Trial record 1 of 9 for:    "Atrioventricular septal defect"
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Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow (L-carn)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified October 2013 by University of California, San Francisco
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01825369
First received: March 28, 2013
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Heart Septal Defects, Ventricular
Atrioventricular Septal Defect
Drug: IV L-carnitine
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Bioavailable nitric oxide [ Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. ] [ Designated as safety issue: No ]
  • Plasma levels of superoxide [ Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. ] [ Designated as safety issue: No ]
  • Carnitine Palmityl Transporter-1 and -2 expression [ Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. ] [ Designated as safety issue: No ]
  • Cardiopulmonary bypass [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks ] [ Designated as safety issue: Yes ]
  • Echocardiographic measurements [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Duration of mechanical ventilation [ Time Frame: During hospitalization which is an average of 2 weeks ] [ Designated as safety issue: No ]
  • Vasopressor infusions [ Time Frame: Duration of hospitalization which is an average of 2 weeks ] [ Designated as safety issue: No ]
  • Need for inhaled nitric oxide [ Time Frame: During hospitalization (average of 2 weeks) ] [ Designated as safety issue: Yes ]
  • Incidence of low cardiac output syndrome [ Time Frame: Postoperative hospitalization (average of 2 weeks) ] [ Designated as safety issue: Yes ]
  • Need for extracorporeal life support [ Time Frame: During hospitalization (average of 2 weeks) ] [ Designated as safety issue: Yes ]
  • Plasma H202 levels [ Time Frame: At enrollment (first dose), and again 24 and 48 hrs after enrollment. ] [ Designated as safety issue: No ]
  • Aortic cross clamp times [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 2 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 15
Study Start Date: December 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   2 Months to 12 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01825369

Contacts
Contact: Jeffrey Fineman, MD 415-502-6390 jeff.fineman@ucsf.edu
Contact: Monique R Radman, MD 415-502-6390 RadmanM@peds.ucsf.edu

Locations
United States, California
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143-0106
Contact: Jeffrey Fineman, MD    415-502-6390    jeff.fineman@ucsf.edu   
Contact: Monique R Radman, MD    415-502-6390    RadmanM@peds.ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Jeffrey Fineman, MD University of California, San Francisco
  More Information

Publications:

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01825369     History of Changes
Other Study ID Numbers: FinemanCarnitine
Study First Received: March 28, 2013
Last Updated: October 7, 2013
Health Authority: United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
congenital heart disease
ventricular septal defect
atrioventricular septal defect
increased pulmonary blood flow
nitric oxide

Additional relevant MeSH terms:
Endocardial Cushion Defects
Heart Defects, Congenital
Heart Diseases
Heart Septal Defects
Heart Septal Defects, Ventricular
Cardiovascular Abnormalities
Cardiovascular Diseases
Congenital Abnormalities
Carnitine
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on October 30, 2014