Inositol to Reduce Retinopathy of Prematurity (INS-3)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT01954082
First received: September 26, 2013
Last updated: May 8, 2014
Last verified: April 2014
  Purpose

This is a Phase 3, randomized, double-masked, placebo-controlled study designed to determine the effectiveness of myo-Inositol 5% Injection to increase the incidence of survival without severe Retinopathy of Prematurity (ROP) through acute/final ROP determination up to 55 weeks postmenstrual age (PMA) in premature infants <28 0/7 weeks' gestation.


Condition Intervention Phase
Retinopathy of Prematurity (ROP)
Drug: myo-Inositol 5% Injection
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: INS-3: A Phase 3, Randomized, Double-Masked, Placebo-Controlled Study of the Efficacy and Safety of Myo-Inositol 5% Injection to Increase Survival Without Severe Retinopathy of Prematurity (Reduce-ROP) in Extremely Premature Infants

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Survival without severe Retinopathy of Prematurity (ROP) [ Time Frame: by 55 weeks PMA ] [ Designated as safety issue: Yes ]

    The primary outcome is survival without severe ROP through Acute/Final ROP status determination (favorable) versus development of severe ROP or death prior to reaching Acute/Final ROP status (unfavorable) followed up to 55 weeks PMA.

    • Death in relation to the primary variable will be defined as from any cause before Acute/Final ROP status is determined.
    • Favorable Acute/Final ROP status requires that no ROP, or only mild ROP has occurred in both eyes and that the eyes have matured beyond the risk of developing severe ROP.
    • Unfavorable ROP determination requires that one or both eyes reach ROP severity warranting intervention.


Secondary Outcome Measures:
  • Bronchopulmonary Dysplasia (BPD) [ Time Frame: 36 weeks PMA ] [ Designated as safety issue: No ]
    NICHD Physiologic Definition: Requiring oxygen to maintain an oxygen saturation of 90% or greater while breathing room air at 36 weeks PMA

  • BPD or Death from BPD [ Time Frame: prior to 37 weeks PMA ] [ Designated as safety issue: Yes ]
    BPD (Physiologic Definition) or Death from BPD prior to 37 weeks PMA, with cause of death certified by the Center PI as the primary cause, or a significant co-contributing cause of death.

  • All cause death [ Time Frame: 22 - 26 months age ] [ Designated as safety issue: No ]
    Defined as death from any cause following randomization

  • Any ROP [ Time Frame: by 55 weeks PMA ] [ Designated as safety issue: No ]
    Any ROP: defined as ROP of any severity that is observed on at least 2 examinations in either eye through the time that Acute/Final ROP status is reached.

  • Type 2 ROP [ Time Frame: by 55 weeks PMA ] [ Designated as safety issue: No ]

    Type 2 ROP through the time that Acute/Final ROP status is reached: defined as 1 or both eyes reaching Type 2 ROP (ETROP 2003), but not Type 1.

    Type 2 ROP is defined as: (ETROP 2003).

    • in Zone II: Stage 3 ROP without Plus Disease, or
    • in Zone I: Stage 1 or 2 ROP without Plus Disease

  • Severe IVH [ Time Frame: approximately 1 to 6 weeks after birth ] [ Designated as safety issue: No ]
    IVH Grades 3 or 4 on either side of the brain, or extensive PVL. IVH will be classified as described by Papile (Papile 1978). PVL will be graded by the characteristics of the periventricular white matter on ultrasound or MRI done between 4 to approximately 6 weeks after birth per usual care (Barkovich 2000) and/or porencephalic cyst.


Other Outcome Measures:
  • The occurrence of adverse events and serious adverse events [ Time Frame: 7 days post study drug discontinuation ] [ Designated as safety issue: Yes ]
  • Necrotizing Enterocolitis (NEC) [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    Stage II or worse, whether treated (medically or surgically) and if the infant survived (modified Bell's classification [Walsh 1986]).

  • Isolated gastrointestinal perforation [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    judged not to be due to NEC

  • Late onset sepsis [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    culture positive septicemia/bacteremia (≥72 hours of age) treated with antibiotics for ≥ 5 days or died before treatment was completed.

  • Patent Ductus Arteriosus (PDA) [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    Occurrence of clinically significant patent ductus arteriosus (PDA), and if received intervention with prostaglandin inhibitors, and/or surgery.

  • Seizures [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    Seizures treated with an anticonvulsant for >72 hours

  • Total days on parenteral nutrition [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    Total days on parenteral nutrition (including amino acids and/or lipids)

  • Days on oxygen, days on ventilator [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
  • Hearing Loss [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ] [ Designated as safety issue: Yes ]
    Hearing loss as defined as never passing a hearing screening in one or both ears

  • Neurodevelopment [ Time Frame: 22-26 months corrected age ] [ Designated as safety issue: No ]
    Neurodevelopment at 22-26 months corrected age (i.e., 22-26 months past due date) using the Bayley Scales of Infant Development III.

