Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
Information source: University of California, San Francisco
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Heart Septal Defects, Ventricular; Atrioventricular Septal Defect
Intervention: IV L-carnitine (Drug)
Phase: Phase 1
Status: Recruiting
Sponsored by: University of California, San Francisco Official(s) and/or principal investigator(s): Jeffrey Fineman, MD, Principal Investigator, Affiliation: University of California, San Francisco
Overall contact: Jeffrey Fineman, MD, Phone: 415-502-6390, Email: jeff.fineman@ucsf.edu
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.
Clinical Details
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
Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Blood carnitine level (free, total, and acylcarnitine)
Secondary outcome: Bioavailable nitric oxidePlasma levels of superoxide Carnitine Palmityl Transporter-1 and -2 expression Cardiopulmonary bypass Echocardiographic measurements Blood BNP level Duration of mechanical ventilation Vasopressor infusions Need for inhaled nitric oxide Incidence of low cardiac output syndrome Need for extracorporeal life support Plasma H202 levels Aortic cross clamp times
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
Minimum age: 2 Months.
Maximum age: 12 Months.
Gender(s): Both.
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
Locations and Contacts
Jeffrey Fineman, MD, Phone: 415-502-6390, Email: jeff.fineman@ucsf.edu
University of California San Francisco, San Francisco, California 94143-0106, United States; Recruiting Jeffrey Fineman, MD, Phone: 415-502-6390, Email: jeff.fineman@ucsf.edu Monique R Radman, MD, Phone: 415-502-6390, Email: RadmanM@peds.ucsf.edu
Additional Information
Related publications: Ghorishi Z, Milstein JM, Poulain FR, Moon-Grady A, Tacy T, Bennett SH, Fineman JR, Eldridge MW. Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3006-18. Epub 2007 Feb 16. Black SM, Kumar S, Wiseman D, Ravi K, Wedgwood S, Ryzhov V, Fineman JR. Pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide. Clin Hemorheol Microcirc. 2007;37(1-2):111-20. Review. Sharma S, Grobe AC, Wiseman DA, Kumar S, Englaish M, Najwer I, Benavidez E, Oishi P, Azakie A, Fineman JR, Black SM. Lung antioxidant enzymes are regulated by development and increased pulmonary blood flow. Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L960-71. Epub 2007 Jul 13. Lakshminrusimha S, Wiseman D, Black SM, Russell JA, Gugino SF, Oishi P, Steinhorn RH, Fineman JR. The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow. Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1491-7. Epub 2007 May 18. Oishi P, Sharma S, Grobe A, Azakie A, Harmon C, Johengen MJ, Hsu JH, Fratz S, Black SM, Fineman JR. Alterations in cGMP, soluble guanylate cyclase, phosphodiesterase 5, and B-type natriuretic peptide induced by chronic increased pulmonary blood flow in lambs. Pediatr Pulmonol. 2007 Nov;42(11):1057-71. Sud N, Sharma S, Wiseman DA, Harmon C, Kumar S, Venema RC, Fineman JR, Black SM. Nitric oxide and superoxide generation from endothelial NOS: modulation by HSP90. Am J Physiol Lung Cell Mol Physiol. 2007 Dec;293(6):L1444-53. Epub 2007 Sep 7. Erratum in: Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L1004. Oishi PE, Wiseman DA, Sharma S, Kumar S, Hou Y, Datar SA, Azakie A, Johengen MJ, Harmon C, Fratz S, Fineman JR, Black SM. Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow: a role for oxidative stress. Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L756-66. doi: 10.1152/ajplung.00146.2007. Epub 2008 Aug 29. Sharma S, Sud N, Wiseman DA, Carter AL, Kumar S, Hou Y, Rau T, Wilham J, Harmon C, Oishi P, Fineman JR, Black SM. Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008 Jan;294(1):L46-56. Epub 2007 Nov 16. Kumar S, Sun X, Sharma S, Aggarwal S, Ravi K, Fineman JR, Black SM. GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP. Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L309-17. doi: 10.1152/ajplung.90538.2008. Epub 2009 May 15. Sharma S, Kumar S, Sud N, Wiseman DA, Tian J, Rehmani I, Datar S, Oishi P, Fratz S, Venema RC, Fineman JR, Black SM. Alterations in lung arginine metabolism in lambs with pulmonary hypertension associated with increased pulmonary blood flow. Vascul Pharmacol. 2009 Nov-Dec;51(5-6):359-64. doi: 10.1016/j.vph.2009.09.005. Epub 2009 Oct 8. Tian J, Smith A, Nechtman J, Podolsky R, Aggarwal S, Snead C, Kumar S, Elgaish M, Oishi P, Göerlach A, Fratz S, Hess J, Catravas JD, Verin AD, Fineman JR, She JX, Black SM. Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension. Physiol Genomics. 2009 Dec 30;40(1):48-60. doi: 10.1152/physiolgenomics.00094.2009. Epub 2009 Oct 13. Aggarwal S, Gross C, Fineman JR, Black SM. Oxidative stress and the development of endothelial dysfunction in congenital heart disease with increased pulmonary blood flow: lessons from the neonatal lamb. Trends Cardiovasc Med. 2010 Oct;20(7):238-46. doi: 10.1016/j.tcm.2011.11.010. Review. Sharma S, Kumar S, Wiseman DA, Kallarackal S, Ponnala S, Elgaish M, Tian J, Fineman JR, Black SM. Perinatal changes in superoxide generation in the ovine lung: Alterations associated with increased pulmonary blood flow. Vascul Pharmacol. 2010 Jul-Aug;53(1-2):38-52. doi: 10.1016/j.vph.2010.03.005. Epub 2010 Mar 31. Aggarwal S, Gross CM, Kumar S, Datar S, Oishi P, Kalkan G, Schreiber C, Fratz S, Fineman JR, Black SM. Attenuated vasodilatation in lambs with endogenous and exogenous activation of cGMP signaling: role of protein kinase G nitration. J Cell Physiol. 2011 Dec;226(12):3104-13. doi: 10.1002/jcp.22692. Sharma S, Sun X, Kumar S, Rafikov R, Aramburo A, Kalkan G, Tian J, Rehmani I, Kallarackal S, Fineman JR, Black SM. Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I. Free Radic Biol Med. 2012 Jul 15;53(2):216-29. doi: 10.1016/j.freeradbiomed.2012.03.016. Epub 2012 Apr 16.
Starting date: December 2014
Last updated: January 12, 2015
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