine), mitochondrial function, ROS and bioavailable NO as described in Aim 3A. Additional blood (0.5-1.0 ml) will be obtained to determine carnitine levels before CPB, and then before and 0.5, 1.5, 3, 5, 9, 12, and 24h after the second dose.
Drug: IV L-carnitine
See arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Blood carnitine level (free, total, and acylcarnitine)
Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. 2 hours after enrollment (at time of second dose) and 0.5, 1.5, 3, 5, 9, 12, and 24h after the second dose.
At enrollment (first dose), and again 24 and 48 hrs after enrollment. 2 hours after enrollment (at time of second dose) and 0.5, 1.5, 3, 5, 9, 12, and 24h after the second dose.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bioavailable nitric oxide
Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment.
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Plasma levels of superoxide
Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment.
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Carnitine Palmityl Transporter-1 and -2 expression
Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment.
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Cardiopulmonary bypass
Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Echocardiographic measurements
Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Estimates of PPA and right ventricular (RV) function by transesophageal ECHO (TEE)
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Blood BNP level
Time Frame: Daily during the hospitalization, estimated to be an average of 2 weeks
Daily during the hospitalization, estimated to be an average of 2 weeks
Duration of mechanical ventilation
Time Frame: During hospitalization which is an average of 2 weeks
During hospitalization which is an average of 2 weeks
Vasopressor infusions
Time Frame: Duration of hospitalization which is an average of 2 weeks
Duration of hospitalization which is an average of 2 weeks
Need for inhaled nitric oxide
Time Frame: During hospitalization (average of 2 weeks)
During hospitalization (average of 2 weeks)
Incidence of low cardiac output syndrome
Time Frame: Postoperative hospitalization (average of 2 weeks)
Postoperative hospitalization (average of 2 weeks)
Need for extracorporeal life support
Time Frame: During hospitalization (average of 2 weeks)
During hospitalization (average of 2 weeks)
Plasma H202 levels
Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment.
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Aortic cross clamp times
Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks

Collaborators and Investigators

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

Sponsor

University of California, San Francisco

Investigators

  • Principal Investigator: Jeffrey Fineman, MD, University of California, San Francisco

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)

December 1, 2014

Primary Completion (Anticipated)

July 1, 2020

Study Completion (Anticipated)

July 1, 2020

Study Registration Dates

First Submitted

March 28, 2013

First Submitted That Met QC Criteria

April 2, 2013

First Posted (Estimate)

April 5, 2013

Study Record Updates

Last Update Posted (Actual)

May 6, 2020

Last Update Submitted That Met QC Criteria

May 4, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FinemanCarnitine

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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