  • Vision loss [ Time Frame: 22-26 Months Corrected Age ] [ Designated as safety issue: No ]
    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.)

  • Hearing loss [ Time Frame: 22-26 Months Corrected Age ] [ Designated as safety issue: No ]
    Hearing loss requiring that hearing aids be prescribed.

  • Cerebral palsy [ Time Frame: 22-26 Months Corrected Age ] [ Designated as safety issue: No ]
    Cerebral palsy by severity category (absent/mild/moderate/severe).

  • Overall health status [ Time Frame: 22-26 Months Corrected Age ] [ Designated as safety issue: No ]
    Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses).


Estimated Enrollment: 1760
Study Start Date: January 2014
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: myo-Inositol 5% Injection
Within 12-72 hours of birth, infants will receive 80 mg myo-inositol 5% Injection per kilogram per day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronologic age, or the time of discharge. myo-Inositol 5% Injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours.
Drug: myo-Inositol 5% Injection

Abbott Nutrition Division, Abbott Laboratories is supplying myo-Inositol 5% Injection to the clinical centers for the duration of the trial.

Inositol: myo-Inositol 5% Injection is an isotonic, preservative-free, sterile 5% solution of myo-inositol in water containing 0.5 gm sodium chloride per liter (8.55mM), pH 6.5-7.5. It is administered via IV infusion using syringe pump over 15-30 minutes twice per day at 12-hour intervals at a dose of 80 mg inositol/kg/day (40 mg inositol/kg/dose), which is equivalent to 1.6 mL/kg/day (0.80 mL/kg/dose).

Other Name: Inositol
Placebo Comparator: 5% glucose(dextrose)
Within 12-72 hours of birth, infants will receive 80 mg 5% glucose(dextrose) USP for intravenous infusion per kilogram per day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronologic age, or the time of discharge. myo-Inositol 5% Injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours.

Detailed Description:

Approximately 1760 infants are to be enrolled at approximately 18 NICHD Neonatal Research Network (NRN) Centers (approximately 44 sites) in the United States. Infants meeting the study selection criteria and for whom informed consent is obtained will be randomized to receive either 80 mg inositol/kg/day or placebo, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily, starting within 12 to 72 hours of birth and continued until the earliest of 34 weeks PMA, 10 weeks chronologic age, or the time of hospital discharge or transfer. Inositol or placebo will be administered IV until enteral feedings reach 120ml/kg/day (or sooner if the infant is no longer receiving IV fluids), at which time the same dose and formulation will be administered enterally every 12 hours.

For publication purposes, the analysis of the primary efficacy outcome will consider the entire study population. In support of a new drug application (NDA) for use of myo-Inositol 5% Injection to increase survival without severe ROP through the determination of acute/final ROP status, the analysis of the primary efficacy outcome will be conducted for the entire study population and separately within pre-specified regulatory sub-studies created by administratively splitting infants enrolled at each study center into two sub-studies.

Assessments performed during the study include customary newborn intensive care procedures including repeat eye examinations until ROP status is final (which often extends after discharge), measurements of growth, cranial ultrasounds or other imaging per usual practice, and the collection of clinical diagnoses throughout hospitalization to evaluate other common morbidities of extreme preterm birth. Adverse events will be recorded from time of treatment initiation until 7 days after the last dose of study drug, and concurrent medications will be recorded from 24 hours prior to randomization until 7 days after the last dose of study drug or until discharge or transfer if sooner. Using the separate NICHD Follow-up protocol, longer term data will be collected at 22-26 months corrected age, including growth, neurodevelopmental testing, overall health status, rehospitalizations, surgeries and diagnoses, including ophthalmic diagnoses and treatments since discharge.

  Eligibility

Ages Eligible for Study:   up to 72 Hours
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Inborn or out born infants of either gender or any race with best obstetrical estimate of gestation <28 weeks (27 6/7 weeks and younger). Gestational age will be determined by best obstetrical estimate using the hierarchy of best obstetrical estimate using early ultrasound dating, maternal menstrual dating confirmed by examination, or neonatal gestational age assessment by physical examination.
  • Alive at 12 hours.
  • Age in hours up to 72 hours, although we will seek enrollment as early as feasible after consent and 12 hours.
  • Informed consent signed and dated by parent and/or guardian, which includes likelihood of completing follow-up ophthalmic examinations as an outpatient, and long-term follow-up.

