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Trial record 2 of 4 for:    Phelps | Retinopathy of Prematurity

Inositol to Reduce Retinopathy of Prematurity (INS-3)

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ClinicalTrials.gov Identifier: NCT01954082
Recruitment Status : Terminated (Study terminated due to safety concerns; participant follow up will continue until March 2018)
First Posted : October 1, 2013
Results First Posted : September 26, 2018
Last Update Posted : March 22, 2019
Sponsor:
Collaborators:
National Eye Institute (NEI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
NICHD Neonatal Research Network

Tracking Information
First Submitted Date  ICMJE September 26, 2013
First Posted Date  ICMJE October 1, 2013
Results First Submitted Date  ICMJE December 29, 2017
Results First Posted Date  ICMJE September 26, 2018
Last Update Posted Date March 22, 2019
Study Start Date  ICMJE April 17, 2014
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status [ Time Frame: by 55 weeks PMA ]
Death is defined as from any cause before Acute/Final ROP status is determined. ROP was identified by routine ophthalmologic examinations beginning at the latter of 31 weeks PMA or 4-6 weeks chronologic age. The favorable ROP endpoint requires that no ROP, or only mild ROP has occurred in both eyes and the eyes have matured beyond the risk of developing Type 1 ROP (severity meeting criteria for surgical intervention). The unfavorable ROP endpoint requires that one or both eyes reach Type 1 ROP. When ROP did not resolve by the time of discharge, participants were followed as outpatients until reaching an ROP endpoint, up to 55 weeks PMA. Since incomplete follow up is more likely among participants with mild or no ROP than for those with aggressive ROP, an independent adjudication process assigned an ROP endpoint of 'most likely never had Type 1 ROP', or 'most likely developed Type 1 ROP' based on clinical and ROP data review to reduce possible missing data bias.
Original Primary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
Survival without severe Retinopathy of Prematurity (ROP) [ Time Frame: by 55 weeks PMA ]
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.
Change History Complete list of historical versions of study NCT01954082 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Number of Participants With Bronchopulmonary Dysplasia (BPD) [ Time Frame: 36 weeks PMA ]
    BPD is defined as supplemental oxygen required to maintain an oxygenation saturation of >90% at 36 weeks postmenstrual age (PMA) (NICHD physiologic definition).
  • Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD [ Time Frame: prior to 37 weeks PMA ]
    BPD is defined as supplemental oxygen required to maintain an oxygenation saturation of >90% at 36 weeks PMA (NICHD physiologic definition). Death from BPD prior to 37 weeks postmenstrual age (PMA) is defined when the cause of death is certified by the Center PI as BPD being the primary cause, or a significant co-contributing cause of death.
  • Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint [ Time Frame: by 55 weeks PMA age ]
    Defined as death from any cause following randomization through primary study follow-up (up to 55 weeks postmenstrual age (PMA))
  • Number of Participants With Any Retinopathy of Prematurity (ROP) [ Time Frame: by 55 weeks PMA ]
    ROP was identified by routine ophthalmologic examinations beginning at the latter of 31 weeks PMA or 4-6 weeks chronologic age. Any ROP is defined as ROP of any severity that is observed on at least 2 independent examinations in either eye through the time that Acute/Final ROP status is reached (up to 55 weeks postmenstrual age (PMA)).
  • Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP) [ Time Frame: by 55 weeks PMA ]
    Defined as one or both eyes reaching Type 2 ROP (ETROP 2003) or the more severe Type 1 ROP (as defined previously) through the time that Acute/Final ROP status is reached (up to 55 weeks postmenstrual age (PMA)). Type 2 ROP is defined as (ETROP 2003): Stage 3 ROP without Plus Disease (i.e. Zone II) or Stage 1 or 2 ROP without Plus Disease (i.e. Zone I).
  • Number of Participants With Severe Intraventricular Hemorrhage (IVH) [ Time Frame: by 28 days PMA ]
    Severe IVH is defined as IVH Grades 3 or 4 on either side of the brain. The evaluation for IVH occurs early (within 28 days from birth) via a cranial sonogram and is classified as described by Papile.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2013)
  • Bronchopulmonary Dysplasia (BPD) [ Time Frame: 36 weeks PMA ]
    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 ]
    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 ]
    Defined as death from any cause following randomization
  • Any ROP [ Time Frame: by 55 weeks PMA ]
    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 ]
    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 ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: September 26, 2013)
  • The Occurrence of Adverse Events and Serious Adverse Events [ Time Frame: 7 days post study drug discontinuation ]
  • Necrotizing Enterocolitis (NEC) [ Time Frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
  • Hearing Loss [ Time Frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Hearing loss as defined as never passing a hearing screening in one or both ears
  • Neurodevelopment [ Time Frame: 22-26 months corrected age ]
    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 ]
    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 ]
    Hearing loss requiring that hearing aids be prescribed.
  • Cerebral Palsy [ Time Frame: 22-26 Months Corrected Age ]
    Cerebral palsy by severity category (absent/mild/moderate/severe).
  • Overall Health Status [ Time Frame: 22-26 Months Corrected Age ]
    Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Inositol to Reduce Retinopathy of Prematurity
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

Approximately 1760 infants are to be enrolled at approximately 18 Eunice Kennedy Shriver National Institute of Child Health and Human Development (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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Retinopathy of Prematurity (ROP)
Intervention  ICMJE
  • 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
  • Drug: Placebo
    % glucose(dextrose)
Study Arms  ICMJE
  • 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.
    Intervention: Drug: myo-Inositol 5% Injection
  • 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 9, 2016)
638
Original Estimated Enrollment  ICMJE
 (submitted: September 26, 2013)
1760
Actual Study Completion Date  ICMJE December 31, 2016
Actual Primary Completion Date December 31, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 72 Hours   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01954082
Other Study ID Numbers  ICMJE NICHD-NRN-0053
U10HD021364 ( U.S. NIH Grant/Contract )
U10HD040689 ( 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 )
U10HD027904 ( U.S. NIH Grant/Contract )
U10HD027880 ( U.S. NIH Grant/Contract )
U10HD034216 ( U.S. NIH Grant/Contract )
U10HD021373 ( U.S. NIH Grant/Contract )
U10HD040492 ( U.S. NIH Grant/Contract )
U10HD053109 ( U.S. NIH Grant/Contract )
U10HD053089 ( U.S. NIH Grant/Contract )
U10HD068244 ( U.S. NIH Grant/Contract )
U10HD068263 ( U.S. NIH Grant/Contract )
U10HD068270 ( U.S. NIH Grant/Contract )
U10HD068278 ( U.S. NIH Grant/Contract )
U10HD068284 ( U.S. NIH Grant/Contract )
U10HD036790 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov).
Supporting Materials: Study Protocol
Time Frame: One year after primary publication
Access Criteria: NICHD Data and Specimen Repository (DASH)
URL: https://dash.nichd.nih.gov/
Responsible Party NICHD Neonatal Research Network
Study Sponsor  ICMJE NICHD Neonatal Research Network
Collaborators  ICMJE
  • National Eye Institute (NEI)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators  ICMJE
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 Children's Hospital Medical Center, Cincinnati
Principal Investigator: Greg Sokol, MD 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
Principal Investigator: Pablo Sanchez, 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
PRS Account NICHD Neonatal Research Network
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP