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

Study Overview
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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.

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.

Official Title
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Phase II Randomized, Double-Masked, Placebo-Controlled, Safety, Pharmacokinetic, and Dose-Ranging Study of Multiple Doses of Inositol in Premature Infants

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

Intervention / Treatment
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* Drug: Inositol lower volume
* Drug: Inositol mid-level volume
* Drug: Inositol high volume
* Drug: Placebo low volume


Participation Criteria
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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)

Ages Eligible for Study
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Minimum Age: 12 Hours
Maximum Age: 72 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inositol low volume<br>10 mg/kg/day Intravenous inositol 5% | Drug: Inositol lower volume<br>* 5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes<br>* Other names: Myo-inositol 5%;|
| Experimental: Inositol mid-level volume<br>40 mg/kg/day Intravenous inositol 5% | Drug: Inositol mid-level volume<br>* 20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes<br>* Other names: Myo-inositol 5%;|
| Experimental: Inositol high volume<br>80 mg/kg/day Intravenous inositol 5% | Drug: Inositol high volume<br>* 40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes<br>* Other names: Myo-inositol 5%;|
| Placebo Comparator: Placebo<br>Glucose 5% given in volumes equal to that of the comparator drug | Drug: Placebo low volume<br>* Glucose 5% given in volumes equal to that of the comparator drug<br>* Other names: Dextrose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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: 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. | 
| 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. | 
| 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. | 
| 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Retinopathy of Prematurity (ROP) | Any ROP is defined as ROP of any severity that is observed at 18-22 month corrected age | 18-22 month corrected age | 
| Number of Participants With Any Retinopathy of Prematurity Through 18-22 Month Corrected Age or Death | Number of participants with any Retinopathy of Prematurity (ROP) through 18-22 month corrected age or death | 18-22 month corrected age | 
| Number of Participants With Any Ophthalmologic Diagnosis | Any ophthalmologic diagnosis at 18-22 month corrected age | 18-22 month corrected age | 
| Number of Participants With Any Ophthalmologic Treatment | Any ophthalmologic treatment at 18-22 month corrected age | 18-22 month corrected age | 
| Number of Participants With Any Ophthalmologic Surgical Treatment | Any ophthalmologic surgical treatment at 18-22 month corrected age | 18-22 month corrected age | 
| Number of Participants With Any Ophthalmologic Medical Treatment | Any ophthalmologic medical treatment at 18-22 month corrected age | 18-22 month corrected age | 
| Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age | A composite outcome that measures the occurrence of neurodevelopmental impairment between birth and 18-22 months corrected age. | 18-22 month corrected age | 
| Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age or Death | 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 | 8-22 months corrected age. | 
| Number of Participants With Moderate or Severe Cerebral Palsy | Cerebral palsy by severity category (absent/mild/moderate/severe). | 18-22 months corrected age. | 
| Number of Participants With Composite Motor Score Less Than 70 | 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. | 18-22 months corrected age | 
| Number of Participants With Composite Cognitive Score Less Than 70 | This is measured as a score of less than 70 on the Bayley Scale of Infant and Toddler Development (BSID)-III composite cognitive score | 18-22 months corrected age. | 
| Number of Participants With Severe Hearing Impairment | 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. | 18-22 months corrected age. | 
| Number of Participants With Severe Vision Loss | 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.) | 18-22 Months Corrected Age | 
| Number of Participants With Gross Motor Function Greater Than or Equal to 2 | 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.) | 18 -22 months corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prematurity, Extremely Low Birth Weight (ELBW), Inositol, Very Low Birth Weight (VLBW), NICHD Neonatal Research Network, Pharmacokinetics