Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)
Condition: Infant, Newborn; Infant, Low Birth Weight; Infant, Small for Gestational Age; Infant, Premature; Retinopathy of Prematurity; Bronchopulmonary Dysplasia (BPD)
MeSH terms: Bronchopulmonary Dysplasia; Retinopathy of Prematurity; Premature Birth; Birth Weight
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Inositol lower volume; Inositol mid-level volume; Inositol high volume; Placebo low volume
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes; 20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes; 40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes; Glucose 5% given in volumes equal to that of the comparator drug
Other intervention name(s): Myo-inositol 5%; Myo-inositol 5%; Myo-inositol 5%; Dextrose
Intervention MeSH terms: Inositol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: NICHD Neonatal Research Network; Pharmacokinetics; Inositol; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW); Prematurity