Exclusion Criteria

  • Major congenital malformations
  • Congenital malformations of the eye identified prior to randomization.
  • Overt evidence of intrauterine congenital infections ("TORCH") or life threatening impairment of renal, hepatic, or cardiac function (considered moribund).
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01954082

Contacts
Contact: Dale L. Phelps, MD 707-897-9063 Dale_Phelps@URMC.Rochester.edu
Contact: Rosemary D. Higgins, MD 301-435-7909 higginsr@mail.nih.gov

Locations
United States, Alabama
University of Alabama at Birmingham Not yet recruiting
Birmingham, Alabama, United States, 35233
Contact: Waldemar A. Carlo, MD    205-934-4680    wcarlo@peds.uab.edu   
Contact: Monica V. Collins, RN BSN    (205) 934-5771    mcollins@peds.uab.edu   
Principal Investigator: Waldemar A. Carlo, MD         
United States, California
University of California - Los Angeles Not yet recruiting
Los Angeles, California, United States, 90025
Contact: Uday Devaskar, MD    310-825-9357    udevaskar@mednet.ucla.edu   
Contact: Teresa Chanlaw, BS    (310) 794-4972    tchanlaw@mednet.ucla.edu   
Principal Investigator: Uday Devaskar, MD         
Stanford University Not yet recruiting
Palo Alto, California, United States, 94304
Contact: Krisa P. Van Meurs, MD    650-723-5711    vanmeurs@leland.stanford.edu   
Contact: M. Bethany Ball, BS CCRC    (650) 725-8342    mbball@stanford.edu   
Principal Investigator: Krisa P. Van Meurs, MD         
United States, Georgia
Emory University Not yet recruiting
Atlanta, Georgia, United States, 30303
Contact: Barbara J. Stoll, MD    404-727-5740    barbara_stoll@oz.ped.emory.edu   
Contact: Ellen Hale, RN BS    (404) 616-4218    ellen_hale@oz.ped.emory.edu   
Principal Investigator: Barbara J. Stoll, MD         
United States, Indiana
Indiana University Not yet recruiting
Indianapolis, Indiana, United States, 46202
Contact: Brenda B. Poindexter, MD MS    317-274-3592    bpoindex@iupui.edu   
Contact: Leslie D. Wilson, RN BSN    (317) 274-8255    ldw@iupui.edu   
Principal Investigator: Brenda B. Poindexter, MD MS         
United States, Iowa
University of Iowa Not yet recruiting
Iowa City, Iowa, United States, 52242
Contact: Edward F. Bell, MD    319-356-4006    edward-bell@uiowa.edu   
Contact: Karen J. Johnson, RN BSN    (319) 356-2924    karen-johnson@uiowa.edu   
Principal Investigator: Edward F. Bell, MD         
United States, Michigan
Wayne State University Not yet recruiting
Detroit, Michigan, United States, 48201
Contact: Seetha Shankaran, MD    313-580-4452    sshankar@med.wayne.edu   
Contact: Rebecca Bara, RN BSN    (313) 745-1436    rbara@med.wayne.edu   
Principal Investigator: Seetha Shankaran, MD         
United States, Missouri
Children's Mercy Hospital Not yet recruiting
Kansas City, Missouri, United States, 64108
Contact: William Truog, MD    816-234-3592    wtruog@cmh.edu   
Contact: Cheri Gauldin, BSN    (816) 234-3920    cagauldin@cmh.edu   
Principal Investigator: William Truog, MD         
United States, New Mexico
University of New Mexico Not yet recruiting
Albuquerque, New Mexico, United States, 87131
Contact: Kristi L. Watterberg, MD    505-272-3967    kwatterberg@salud.unm.edu   
Contact: Conra Backstrom Lacy, RN    (505) 272-0367    cbackstrom@salud.unm.edu   
Principal Investigator: Kristi L. Watterberg, MD         
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14642
Contact: Carl T D'Angio, MD    585-273-4911    carl_dangio@urmc.rochester.edu   
Contact: Holly Wadkins    585-275-0218    Holly_Wadkins@urmc.rochester.edu   
Principal Investigator: Carl T D'Angio, MD         
United States, North Carolina
Duke University Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Ronald N. Goldberg, MD    919-681-6025    goldb008@mc.duke.edu   
Contact: Joanne Finkle, BSN    919-681-4911    j.finkle@duke.edu   
Principal Investigator: Ronald N. Goldberg, MD         
Sub-Investigator: C. Michael Cotten, MD MHS         
RTI International Not yet recruiting
Durham, North Carolina, United States, 27705
Contact: Abhik Das, PhD    301-770-8214    adas@rti.org   
Contact: Kristin Zaterka-Baxter, RN    (919) 485-7750    kzaterka@rti.org   
Principal Investigator: Abhik Das, PhD         
United States, Ohio
Cincinnati Children's Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45267
Contact: Kurt Schibler, MD    513-636-3972    kurt.schibler@cchmc.org   
