Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
Condition: Prematurity; Neurodevelopmental Disorder; Carnitine Deficiency
MeSH terms: Premature Birth; Neurodevelopmental Disorders
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): L-carnitine; 5% Dextrose
Intervention type(s): Drug; Drug
Intervention description(s): Infants will receive L-carnitine 50 micromoles/kg/day, divided into three doses, intravenously for a minimum of 2 weeks or until they achieve enteral feeding volume of 100 cc/kg/day. If infant is receiving 100 cc/kg/day of enteral feeds before the supplementation endpoint, an equivalent dose of enteral L-carnitine will be given to the study patients.; Infants will receive 5% dextrose (placebo) three times a day (volume equivalent to the experimental drug) intravenously for a minimum of 2 weeks or until they achieve enteral feeding volume of 100 cc/kg/day. If infant is receiving 100 cc/kg/day of enteral feeds before the supplementation endpoint, an equivalent volume of enteral placebo (5% Dextrose) will be given to the study patients.
Other intervention name(s): Levocarnitine; Carnitor
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Prematurity; Carnitine supplementation; Neonatal Intensive Care; MRI; Amplitude-integrated EEG; NICU Network Neurobehavioral Scale; Bayley Scale of Infant Development III