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

Retinopathy of Prematurity Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01030575
• Other study ID #: NICHD-NRN-0036-2
• Secondary ID: U10HD021364U10HD
• Status: Completed
• Phase: Phase 2
• Start date: January 2010
• Est. completion date: September 2013

Study information

• Verified date: March 2022
• Source: NICHD Neonatal Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 125
• Est. completion date: September 2013
• Est. primary completion date: May 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 72 Hours

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

Drug:
• Inositol lower volume
5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
• Inositol mid-level volume
20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
• Inositol high volume
40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
• Placebo low volume
Glucose 5% given in volumes equal to that of the comparator drug

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Tufts Medical Center	Boston	Massachusetts
United States	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	RTI International	Durham	North Carolina
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Yale University	New Haven	Connecticut
United States	Stanford University	Palo Alto	California
United States	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	University of Rochester	Rochester	New York
United States	University of Utah	Salt Lake City	Utah

Sponsors (4)

Lead Sponsor	Collaborator
NICHD Neonatal Research Network	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Research Resources (NCRR), National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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, Sánchez PJ, Bell EF, Shankar — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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	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
Secondary	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
Secondary	Number of Participants With Any Ophthalmologic Diagnosis	Any ophthalmologic diagnosis at 18-22 month corrected age	18-22 month corrected age
Secondary	Number of Participants With Any Ophthalmologic Treatment	Any ophthalmologic treatment at 18-22 month corrected age	18-22 month corrected age
Secondary	Number of Participants With Any Ophthalmologic Surgical Treatment	Any ophthalmologic surgical treatment at 18-22 month corrected age	18-22 month corrected age
Secondary	Number of Participants With Any Ophthalmologic Medical Treatment	Any ophthalmologic medical treatment at 18-22 month corrected age	18-22 month corrected age
Secondary	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
Secondary	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.
Secondary	Number of Participants With Moderate or Severe Cerebral Palsy	Cerebral palsy by severity category (absent/mild/moderate/severe).	18-22 months corrected age.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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

External Links

•   NICHD Neonatal Research Network