Clinical trial NCT01030575: Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)
Official title: Phase II Randomized, Double-Masked, Placebo-Controlled, Safety, Pharmacokinetic, and Dose-Ranging Study of Multiple Doses of Inositol in Premature Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infant, Newborn
Infant, Low Birth Weight
Infant, Small for Gestational Age
Infant, Premature
Retinopathy of Prematurity
Bronchopulmonary Dysplasia (BPD)
Keywords: NICHD Neonatal Research Network
Pharmacokinetics
Inositol
Very Low Birth Weight (VLBW)
Extremely Low Birth Weight (ELBW)
Prematurity
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Eye Institute (NEI)
name: National Center for Research Resources (NCRR)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2009-12-11
Enrollment: 125
Sex: ALL
Minimum age (years): 12
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Population Pharmacokinetics: V - Volume
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: Population Pharmacokinetics: Cl - Clearance
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: Population Pharmacokinetics: R - Endogenous Infusion Rate
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: Population Pharmacokinetics: k - Elimination Rate (Cl/V)
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: Population Pharmacokinetics: t1/2 - Half-Life (0.693/k)
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: Population Pharmacokinetics: E - Concentration Due to Endogenous Infusion (R/Cl)
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
measure: SD of Residual Error (mg/l)
timeFrame: 8-10 blood samples per infant were drawn over 10 weeks for infant safety with the full study duration represented across all infants. Samples were drawn at baseline & on days 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 35, 42, 56, and 70.
Secondary outcomes:
measure: Number of Participants With Any Retinopathy of Prematurity (ROP)
timeFrame: 18-22 month corrected age
measure: Number of Participants With Any Retinopathy of Prematurity Through 18-22 Month Corrected Age or Death
timeFrame: 18-22 month corrected age
measure: Number of Participants With Any Ophthalmologic Diagnosis
timeFrame: 18-22 month corrected age
measure: Number of Participants With Any Ophthalmologic Treatment
timeFrame: 18-22 month corrected age
measure: Number of Participants With Any Ophthalmologic Surgical Treatment
timeFrame: 18-22 month corrected age
measure: Number of Participants With Any Ophthalmologic Medical Treatment
timeFrame: 18-22 month corrected age
measure: Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age
timeFrame: 18-22 month corrected age
measure: Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age or Death
timeFrame: 8-22 months corrected age.
measure: Number of Participants With Moderate or Severe Cerebral Palsy
timeFrame: 18-22 months corrected age.
measure: Number of Participants With Composite Motor Score Less Than 70
timeFrame: 18-22 months corrected age
measure: Number of Participants With Composite Cognitive Score Less Than 70
timeFrame: 18-22 months corrected age.
measure: Number of Participants With Severe Hearing Impairment
timeFrame: 18-22 months corrected age.
measure: Number of Participants With Severe Vision Loss
timeFrame: 18-22 Months Corrected Age
measure: Number of Participants With Gross Motor Function Greater Than or Equal to 2
timeFrame: 18 -22 months corrected age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R. Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C. Walsh, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Ronald N. Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Barbara J. Stoll, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Brenda B. Poindexter, MD MS
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P. Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts Medical Center
name: Ivan D. Frantz III, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Kurt Schibler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A. Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Edward F Bell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Kristi L. Watterberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Dale L. Phelps, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Pablo J. Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Kathleen A. Kennedy, MD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Roger G. Faix, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Richard A. Ehrenkranz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.