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

Study Status: Recruiting
Recruit Status: Unknown status
Study Type: Interventional

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 Summary:

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 recomme
Sponsor: University of California, San Francisco

Current Primary Outcome: 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. ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Bioavailable nitric oxide [ Time Frame: 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. ]
  • Carnitine Palmityl Transporter-1 and -2 expression [ Time Frame: 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 ]
  • 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)
  • Blood BNP level [ Time Frame: 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 ]
  • Vasopressor infusions [ Time Frame: Duration of hospitalization which is an average of 2 weeks ]
  • Need for inhaled nitric oxide [ Time Frame: During hospitalization (average of 2 weeks) ]
  • Incidence of low cardiac output syndrome [ Time Frame: Postoperative hospitalization (average of 2 weeks) ]
  • Need for extracorporeal life support [ Time Frame: During hospitalization (average of 2 weeks) ]
  • Plasma H202 levels [ Time Frame: 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 ]


Original Secondary Outcome:

  • Bioavailable nitric oxide [ Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. ]
  • Plasma levels of both superoxide and H2O2 [ Time Frame: 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. ]
  • Peri/intra-operative data [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks ]
    Cardiopulmonary bypass time and aortic cross clamp times, other intra-operative interventions.
  • 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)
  • Blood BNP level [ Time Frame: 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 ]
  • Vasopressor infusions [ Time Frame: Duration of hospitalization which is an average of 2 weeks ]


Information By: University of California, San Francisco

Dates:
Date Received: March 28, 2013
Date Started: December 2014
Date Completion: July 2015
Last Updated: January 12, 2015
Last Verified: January 2015