Single-Dose Intravenous Inositol Pharmacokinetics in Preterm Infants (INS-1)

This pilot study was 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 a single intravenous dose 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 was to evaluate the single-dose pharmacokinetics and safety of different amounts of intravenous myo-inositol (provided by Ross Products Division, Abbott Laboratories) in very low birth weight neonates, in preparation for a future Phase III multi-center randomized controlled trial. This study enrolled 74 infants at high risk for retinopathy at 9 NICHD Neonatal Research Network sites, and randomly assigned them to receive either 60mg/kg of 5% inositol, 120 mg/kg of 5% inositol, 60 mg/kg of 5% glucose (the placebo), or 120 mg/kg of 5% glucose.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity; Bronchopulmonary Dysplasia (BPD); Infant, Small for Gestational Age; Infant, Premature; Infant, Low Birth Weight; Infant, Newborn
• Intervention / Treatment: Drug: Inositol lower volume; Drug: Inositol higher volume; Drug: Placebo lower volume; Drug: Placebo higher volume

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 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. Two randomized trials have shown that intravenous inositol supplementation in the first week significantly reduced death, bronchopulmonary dysplasia (BPD), and retinopathy. One study of oral supplements was less convincing, but also supported reduction of retinopathy.

This pilot study evaluated the half-life pharmacokinetics of a single-dose of myo-inositol (provided by Ross Products Division, Abbott Laboratories) in very low birth weight infants, looking at changes in blood and urine inositol levels. 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 doses for a subsequent multi-dose pilot study, and for the planned large multi-center trials.

In this study, nine NICHD Neonatal Research Network sites enrolled 74 infants of less than 30 weeks gestation and randomly assigned them to receive either 60mg/kg of 5% inositol, 120 mg/kg of 5% inositol, 60 mg/kg of 5% glucose (the placebo), or 120 mg/kg of 5% glucose. Concentrations of inositol were measured in both blood and urine to determine population pharmacokinetic parameters for these infants.

Stratification: Enrolled infants were stratified by age with 37 infants of 23 0/7 to 26 6/7 weeks in one group and 37 infants of 27 0/7 to 29 6/7 weeks in a second group.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University, Women & Infants Hospital of Rhode Island
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 days to 6 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 23 0/7 to 26 6/7 weeks gestational age (36 infants) or
• 27 0/7 to 29 6/7 weeks gestational age (36 infants)
• 600-1500 grams birth weight
• No enteral feedings since birth at enrollment
• 3-6 days (25-132 hours) postnatal age

Note: Because of the high mortality expected in this population (15-20%), the study design (originally for 72 infants) required recruitment of a replacement subject if any infant failed to complete the four blood samples during the first week of the study.

Exclusion Criteria:

• Major congenital anomalies
• Moribund or not to be provided continued support
• Renal failure suspected (creatinine >2.5 with oliguria)
• Exchange transfusion received or expected to receive

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inositol low volume; Single dose of intravenous inositol 5%, 60 mg/kg (1.2ml/kg) given over 20 minutes	Drug: Inositol lower volume; 60 mg/kg (1.2ml/kg) of myo-inositol 5% given intravenously over 20 minutes.
Experimental: Inositol high volume; Single dose of intravenous inositol 5%, 120 mg/kg (2.4ml/kg) given over 20 minutes	Drug: Inositol higher volume; 120 mg/kg (2.4ml/kg) of myo-inositol 5% given intravenously over 20 minutes.
Placebo Comparator: Placebo low volume; Placebo (5% glucose) at a volume equal to 60 mg/kg (1.2 ml/kg) given via IV over 20 minutes.	Drug: Placebo lower volume; 60 mg/kg (1.2ml/kg) of glucose 5% given intravenously over 20 minutes.
Placebo Comparator: Placebo high volume; Placebo (5% glucose) at a volume equal to 120 mg/kg (2.4 ml/kg) given via IV over 20 minutes	Drug: Placebo higher volume; 120 mg/kg (2.4ml/kg) of glucose 5% given intravenously over 20 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Population pharmacokinetics	0-100 hours following infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events during and following infusion, using a neonatal toxicity classification	Until discharge

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Eye Institute (NEI); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Ivan D. Frantz, III, MD, Tufts Medical Center

Publications and helpful links

Helpful Links

• NICHD Neonatal Research Network

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): December 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: July 6, 2006
• First Submitted That Met QC Criteria: July 6, 2006
• First Posted (Estimate): July 10, 2006

Study Record Updates

• Last Update Posted (Actual): June 20, 2017
• Last Update Submitted That Met QC Criteria: June 19, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Prematurity; Inositol; NICHD Neonatal Research Network; Very Low Birth Weight (VLBW); Extremely Low Birth Weight (ELBW)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Eye Diseases; Infant, Newborn, Diseases; Retinal Diseases; Body Weight; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Premature Birth; Birth Weight; Retinopathy of Prematurity; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Inositol
• Other Study ID Numbers: NICHD-NRN-0036-1; U10HD036790 (U.S. NIH Grant/Contract); U10HD021364 (U.S. NIH Grant/Contract); U10HD021373 (U.S. NIH Grant/Contract); U10HD021385 (U.S. NIH Grant/Contract); U10HD027851 (U.S. NIH Grant/Contract); U10HD027853 (U.S. NIH Grant/Contract); U10HD027856 (U.S. NIH Grant/Contract); U10HD027871 (U.S. NIH Grant/Contract); U10HD027880 (U.S. NIH Grant/Contract); U10HD027904 (U.S. NIH Grant/Contract); U10HD034216 (U.S. NIH Grant/Contract); U10HD040492 (U.S. NIH Grant/Contract); U10HD040689 (U.S. NIH Grant/Contract); U10HD053089 (U.S. NIH Grant/Contract); U10HD053109 (U.S. NIH Grant/Contract); U10HD053119 (U.S. NIH Grant/Contract); U10HD053124 (U.S. NIH Grant/Contract); UL1RR024139 (U.S. NIH Grant/Contract); UL1RR025744 (U.S. NIH Grant/Contract); UL1RR024979 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No