Multi-dose Pharmacokinetics and Dose Ranging of Inositol in Premature Infants (INS-2)
- Conditions
- Bronchopulmonary Dysplasia (BPD)Infant, NewbornInfant, Low Birth WeightInfant, PrematureRetinopathy of PrematurityInfant, Small for Gestational Age
- Interventions
- Drug: Placebo low volume
- Registration Number
- NCT01030575
- Lead Sponsor
- NICHD Neonatal Research Network
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 125
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo low volume Glucose 5% given in volumes equal to that of the comparator drug Inositol low volume Inositol lower volume 10 mg/kg/day Intravenous inositol 5% Inositol high volume Inositol high volume 80 mg/kg/day Intravenous inositol 5% Inositol mid-level volume Inositol mid-level volume 40 mg/kg/day Intravenous inositol 5%
- Primary Outcome Measures
Name Time Method Population Pharmacokinetics: V - Volume 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. Population Pharmacokinetics: Cl - Clearance 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. Population Pharmacokinetics: k - Elimination Rate (Cl/V) 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. SD of Residual Error (mg/l) 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. Population Pharmacokinetics: t1/2 - Half-Life (0.693/k) 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. Population Pharmacokinetics: E - Concentration Due to Endogenous Infusion (R/Cl) 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. Population Pharmacokinetics: R - Endogenous Infusion Rate 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 Outcome Measures
Name Time Method Number of Participants With Any Retinopathy of Prematurity (ROP) 18-22 month corrected age Any ROP is defined as ROP of any severity that is observed at 18-22 month corrected age
Number of Participants With Any Retinopathy of Prematurity Through 18-22 Month Corrected Age or Death 18-22 month corrected age Number of participants with any Retinopathy of Prematurity (ROP) through 18-22 month corrected age or death
Number of Participants With Any Ophthalmologic Diagnosis 18-22 month corrected age Any ophthalmologic diagnosis at 18-22 month corrected age
Number of Participants With Any Ophthalmologic Treatment 18-22 month corrected age Any ophthalmologic treatment at 18-22 month corrected age
Number of Participants With Composite Cognitive Score Less Than 70 18-22 months corrected age. This is measured as a score of less than 70 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score
Number of Participants With Moderate or Severe Cerebral Palsy 18-22 months corrected age. Cerebral palsy by severity category (absent/mild/moderate/severe).
Number of Participants With Any Ophthalmologic Surgical Treatment 18-22 month corrected age Any ophthalmologic surgical treatment at 18-22 month corrected age
Number of Participants With Any Ophthalmologic Medical Treatment 18-22 month corrected age Any ophthalmologic medical treatment at 18-22 month corrected age
Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age or Death 8-22 months corrected age. Moderate or Severe NDI defined as occurrence of any of the following: GMFCS level II or higher (severe is level 4 or 5), Bayley III cognitive composite score \< 85 (severe is \<70), Bayley III motor composite score \< 85 (severe is \<70), unilateral blind or bilateral blind, permanent hearing loss that does not permit child to understand directions of the examiner and communicate despite amplification with cochlear implant or hearing aid
Number of Participants With Gross Motor Function Greater Than or Equal to 2 18 -22 months corrected age A Gross Motor Function Classification System (GMFCS) level of at least II (on a scale from level I to V, with I indicating normal gross motor function and higher levels indicating greater impairment). Level II is defined as Infants maintain floor sitting but may need to use their hands for support to maintain balance. Infants creep on their stomach or crawl on hands and knees with reciprocal leg movement. Infants may pull to stand and take steps holding on to furniture.)
Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age 18-22 month corrected age A composite outcome that measures the occurrence of neurodevelopmental impairment between birth and 18-22 months corrected age.
Number of Participants With Composite Motor Score Less Than 70 18-22 months corrected age This is measured as a scored of less than 70 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite motor score. Higher scores indicate better performance.
Number of Participants With Severe Hearing Impairment 18-22 months corrected age. Defined as permanent hearing loss that does not permit child to understand directions of the examiner and communicate despite amplification with cochlear implant or hearing aid.
Number of Participants With Severe Vision Loss 18-22 Months Corrected Age Vision loss as diagnosed by an ophthalmologist as legally blind, and subdivided into "ophthalmic origin", or "not ophthalmic origin" (i.e., cortical blindness is non-ophthalmic in origin and indicates that there is no retinal detachment or other abnormal fundus or ocular finding, except optic atrophy. Such cases will be considered central \[neurologic\] in origin.)
Trial Locations
- Locations (17)
University of Iowa
🇺🇸Iowa City, Iowa, United States
Stanford University
🇺🇸Palo Alto, California, United States
Emory University
🇺🇸Atlanta, Georgia, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
RTI International
🇺🇸Durham, North Carolina, United States
Duke University
🇺🇸Durham, North Carolina, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital
🇺🇸Cleveland, Ohio, United States
Brown University, Women & Infants Hospital of Rhode Island
🇺🇸Providence, Rhode Island, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
University of Rochester
🇺🇸Rochester, New York, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States