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Trial record 3 of 4 for:    Phelps | Retinopathy of Prematurity

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01030575
Recruitment Status : Completed
First Posted : December 11, 2009
Results First Posted : March 12, 2021
Last Update Posted : June 14, 2022
Sponsor:
Collaborators:
National Eye Institute (NEI)
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Infant, Newborn Infant, Low Birth Weight Infant, Small for Gestational Age Infant, Premature Retinopathy of Prematurity Bronchopulmonary Dysplasia (BPD) Drug: Inositol lower volume Drug: Inositol mid-level volume Drug: Inositol high volume Drug: Placebo low volume Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Phase II Randomized, Double-Masked, Placebo-Controlled, Safety, Pharmacokinetic, and Dose-Ranging Study of Multiple Doses of Inositol in Premature Infants
Study Start Date : January 2010
Actual Primary Completion Date : May 2011
Actual Study Completion Date : September 2013


Arm Intervention/treatment
Experimental: Inositol low volume
10 mg/kg/day Intravenous inositol 5%
Drug: Inositol lower volume
5 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
Other Name: Myo-inositol 5%

Experimental: Inositol mid-level volume
40 mg/kg/day Intravenous inositol 5%
Drug: Inositol mid-level volume
20 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
Other Name: Myo-inositol 5%

Experimental: Inositol high volume
80 mg/kg/day Intravenous inositol 5%
Drug: Inositol high volume
40 mg/kg/dose inositol every 12 hours, given intravenously over 20 minutes
Other Name: Myo-inositol 5%

Placebo Comparator: Placebo
Glucose 5% given in volumes equal to that of the comparator drug
Drug: Placebo low volume
Glucose 5% given in volumes equal to that of the comparator drug
Other Name: Dextrose




Primary Outcome Measures :
  1. Population Pharmacokinetics: V - Volume [ Time Frame: 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. ]
  2. Population Pharmacokinetics: Cl - Clearance [ Time Frame: 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. ]
  3. Population Pharmacokinetics: R - Endogenous Infusion Rate [ Time Frame: 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. ]
  4. Population Pharmacokinetics: k - Elimination Rate (Cl/V) [ Time Frame: 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. ]
  5. Population Pharmacokinetics: t1/2 - Half-Life (0.693/k) [ Time Frame: 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. ]
  6. Population Pharmacokinetics: E - Concentration Due to Endogenous Infusion (R/Cl) [ Time Frame: 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. ]
  7. SD of Residual Error (mg/l) [ Time Frame: 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 :
  1. Number of Participants With Any Retinopathy of Prematurity (ROP) [ Time Frame: 18-22 month corrected age ]
    Any ROP is defined as ROP of any severity that is observed at 18-22 month corrected age

  2. Number of Participants With Any Retinopathy of Prematurity Through 18-22 Month Corrected Age or Death [ Time Frame: 18-22 month corrected age ]
    Number of participants with any Retinopathy of Prematurity (ROP) through 18-22 month corrected age or death

  3. Number of Participants With Any Ophthalmologic Diagnosis [ Time Frame: 18-22 month corrected age ]
    Any ophthalmologic diagnosis at 18-22 month corrected age

  4. Number of Participants With Any Ophthalmologic Treatment [ Time Frame: 18-22 month corrected age ]
    Any ophthalmologic treatment at 18-22 month corrected age

  5. Number of Participants With Any Ophthalmologic Surgical Treatment [ Time Frame: 18-22 month corrected age ]
    Any ophthalmologic surgical treatment at 18-22 month corrected age

  6. Number of Participants With Any Ophthalmologic Medical Treatment [ Time Frame: 18-22 month corrected age ]
    Any ophthalmologic medical treatment at 18-22 month corrected age

  7. Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age [ Time Frame: 18-22 month corrected age ]
    A composite outcome that measures the occurrence of neurodevelopmental impairment between birth and 18-22 months corrected age.

  8. Number of Participants With Moderate or Severe Neurodevelopmental Impairment at 18-22 Month Corrected Age or Death [ Time Frame: 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

  9. Number of Participants With Moderate or Severe Cerebral Palsy [ Time Frame: 18-22 months corrected age. ]
    Cerebral palsy by severity category (absent/mild/moderate/severe).

  10. Number of Participants With Composite Motor Score Less Than 70 [ Time Frame: 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.