Contact: Cathy Grisby, BSN CCRC    (513) 558-4953    grisbyca@email.uc.edu   
Principal Investigator: Kurt Schibler, MD         
Case Western Reserve University, Rainbow Babies and Children's Hospital Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Michele C. Walsh, MD MS    216-844-3759    mcw3@cwru.edu   
Contact: Nancy S. Newman, BA RN    (216) 368-3084    nxs5@cwru.edu   
Principal Investigator: Michele C. Walsh, MD MS         
Research Institute at Nationwide Children's Hospital Not yet recruiting
Columbus, Ohio, United States, 43205
Contact: Leif Nelin, MD    614-722-3030    Leif.Nelin@nationwidechildrens.org   
Contact: Chris Fortney, MS, RN    614-722-6489    christine.fortney@nationwidechildrens.org   
Principal Investigator: Leif Nelin, MD         
United States, Pennsylvania
Univeristy of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Barbara Schmidt, MD    215-662-3228    barbara.schmidt@uphs.upenn.edu   
Contact: Aasma Chaudhary, BS    215-615-5442    aasma.chaudhary@uphs.upenn.edu   
Principal Investigator: Barbara Schmidt, MD         
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island Not yet recruiting
Providence, Rhode Island, United States, 02905
Contact: Abbot R. Laptook, MD    401-274-1122    alaptook@WIHRI.org   
Contact: Angelita Hensman    (401) 274-1122    ahensman@wihri.org   
Principal Investigator: Abbot R. Laptook, MD         
United States, Texas
University of Texas Southwestern Medical Center at Dallas Not yet recruiting
Dallas, Texas, United States, 75235
Contact: Pablo J. Sanchez, MD    214-648-3753    Pablo.Sanchez@UTSouthwestern.edu   
Contact: Diana M. Vasil, RNC-NIC    (214) 648-3789    Diana.Vasil@utsouthwestern.edu   
Principal Investigator: Pablo J. Sanchez, MD         
University of Texas Health Science Center at Houston Not yet recruiting
Houston, Texas, United States, 77030
Contact: Kathleen A. Kennedy, MD MPH    713-500-6708    Kathleen.A.Kennedy@uth.tmc.edu   
Contact: Georgia E. McDavid, RN    (713) 500-5734    Georgia.E.McDavid@uth.tmc.edu   
Principal Investigator: Kathleen A. Kennedy, MD MPH         
Sub-Investigator: Jon E. Tyson, MD MPH         
Sponsors and Collaborators
Investigators
Principal Investigator: Michele C Walsh, MD Case Western Reserve University, Rainbow Babies and Children's Hospital
Principal Investigator: Abhik Das, PhD RTI International
Principal Investigator: Seetha Shankaran, MD Wayne State University
Principal Investigator: Barbara J Stoll, MD Emory University
Principal Investigator: Kurt Schibler, MD Cincinnati Children's Medical Center
Principal Investigator: Brenda B Poindexter, MD, MS Indiana University
Principal Investigator: Abbot R Laptook, MD Brown University, Women & Infants Hospital of Rhode Island
Principal Investigator: Krisa P Van Meurs, MD Stanford University
Principal Investigator: Waldemar A Carlo, MD University of Alabama at Birmingham
Principal Investigator: Kathleen A Kennedy, MD, MPH The University of Texas Health Science Center, Houston
Principal Investigator: Ronald N Goldberg, MD Duke University
Principal Investigator: Edward F Bell, MD University of Iowa
Study Director: Dale L Phelps, MD University of Rochester
Principal Investigator: Carl T D'Angio, MD University of Rochester
Principal Investigator: William Truog, MD Children's Mercy Hospital-Kansas City, MO
Principal Investigator: Leif Nelin, MD Research Institute at Nationwide Children's Hospital
Principal Investigator: Uday Devaskar, MD University of California, Los Angeles
Principal Investigator: Myra Wyckoff, MD University of Texas at Southwestern
Principal Investigator: Kristi L Watterberg, MD University of New Mexico
Principal Investigator: Barbara Schmidt, MD University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT01954082     History of Changes
Other Study ID Numbers: NICHD-NRN-0053, U10HD021364, U10HD040689, U10HD021385, U10HD027851, U10HD027853, U10HD027856, U10HD027904, U10HD027880, U10HD034216, U10HD021373, U10HD040492, U10HD053109, U10HD053089, U10HD068244, U10HD068263, U10HD068270, U10HD068278, U10HD068284, U10HD036790
Study First Received: September 26, 2013
Last Updated: May 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
Retinopathy
Prematurity
Infant, Newborn, Diseases

Additional relevant MeSH terms:
Infant, Premature, Diseases
Infant, Newborn, Diseases
Retinal Diseases
Retinopathy of Prematurity
Eye Diseases
Inositol
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 20, 2014