Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)

This pilot study is a randomized, placebo-controlled, clinical trial to measure changes in blood and urine levels of inositol in premature infants at high risk for retinopathy of prematurity (ROP) following repeated doses of inositol. Based on previous studies, the premise is that maintaining inositol concentrations similar to those occurring naturally in utero will reduce the rates of ROP and bronchopulmonary dysplasia in premature infants. The objective is to evaluate pharmacokinetics, safety, and clinical outcomes of multiple doses of three different dose amounts of myo-inositol (provided by Abbott Laboratories) in very low birth weight premature infants. This study will enroll an estimated 96 infants at 17 NICHD Neonatal Research Network sites. Infants will be randomly assigned to receive either 10 mg/kg of 5% inositol, 40 mg/kg of 5% inositol, 80 mg/kg of 5% inositol, or 5% glucose given in the same volumes and timings as the inositol dosage to maintain masking. Enrollees will receive their assigned dose or placebo daily, starting within 72 hours of birth, and continuing until they reach 34 weeks post-menstrual age, 10 weeks chronologic age, or until the time of hospital discharge, whichever occurs first. The study drug will be administered first intravenously; as the infants progress to full feeding, the drug will be given enterally (orally or via feeding tube). Enrollees will be seen for a follow-up examination at 18-22 months corrected age. This pilot study is in preparation for a future Phase III multi-center randomized controlled trial.

Retinopathy of prematurity (ROP) is an abnormal growth of the blood vessels in the eye that occurs primarily in very premature infants. Eye development occurs normally in the womb; in infants born prematurely, however, the blood vessels must finish developing outside the protective environment of the uterus. Retinopathy of prematurity (also known as retrolental fibroplasia) is a leading cause of blindness and other vision impairments (myopia, strabismus, and amblyopia) in children, both in developed and developing countries.

Inositol is a naturally-occurring sugar alcohol produced by the fetus and placenta and is present in high levels in fetal blood throughout pregnancy in humans and other animals. Serum levels fall rapidly after birth, although this fall is moderated in infants who receive breast milk or fortified formula. Two randomized trials have shown that intravenous inositol supplementation in the first week significantly reduced death, bronchopulmonary dysplasia (BPD), and retinopathy. One study of enteral supplements (given orally or via feeding tube) was less convincing, but also supported reduction of retinopathy.

This pilot study will evaluate changes in blood and urine inositol levels (half-life pharmacokinetics) of multiple doses of myo-inositol (provided by Abbott Laboratories, Abbott Nutrition Division) given to very low birth weight infants. The premise is that maintaining inositol concentrations similar to those occurring naturally in utero will reduce the rates of retinopathy and bronchopulmonary dysplasia in premature infants. Results from this study will be used to select the dose for a large multi-center trial.

In this study, 17 NICHD Neonatal Research Network sites will enroll approximately 96 infants at 12-72 hours of age. Enrolled infants will be randomly assigned to receive either 10mg/kg of 5% inositol, 40 mg/kg of 5% inositol, 80 mg/kg of 5% inositol, or 5% glucose given in the same volumes and timings as the inositol dosage to maintain masking. Inositol will be administered intravenously until babies are feeding normally, at which time the same dose and formulation will be administered enterally (orally or via feeding tube). Concentrations of inositol will be measured in blood, urine, and milk received.

Stratification: Recruitment will be stratified by gestational age into infants born at 23 0/7 to 26 6/7 weeks gestational age and infants born at 27 0/7 to 29 6/7 weeks gestational age.

• Infant, Newborn
• Infant, Low Birth Weight
• Infant, Small for Gestational Age
• Infant, Premature
• Retinopathy of Prematurity
• Bronchopulmonary Dysplasia (BPD)

• Drug: Inositol lower volume
  5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
  Other Name: Myo-inositol 5%
• Drug: Inositol mid-level volume
  20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
  Other Name: Myo-inositol 5%
• Drug: Inositol high volume
  40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
  Other Name: Myo-inositol 5%
• Drug: Placebo low volume
  Glucose 5% given in volumes equal to that of the comparator drug
  Other Name: Dextrose

• Experimental: Inositol low volume
  10 mg/kg/day Intravenous inositol 5%
  Intervention: Drug: Inositol lower volume
• Experimental: Inositol mid-level volume
  40 mg/kg/day Intravenous inositol 5%
  Intervention: Drug: Inositol mid-level volume
• Experimental: Inositol high volume
  80 mg/kg/day Intravenous inositol 5%
  Intervention: Drug: Inositol high volume
• Placebo Comparator: Placebo
  Glucose 5% given in volumes equal to that of the comparator drug
  Intervention: Drug: Placebo low volume

Inclusion Criteria:

• 23 0/7 to 26 6/7 weeks gestational age (48 infants) or
• 27 0/7 to 29 6/7 weeks gestational age (48 infants)
• 401 grams birth weight or larger
• 12-72 hours of age

Exclusion Criteria:

• Major congenital and intracranial anomalies
• Moribund or not to be provided continued support
• Seizures
• Suspected renal failure (oliguria <0.6 cc/kg/hr for >24 hours or creatinine >2.5 mg/dL)

• National Eye Institute (NEI)
• National Center for Research Resources (NCRR)