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Trial record 1 of 11 for:    "Atrioventricular septal defect"
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Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow (L-carn)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified January 2015 by University of California, San Francisco.
Recruitment status was:  Recruiting
Sponsor:
ClinicalTrials.gov Identifier:
NCT01825369
First Posted: April 5, 2013
Last Update Posted: January 13, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
University of California, San Francisco
  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: Intervention Model: Single Group Assignment
Masking: None (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. ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 15
Study Start Date: December 2014
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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   2 Months to 12 Months   (Child)
Sexes Eligible for Study:   All
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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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 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:
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.

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01825369     History of Changes
Other Study ID Numbers: FinemanCarnitine
First Submitted: March 28, 2013
First Posted: April 5, 2013
Last Update Posted: January 13, 2015
Last Verified: January 2015

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:
Heart Diseases
Heart Defects, Congenital
Heart Septal Defects
Heart Septal Defects, Ventricular
Endocardial Cushion Defects
Cardiovascular Diseases
Cardiovascular Abnormalities
Congenital Abnormalities


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