Clinical trial NCT01783041: Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
Official title: A Double-Blind, Controlled, Randomized Clinical Trial of the Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Prematurity
Neurodevelopmental Disorder
Carnitine Deficiency
Keywords: Prematurity
Carnitine supplementation
Neonatal Intensive Care
MRI
Amplitude-integrated EEG
NICU Network Neurobehavioral Scale
Bayley Scale of Infant Development III
Lead sponsor: Montefiore Medical Center
Sponsor class: OTHER
Collaborators: name: The Gerber Foundation
First posted: 2013-02-04
Enrollment: 144
Sex: ALL
Minimum age (years): 1
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Preterm infants are vulnerable to brain injury, nutritional deficiencies and poor early growth which places them at increased risk for developmental problems later in life. The micronutrient carnitine, which is present in breast milk and stored in the fetus late in pregnancy, has been shown to protect against brain injury in animal studies. Without supplementation, almost all preterm infants develop carnitine deficiency soon after birth. Thus it is important to determine if carnitine supplementation protects against brain injury and improves developmental outcomes in these vulnerable preterm infants. We hypothesize that preterm infants supplemented early with L-carnitine while receiving parenteral nutrition will not develop carnitine deficiency and will have improved growth in the first two weeks of life and higher scores on developmental tests when compared to control infants who did not receive carnitine.

Detailed description: Hypothesis: We hypothesize that preterm infants supplemented with early physiologic doses of L-carnitine while on parenteral nutrition will have improved short-term growth parameters and significantly higher neurobehavioral scores when compared with control infants.

Methods/Design: This is a prospective, randomized controlled clinical trial involving infants with gestational age (GA) \<32 wks who are born at either the Jack D. Weiler Hospital or the Wakefield Division of Montefiore and admitted to theirNeonatal Intensive Care Unit. Informed consent will be obtained from the parents of eligible patients as early as possible within 72 hours of birth. Infants whose parents have signed an informed consent form will be randomized to receive either carnitine supplementation (50 μmol/kg/day) versus placebo within 72-96 hours of birth.

Randomization: As previously described by Pande et al., enrolled patients will be randomized to either the treatment group (L-carnitine, 50 μmol/kg/day) or placebo group (5% glucose, similar volume as the L-carnitine group).28 Patients who meet study entry criteria and have signed informed parental/guardian consent will be enrolled in the study. Because gestational age and small for gestational age (SGA) status will impact our outcome measures, we will ensure they are equally distributed in the arms of the study by stratifying based upon these variables. We will analyze the two study arms using an intent-to-treat analysis. Therefore, enrolled patients will be stratified into fourgroups: gestational age 23 to 26 6/7 weeks, gestational age 27 to 29 6/7weeks, gestational age 30 to 31 6/7 weeks and small for gestational age (SGA). Patients within each stratum will be randomized by the pharmacist using a computerized block-generation with sets of 4. In the case of multiple births, all infants must meet study criteria, and the infants will be randomized as a set. One infant of the multiple-birth set will be randomly chosen for inclusion in the analysis. A recruitment log of all screened infants will be maintained. Clinicians and the nursing staff will be unaware of the arm of the treatment protocol to which the patient is assigned. Codes will be unblinded only after all patients have reached the study end-point, or at the request of the Data Safety Monitoring Board.

Study supplementation: Infants randomized to the treatment group will receive 50 μmol/kg/day of L-carnitine intravenously for 2 weeks, and infants randomized to placebo will received 5% glucose, similar volume to the L-carnitine group. At two weeks, sufficient carnitine is provided in enteral feeds of either breast milk or infant formula. If no intravenous access is available before the supplementation endpoint, the equivalent dose of enteral study supplement (L-carnitine or placebo) will be administered.41 Parenteral and enteral nutrition will be provided according to standard NICU protocol.

Of note, as many as 10% of the infants in the study will likely continue to rely primarily on parenteral nutrition beyond the proposed two-week supplementation period. Enteral feeds may be withheld from these infants due to underlying illnesses such as sepsis or gastrointestinal disorders like necrotizing enterocolitis. Due to the presence of underlying illness, these infants are at an even higher risk for developing developmental delays. Therefore, in study patients who are not receiving adequate enteral nutrition (100 cc/kg/day of enteral intake) after 2-weeks of study supplements, carnitine supplementation will be continued until these infant are receiving adequate enteral feeds; at this point, their physiologic carnitine requirements will be met by enteral nutrition alone.

Eligibility criteria: Inclusion Criteria:

* Infants born at equal to or less than 30 weeks gestation and with birth weight \< 1250 grams
* Less than 72 hours of age
* Signed parental consent

Exclusion Criteria:

* Critically ill infants with life expectancy less than 72 hours
* Inability to obtain consent within 72 hours of birth
* Potentially life-threatening congenital anomalies
* Known hereditary metabolic disorders
* Known chromosomal abnormalities
* Terratogen exposure with symptomatic substance withdrawal
* Congenital viral infections
* Microcephaly
* Grade IV intraventricular hemorrhage or seizures documented within the first 72 hours of life

Primary outcomes:
measure: Time to Regain Birthweight in Infants Who Receive L-carnitine Supplementation Compared to Controls
timeFrame: up to 3 weeks of age
measure: Neurodevelopment Indices in Infants Who Receive L-carnitine Supplementation Compared to Controls (NNNS)
timeFrame: at term equivalent age (38 weeks +/-1 week corrected age)
Secondary outcomes:
measure: Brain Volumes in Infants Who Received L-carnitine Supplementation Compared to Controls
timeFrame: at corrected age (38 weeks +/- 1 week)
measure: Rate of Head Growth in Infants Who Receive L-carnitine Supplementation Compared to Controls
timeFrame: 36 weeks corrected age
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center - Jack D. Weiler Division
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Wakefield Division
state: New York
Study officials:
affiliation: Montefiore Medical Center
name: Mamta Fuloria, MD
role: PRINCIPAL_INVESTIGATOR
References: