Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Infant, Newborn Infant, Low Birth Weight Infant, Small for Gestational Age Infant, Premature Retinopathy of Prematurity Bronchopulmonary Dysplasia (BPD) |
Drug: Inositol lower volume Drug: Inositol mid-level volume Drug: Inositol high volume Drug: Placebo low volume |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention |
| Official Title: | Phase II Randomized, Double-Masked, Placebo-Controlled, Safety, Pharmacokinetic, and Dose-Ranging Study of Multiple Doses of Inositol in Premature Infants |
- Population pharmacokinetics [ Time Frame: Until 10 weeks of age or hospital discharge ] [ Designated as safety issue: Yes ]
- Adverse events during and following infusion, using a neonatal toxicity classification [ Time Frame: Until hospital discharge ] [ Designated as safety issue: Yes ]
| Enrollment: | 125 |
| Study Start Date: | January 2010 |
| Estimated Study Completion Date: | May 2013 |
| Primary Completion Date: | May 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Inositol low volume
10 mg/kg/day Intravenous inositol 5%
|
Drug: Inositol lower volume
5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
Other Name: Myo-inositol 5%
|
|
Experimental: Inositol mid-level volume
40 mg/kg/day Intravenous 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%
|
|
Experimental: Inositol high volume
80 mg/kg/day Intravenous inositol 5%
|
Drug: Inositol high volume
40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
Other Name: Myo-inositol 5%
|
|
Placebo Comparator: Placebo
Glucose 5% given in volumes equal to that of the comparator drug
|
Drug: Placebo low volume
Glucose 5% given in volumes equal to that of the comparator drug
Other Name: Dextrose
|
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.
Eligibility| Ages Eligible for Study: | up to 72 Hours |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
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)
Contacts and Locations| United States, Alabama | |
| University of Alabama at Birmingham | |
| Birmingham, Alabama, United States, 35233 | |
| United States, California | |
| Stanford University | |
| Palo Alto, California, United States, 94304 | |
| United States, Connecticut | |
| Yale University | |
| New Haven, Connecticut, United States, 06504 | |
| United States, Georgia | |
| Emory University | |
| Atlanta, Georgia, United States, 30303 | |
| United States, Indiana | |
| Indiana University | |
| Indianapolis, Indiana, United States, 46202 | |
| United States, Iowa | |
| University of Iowa | |
| Iowa City, Iowa, United States, 52242 | |
| United States, Massachusetts | |
| Tufts Medical Center | |
| Boston, Massachusetts, United States, 02111 | |
| United States, Michigan | |
| Wayne State University | |
| Detroit, Michigan, United States, 48201 | |
| United States, New Mexico | |
| University of New Mexico | |
| Albuquerque, New Mexico, United States, 87131 | |
| United States, New York | |
| University of Rochester | |
| Rochester, New York, United States, 14642 | |
| United States, North Carolina | |
| Duke University | |
| Durham, North Carolina, United States, 27710 | |
| RTI International | |
| Durham, North Carolina, United States, 27705 | |
| United States, Ohio | |
| Case Western Reserve University, Rainbow Babies and Children's Hospital | |
| Cleveland, Ohio, United States, 44106 | |
| United States, Rhode Island | |
| Brown University, Women & Infants Hospital of Rhode Island | |
| Providence, Rhode Island, United States, 02905 | |
| United States, Texas | |
| University of Texas Southwestern Medical Center at Dallas | |
| Dallas, Texas, United States, 75235 | |
| University of Texas Health Science Center at Houston | |
| Houston, Texas, United States, 77030 | |
| United States, Utah | |
| University of Utah | |
| Salt Lake City, Utah, United States, 84108 | |
| Principal Investigator: | Abbot R. Laptook, MD | Brown University, Women & Infants Hospital of Rhode Island |
| Principal Investigator: | Michele C. Walsh, MD MS | Case Western Reserve University, Rainbow Babies and Children's Hospital |
| Principal Investigator: | Ronald N. Goldberg, MD | Duke University |
| Principal Investigator: | Barbara J. Stoll, MD | Emory University |
| Principal Investigator: | Brenda B. Poindexter, MD MS | Indiana University |
| Principal Investigator: | Abhik Das, PhD | RTI International |
| Principal Investigator: | Krisa P. Van Meurs, MD | Stanford University |
| Principal Investigator: | Ivan D. Frantz III, MD | Tufts Medical Center |
| Principal Investigator: | Kurt Schibler, MD | Cincinnati Children's Medical Center |
| Principal Investigator: | Waldemar A. Carlo, MD | University of Alabama at Birmingham |
| Principal Investigator: | Edward F Bell, MD | University of Iowa |
| Principal Investigator: | Kristi L. Watterberg, MD | University of New Mexico |
| Principal Investigator: | Dale L. Phelps, MD | University of Rochester |
| Principal Investigator: | Pablo J. Sanchez, MD | University of Texas Southwestern Medical Center at Dallas |
| Principal Investigator: | Kathleen A. Kennedy, MD MPH | The University of Texas Health Science Center, Houston |
| Principal Investigator: | Roger G. Faix, MD | University of Utah |
| Principal Investigator: | Seetha Shankaran, MD | Wayne State University |
| Principal Investigator: | Richard A. Ehrenkranz, MD | Yale University |
More Information
Additional Information:
No publications provided
| Responsible Party: | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| ClinicalTrials.gov Identifier: | NCT01030575 History of Changes |
| Other Study ID Numbers: | NICHD-NRN-0036-2, U10HD021364, U10HD021373, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027871, U10HD027880, U10HD027904, U10HD034216, U10HD036790, U10HD040492, U10HD040689, U10HD053089, U10HD053109, U10HD053119, U10HD053124, UL1RR024139, UL1RR025744, UL1RR024979, M01RR008084 |
| Study First Received: | December 10, 2009 |
| Last Updated: | February 13, 2013 |
| Health Authority: | United States: Federal Government United States: Institutional Review Board United States: Food and Drug Administration |
Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
|
NICHD Neonatal Research Network Pharmacokinetics Inositol |
Very Low Birth Weight (VLBW) Extremely Low Birth Weight (ELBW) Prematurity |
Additional relevant MeSH terms:
|
Birth Weight Bronchopulmonary Dysplasia Retinal Diseases Retinopathy of Prematurity Body Weight Signs and Symptoms Ventilator-Induced Lung Injury Lung Injury Lung Diseases Respiratory Tract Diseases |
Infant, Premature, Diseases Infant, Newborn, Diseases Eye Diseases Inositol Vitamin B Complex Vitamins Micronutrients Growth Substances Physiological Effects of Drugs Pharmacologic Actions |
ClinicalTrials.gov processed this record on May 22, 2013