  11. Number of Participants With Composite Cognitive Score Less Than 70 [ Time Frame: 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

  12. Number of Participants With Severe Hearing Impairment [ Time Frame: 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.

  13. Number of Participants With Severe Vision Loss [ Time Frame: 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.)

  14. Number of Participants With Gross Motor Function Greater Than or Equal to 2 [ Time Frame: 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.)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 72 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01030575


Locations
Show Show 17 study locations
Sponsors and Collaborators
NICHD Neonatal Research Network
National Eye Institute (NEI)
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Layout table for investigator information
Principal Investigator: Abbot R. Laptook, MD Brown University, Women & Infants Hospital of Rhode Island
Principal Investigator: Michele C. Walsh, MD MS Case Western Reserve University, Rainbow Babies and Children's Hospital
Principal Investigator: Ronald N. Goldberg, MD Duke University
Principal Investigator: Barbara J. Stoll, MD Emory University
Principal Investigator: Brenda B. Poindexter, MD MS Indiana University
Principal Investigator: Abhik Das, PhD RTI International
Principal Investigator: Krisa P. Van Meurs, MD Stanford University
Principal Investigator: Ivan D. Frantz III, MD Tufts Medical Center
Principal Investigator: Kurt Schibler, MD Children's Hospital Medical Center, Cincinnati
Principal Investigator: Waldemar A. Carlo, MD University of Alabama at Birmingham
Principal Investigator: Edward F Bell, MD University of Iowa
Principal Investigator: Kristi L. Watterberg, MD University of New Mexico
Principal Investigator: Dale L. Phelps, MD University of Rochester
Principal Investigator: Pablo J. Sanchez, MD University of Texas, Southwestern Medical Center at Dallas
Principal Investigator: Kathleen A. Kennedy, MD MPH The University of Texas Health Science Center, Houston
Principal Investigator: Roger G. Faix, MD University of Utah
Principal Investigator: Seetha Shankaran, MD Wayne State University
Principal Investigator: Richard A. Ehrenkranz, MD Yale University
Additional Information:
Publications of Results:
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Responsible Party: NICHD Neonatal Research Network
ClinicalTrials.gov Identifier: NCT01030575    
Other Study ID Numbers: NICHD-NRN-0036-2
U10HD021364 ( U.S. NIH Grant/Contract )
U10HD021373 ( U.S. NIH Grant/Contract )
U10HD021385 ( U.S. NIH Grant/Contract )
U10HD027851 ( U.S. NIH Grant/Contract )
U10HD027853 ( U.S. NIH Grant/Contract )
U10HD027856 ( U.S. NIH Grant/Contract )
U10HD027871 ( U.S. NIH Grant/Contract )
U10HD027880 ( U.S. NIH Grant/Contract )
U10HD027904 ( U.S. NIH Grant/Contract )
U10HD034216 ( U.S. NIH Grant/Contract )
U10HD036790 ( U.S. NIH Grant/Contract )
U10HD040492 ( U.S. NIH Grant/Contract )
U10HD040689 ( U.S. NIH Grant/Contract )
U10HD053089 ( U.S. NIH Grant/Contract )
U10HD053109 ( U.S. NIH Grant/Contract )
U10HD053119 ( U.S. NIH Grant/Contract )
U10HD053124 ( U.S. NIH Grant/Contract )
UL1RR024139 ( U.S. NIH Grant/Contract )
UL1RR025744 ( U.S. NIH Grant/Contract )
UL1RR024979 ( U.S. NIH Grant/Contract )
M01RR008084 ( U.S. NIH Grant/Contract )
First Posted: December 11, 2009    Key Record Dates
Results First Posted: March 12, 2021
Last Update Posted: June 14, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NDASG

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NICHD Neonatal Research Network:
NICHD Neonatal Research Network
Pharmacokinetics
Inositol
Very Low Birth Weight (VLBW)
Extremely Low Birth Weight (ELBW)
Prematurity
Additional relevant MeSH terms:
Layout table for MeSH terms
Retinopathy of Prematurity
Premature Birth
Obstetric Labor, Premature
Retinal Diseases
Infant, Premature, Diseases
Bronchopulmonary Dysplasia
Birth Weight
Obstetric Labor Complications
Pregnancy Complications
Eye Diseases
Body Weight
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Newborn, Diseases
Inositol
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs