Inositol to Reduce Retinopathy of Prematurity (INS-3)

March 20, 2019 updated by: NICHD Neonatal Research Network

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

638

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham
    • California
      • Los Angeles, California, United States, 90025
        • University of California - Los Angeles
      • Palo Alto, California, United States, 94304
        • Stanford University
    • Georgia
      • Atlanta, Georgia, United States, 30303
        • Emory University
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Wayne State University
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico
    • New York
      • Rochester, New York, United States, 14642
        • University of Rochester
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University
      • Durham, North Carolina, United States, 27705
        • RTI International
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • Cincinnati Children's Medical Center
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University, Rainbow Babies and Children's Hospital
      • Columbus, Ohio, United States, 43205
        • Research Institute at Nationwide Children's Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Univeristy of Pennsylvania
    • Rhode Island
      • Providence, Rhode Island, United States, 02905
        • Brown University, Women & Infants Hospital of Rhode Island
    • Texas
      • Dallas, Texas, United States, 75235
        • University of Texas Southwestern Medical Center at Dallas
      • Houston, Texas, United States, 77030
        • University of Texas Health Science Center at Houston

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 hours to 3 days (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • 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.
Drug: Placebo
% glucose(dextrose)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
by 55 weeks PMA

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
36 weeks PMA
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.
prior to 37 weeks PMA
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))
by 55 weeks PMA age
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)).
by 55 weeks 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).
by 55 weeks PMA
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.
by 28 days PMA

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Occurrence of Adverse Events and Serious Adverse Events
Time Frame: 7 days post study drug discontinuation
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]).
NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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
NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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.
NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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.
NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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
NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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)
NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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
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
NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
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.
22-26 months corrected age
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.)
22-26 Months Corrected Age
Hearing Loss
Time Frame: 22-26 Months Corrected Age
Hearing loss requiring that hearing aids be prescribed.
22-26 Months Corrected Age
Cerebral Palsy
Time Frame: 22-26 Months Corrected Age
Cerebral palsy by severity category (absent/mild/moderate/severe).
22-26 Months Corrected Age
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).
22-26 Months Corrected Age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NICHD Neonatal Research Network

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Eye Institute (NEI)

Investigators

  • Principal Investigator: Kathleen A Kennedy, MD, MPH, The University of Texas Health Science Center, Houston
  • Principal Investigator: Barbara J Stoll, MD, Emory University
  • Principal Investigator: Ronald N Goldberg, MD, Duke University
  • Study Director: Dale L Phelps, MD, University of Rochester
  • Principal Investigator: Myra Wyckoff, MD, University of Texas at Southwestern

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 17, 2014

Primary Completion (Actual)

December 31, 2016

Study Completion (Actual)

December 31, 2016

Study Registration Dates

First Submitted

September 26, 2013

First Submitted That Met QC Criteria

September 26, 2013

First Posted (Estimate)

October 1, 2013

Study Record Updates

Last Update Posted (Actual)

March 22, 2019

Last Update Submitted That Met QC Criteria

March 20, 2019

Last Verified

March 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NICHD-NRN-0053
  • U10HD036790 (U.S. NIH Grant/Contract)
  • 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)
  • U10HD027880 (U.S. NIH Grant/Contract)
  • U10HD027904 (U.S. NIH Grant/Contract)
  • U10HD034216 (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)
  • 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)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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).

IPD Sharing Time Frame

One year after primary publication

IPD Sharing Access Criteria

NICHD Data and Specimen Repository (DASH)

IPD Sharing Supporting Information Type

  • Study Protocol

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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