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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

125 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-01-31

Study Completion Date

2013-09-30

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Inositol low volume

10 mg/kg/day Intravenous inositol 5%

Group Type EXPERIMENTAL

Inositol lower volume

Intervention Type DRUG

5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Inositol mid-level volume

40 mg/kg/day Intravenous inositol 5%

Group Type EXPERIMENTAL

Inositol mid-level volume

Intervention Type DRUG

20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Inositol high volume

80 mg/kg/day Intravenous inositol 5%

Group Type EXPERIMENTAL

Inositol high volume

Intervention Type DRUG

40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Placebo

Glucose 5% given in volumes equal to that of the comparator drug

Group Type PLACEBO_COMPARATOR

Placebo low volume

Intervention Type DRUG

Glucose 5% given in volumes equal to that of the comparator drug

Interventions

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Inositol lower volume

5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Intervention Type DRUG

Inositol mid-level volume

20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Intervention Type DRUG

Inositol high volume

40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes

Intervention Type DRUG

Placebo low volume

Glucose 5% given in volumes equal to that of the comparator drug

Intervention Type DRUG

Other Intervention Names

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Myo-inositol 5% Myo-inositol 5% Myo-inositol 5% Dextrose

Eligibility Criteria

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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)

Minimum Eligible Age

12 Hours

Maximum Eligible Age

72 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Abbot R. Laptook, MD

Role: PRINCIPAL_INVESTIGATOR

Brown University, Women & Infants Hospital of Rhode Island

Michele C. Walsh, MD MS

Role: PRINCIPAL_INVESTIGATOR

Case Western Reserve University, Rainbow Babies and Children's Hospital

Ronald N. Goldberg, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Barbara J. Stoll, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Brenda B. Poindexter, MD MS

Role: PRINCIPAL_INVESTIGATOR

Indiana University

Abhik Das, PhD

Role: PRINCIPAL_INVESTIGATOR

RTI International

Krisa P. Van Meurs, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Ivan D. Frantz III, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Kurt Schibler, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital Medical Center, Cincinnati

Waldemar A. Carlo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Edward F Bell, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa

Kristi L. Watterberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico

Dale L. Phelps, MD

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Pablo J. Sanchez, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas, Southwestern Medical Center at Dallas

Kathleen A. Kennedy, MD MPH

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center, Houston

Roger G. Faix, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Seetha Shankaran, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Richard A. Ehrenkranz, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

Stanford University

Palo Alto, California, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

Indiana University

Indianapolis, Indiana, United States

Site Status

University of Iowa

Iowa City, Iowa, United States

Site Status

Tufts Medical Center

Boston, Massachusetts, United States

Site Status

Wayne State University

Detroit, Michigan, United States

Site Status

University of New Mexico

Albuquerque, New Mexico, United States

Site Status

University of Rochester

Rochester, New York, United States

Site Status

RTI International

Durham, North Carolina, United States

Site Status

Duke University

Durham, North Carolina, United States

Site Status

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

Site Status

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Site Status

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Site Status

University of Texas Health Science Center at Houston

Houston, Texas, United States

Site Status

University of Utah

Salt Lake City, Utah, United States

Site Status

Countries

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United States

References

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Phelps DL, Ward RM, Williams RL, Nolen TL, Watterberg KL, Oh W, Goedecke M, Ehrenkranz RA, Fennell T, Poindexter BB, Cotten CM, Hallman M, Frantz ID 3rd, Faix RG, Zaterka-Baxter KM, Das A, Ball MB, Lacy CB, Walsh MC, Carlo WA, Sanchez PJ, Bell EF, Shankaran S, Carlton DP, Chess PR, Higgins RD. Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatr Res. 2016 Aug;80(2):209-17. doi: 10.1038/pr.2016.97. Epub 2016 Apr 13.

Reference Type RESULT

PMID: 27074126 (View on PubMed)