Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow

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Brief Title

Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow

Official Title

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

Brief Summary

      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.
    

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 Phase

Phase 1

Study Type

Interventional


Primary Outcome

Blood carnitine level (free, total, and acylcarnitine)

Secondary Outcome

 Bioavailable nitric oxide

Condition

Heart Septal Defects, Ventricular

Intervention

IV L-carnitine

Study Arms / Comparison Groups

 IV L-carnitine
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

0

Start Date

December 2014

Completion Date

July 2020

Primary Completion Date

July 2020

Eligibility Criteria

        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
      

Gender

All

Ages

2 Months - 12 Months

Accepts Healthy Volunteers

No

Contacts

Jeffrey Fineman, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01825369

Organization ID

FinemanCarnitine


Responsible Party

Sponsor

Study Sponsor

University of California, San Francisco


Study Sponsor

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


Verification Date

May 2020