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Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow (L-carn)

Primary Purpose

Heart Septal Defects, Ventricular, Atrioventricular Septal Defect

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
IV L-carnitine
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Septal Defects, Ventricular focused on measuring congenital heart disease, ventricular septal defect, atrioventricular septal defect, increased pulmonary blood flow, nitric oxide

Eligibility Criteria

2 Months - 12 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California San Francisco

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IV L-carnitine

Arm 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.

Outcomes

Primary Outcome Measures

Blood carnitine level (free, total, and acylcarnitine)

Secondary Outcome Measures

Bioavailable nitric oxide
Plasma levels of superoxide
Carnitine Palmityl Transporter-1 and -2 expression
Cardiopulmonary bypass
Echocardiographic measurements
Estimates of PPA and right ventricular (RV) function by transesophageal ECHO (TEE)
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

Full Information

First Posted
March 28, 2013
Last Updated
May 4, 2020
Sponsor
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT01825369
Brief Title
Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
Acronym
L-carn
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 Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Changes to cardiac surgery program
Study Start Date
December 2014 (Actual)
Primary Completion Date
July 2020 (Anticipated)
Study Completion Date
July 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Septal Defects, Ventricular, Atrioventricular Septal Defect
Keywords
congenital heart disease, ventricular septal defect, atrioventricular septal defect, increased pulmonary blood flow, nitric oxide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IV L-carnitine
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
IV L-carnitine
Intervention Description
See arm description
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Bioavailable nitric oxide
Time Frame
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Title
Plasma levels of superoxide
Time Frame
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Title
Carnitine Palmityl Transporter-1 and -2 expression
Time Frame
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Title
Cardiopulmonary bypass
Time Frame
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Title
Echocardiographic measurements
Description
Estimates of PPA and right ventricular (RV) function by transesophageal ECHO (TEE)
Time Frame
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks
Title
Blood BNP level
Time Frame
Daily during the hospitalization, estimated to be an average of 2 weeks
Title
Duration of mechanical ventilation
Time Frame
During hospitalization which is an average of 2 weeks
Title
Vasopressor infusions
Time Frame
Duration of hospitalization which is an average of 2 weeks
Title
Need for inhaled nitric oxide
Time Frame
During hospitalization (average of 2 weeks)
Title
Incidence of low cardiac output syndrome
Time Frame
Postoperative hospitalization (average of 2 weeks)
Title
Need for extracorporeal life support
Time Frame
During hospitalization (average of 2 weeks)
Title
Plasma H202 levels
Time Frame
At enrollment (first dose), and again 24 and 48 hrs after enrollment.
Title
Aortic cross clamp times
Time Frame
Participants will be followed for the duration of hospital stay, an expected average of 2 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Fineman, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143-0106
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17308003
Citation
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. doi: 10.1152/ajpheart.01012.2006. Epub 2007 Feb 16.
Results Reference
background
PubMed Identifier
17641401
Citation
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.
Results Reference
background
PubMed Identifier
17631609
Citation
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. doi: 10.1152/ajplung.00449.2006. Epub 2007 Jul 13.
Results Reference
background
PubMed Identifier
17513498
Citation
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. doi: 10.1152/ajpheart.00185.2007. Epub 2007 May 18.
Results Reference
background
PubMed Identifier
17902145
Citation
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. doi: 10.1002/ppul.20696.
Results Reference
background
PubMed Identifier
17827253
Citation
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. doi: 10.1152/ajplung.00175.2007. Epub 2007 Sep 7. Erratum In: Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L1004.
Results Reference
background
PubMed Identifier
18757524
Citation
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.
Results Reference
background
PubMed Identifier
18024721
Citation
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. doi: 10.1152/ajplung.00247.2007. Epub 2007 Nov 16.
Results Reference
background
PubMed Identifier
19447893
Citation
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.
Results Reference
background
PubMed Identifier
19818875
Citation
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.
Results Reference
background
PubMed Identifier
19825830
Citation
Tian J, Smith A, Nechtman J, Podolsky R, Aggarwal S, Snead C, Kumar S, Elgaish M, Oishi P, Goerlach 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.
Results Reference
background
PubMed Identifier
22293025
Citation
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.
Results Reference
background
PubMed Identifier
20362073
Citation
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.
Results Reference
background
PubMed Identifier
21351102
Citation
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.
Results Reference
background
PubMed Identifier
22583703
Citation
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.
Results Reference
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Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow

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