Effects of Parenteral L-carnitine Supplementation in Premature Neonates

Complication of Prematurity Clinical Trial

— CarniPrema  

Official title:

Effects of Parenteral L-carnitine Supplementation in Premature Neonates

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00841295
• Other study ID #: PHRI06-FL / CARNIPREMA
• Secondary ID: N° EudraCT: 2007
• Status: Completed
• Phase: N/A
• Start date: July 2008
• Est. completion date: July 2013

Study information

• Verified date: October 2018
• Source: University Hospital, Tours
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background: Carnitine is the essential cofactor for various enzyme activities of human metabolism, especially for the mitochondrial carnitine shuttle that transfers long-chain fatty acids as acylcarnitine esters across the inner mitochondrial membrane for Beta-oxidation and energy production. Intracellular carnitine deficiency induces an impairment of long-chain fatty acid oxidation. In human, approximately 75% of carnitine comes from the diet and 25% from endogenous liver synthesis. In the neonatal period, more specifically in the premature, liver synthesis capacity is reduced because of immaturity of the biosynthetic pathway, and carnitine levels are related to exogenous sources. Traditionally, carnitine is not added to parenteral nutrition. Indeed, without enteral feeds and carnitine supplementation of parenteral nutrition, preterm infants' plasma carnitine levels fall during the first weeks of life, particularly in subjects requiring a prolonged exclusive parenteral nutrition. The potential deleterious role of carnitine deficiency has not been clearly demonstrated in these infants. However, most patients with primary carnitine deficiency, a genetic defect of carnitine transport inducing a severe carnitine deficiency, commonly develop liver symptoms (encompassing visceral steatosis, hyperammonemia and recurrent hypoketotic hypoglycemias) and/or cardiomyopathy and myopathy. In these latter patients, carnitine supplementation improves all the symptoms.

Hypothesis: Carnitine deficiency of the premature and very low birth weight infants may be one of the factors involved in the liver disease frequently associated with prolonged parenteral nutrition, and may have deleterious effects on cardiac and muscle metabolism and functions.

Aims: To demonstrate beneficial effects of parenteral carnitine supplementation in premature neonates for liver, heart and muscle metabolism and functions.

Study Type: Multicentric prospective and randomised study

Subjects: Premature and very low birth weight neonates, defined by gestational age minor or equal to 28 weeks and/or birth weight minor or equal to 1000 grams, 80 subjects will be enrolled during 2.5 years

Interventions: Arm 1 (experimental): parenteral carnitine supplementation (9 ± 1 mg/kg/d), from day 4, until than enteral nutrition provides sufficient carnitine source; Arm 2 (Placebo comparator): parenteral supplementation with an equivalent volume of sterile water.

Description:

Background: Carnitine is the essential cofactor for various enzyme activities of human metabolism, especially for the mitochondrial carnitine shuttle that transfers long-chain fatty acids as acylcarnitine esters across the inner mitochondrial membrane for Beta-oxidation and energy production. Intracellular carnitine deficiency induces an impairment of long-chain fatty acid oxidation. In human, approximately 75% of carnitine comes from the diet and 25% from endogenous liver synthesis. In the neonatal period, more specifically in the premature, liver synthesis capacity is reduced because of immaturity of the biosynthetic pathway, and carnitine levels are related to exogenous sources. Traditionally, carnitine is not added to parenteral nutrition. Indeed, without enteral feeds and carnitine supplementation of parenteral nutrition, preterm infants' plasma carnitine levels fall during the first weeks of life, particularly in subjects requiring a prolonged exclusive parenteral nutrition. The potential deleterious role of carnitine deficiency has not been clearly demonstrated in these infants. However, most patients with primary carnitine deficiency, a genetic defect of carnitine transport inducing a severe carnitine deficiency, commonly develop liver symptoms (encompassing visceral steatosis, hyperammonemia and recurrent hypoketotic hypoglycemias) and/or cardiomyopathy and myopathy. In these latter patients, carnitine supplementation improves all the symptoms.

Hypothesis: Carnitine deficiency of the premature and very low birth weight infants may be one of the factors involved in the liver disease frequently associated with prolonged parenteral nutrition, and may have deleterious effects on cardiac and muscle metabolism and functions.

Aims: To demonstrate beneficial effects of parenteral carnitine supplementation in premature neonates for liver, heart and muscle metabolism and functions.

Study Type: Multicentric prospective and randomised study

Subjects: Premature and very low birth weight neonates, defined by gestational age minor or equal to 28 weeks and/or birth weight minor or equal to 1000 grams, 80 subjects will be enrolled during 2.5 years

Interventions: Arm 1 (experimental): parenteral carnitine supplementation (9 ± 1 mg/kg/d), from day 4, until than enteral nutrition provides sufficient carnitine source; Arm 2 (Placebo comparator): parenteral supplementation with an equivalent volume of sterile water.

Primary Outcome: Plasma Gamma Glutamyl Transferase level after 21 days of parenteral supplementation.

Secondary Outcomes: Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcomes: 1) Liver function (levels of ammonemia, hyaluronic acid, bilirubin, prothrombin time test, ursodeoxycholic acid therapy), 2) cardiac function (echocardiography, EKG), 3) muscle integrity (CK levels), 4) neurological injuries (brain ultrasound and MRI), 5) respiratory immaturity, 6) acylcarnitine profile and other fatty acid derivatives.

Expected Findings: Systematic parenteral carnitine supplementation will prevent systemic carnitine deficiency, and will improve liver dysfunction (decreased duration and severity of liver disease) associated with prolonged parenteral nutrition, will improve cardiac and muscle functions, and will prevent cerebral injury in premature infants with very low birth weight.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: July 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 28 Weeks

Eligibility

Inclusion Criteria:

• Premature newborn admitted in Intensive Care Unit,

• Gestational age minor or equal than 28 weeks and 6 days,

• Needing prolonged parenteral nutrition through a central intravenous catheter,

• Parenteral nutrition started before 6 days of life,

• Both parents (or legal tutor) gave written informed consent for their children,

• Patient affiliated to "Sécurité Sociale" of his parents.

Exclusion Criteria:

• Severe associated disorder, with a probable short-term death,

• Identified genetic disease,

• Polymalformative syndrome, or severe malformation (heart, brain, others…),

• Inborn error of metabolism,

• Probable transfer of the subject before 25 days of life in another hospital that do not collaborate to this study.

Related Conditions & MeSH terms

• Complication of Prematurity
• Premature Birth

Intervention

Drug:
• Parenteral L-carnitine supplementation
Parenteral carnitine supplementation (9 ± 1 mg/kg/d), from day 4, until than enteral nutrition provides sufficient carnitine source.
• Parenteral supplementation with sterile water
Parenteral supplementation with an equivalent volume of sterile water

Locations

Country	Name	City	State
France	UH Porte Madeleine	Orleans
France	Hôpital Clocheville, University Hospital, Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma Gamma Glutamyl Transferase level		After 21 days of parenteral supplementation.
Secondary	Liver function: levels of ammonemia, hyaluronic acid, bilirubin, prothrombin time test, use of ursodeoxycholic acid therapy.		Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcome
Secondary	Cardiac function: echocardiography, EKG.		Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcome
Secondary	Muscle integrity: CK levels.		Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcome
Secondary	Neurological injuries: brain ultrasound and MRI.		Short- (during parenteral supplementation, ultrasound) and long- (3 to 5 months of age, MRI) term outcome
Secondary	Respiratory immaturity		Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcome
Secondary	Acylcarnitine profile, and other fatty acid derivative levels.		Short- (during parenteral supplementation) and long- (3 to 5 months of age) term outcome