Inositol to Reduce Retinopathy of Prematurity (INS-3)

• ClinicalTrials.gov Identifier: NCT01954082
• Recruitment Status: Terminated
• First Posted: October 1, 2013
• Results First Posted: September 26, 2018
• Last Update Posted: March 22, 2019
• Sponsor: NICHD Neonatal Research Network
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Retinopathy of Prematurity (ROP)	Drug: myo-Inositol 5% Injection; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 638 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: April 17, 2014
• Actual Primary Completion Date: December 31, 2016
• Actual Study Completion Date: December 31, 2016

Arms and Interventions

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 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.	Drug: Placebo; % glucose(dextrose)

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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).
2. 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.
3. 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))
4. 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)).
5. 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).
6. 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.

Other Outcome Measures:

1. The Occurrence of Adverse Events and Serious Adverse Events [ Time Frame: 7 days post study drug discontinuation ]
2. 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]).
3. 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
4. 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.
5. 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.
6. 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
7. 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)
8. 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 ]
9. 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
10. 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.
11. 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.)
12. Hearing Loss [ Time Frame: 22-26 Months Corrected Age ]
    Hearing loss requiring that hearing aids be prescribed.
13. Cerebral Palsy [ Time Frame: 22-26 Months Corrected Age ]
    Cerebral palsy by severity category (absent/mild/moderate/severe).
14. 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).

Eligibility Criteria

• Ages Eligible for Study: 12 Hours to 72 Hours (Child)
• Sexes Eligible for Study: All
• 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

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

United States, California

University of California - Los Angeles

Los Angeles, California, United States, 90025

Stanford University

Palo Alto, California, United States, 94304

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30303

United States, Indiana

Indiana University

Indianapolis, Indiana, United States, 46202

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Michigan

Wayne State University

Detroit, Michigan, United States, 48201

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87131

United States, New York

University of Rochester

Rochester, New York, United States, 14642

United States, North Carolina

RTI International

Durham, North Carolina, United States, 27705

Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati Children's Medical Center

Cincinnati, Ohio, United States, 45267

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Univeristy of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Rhode Island

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, United States, 02905

United States, Texas

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States, 75235

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

Sponsors and Collaborators

NICHD Neonatal Research Network

National Eye Institute (NEI)

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

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; 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

More Information

Additional Information:

NICHD NRN Website 

NICHD Pregnancy & Perinatology Branch 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Brumbaugh JE, Bell EF, Hirsch SC, Crenshaw EG, DeMauro SB, Adams-Chapman IS, Lowe JR, Natarajan G, Wyckoff MH, Vohr BR, Colaizy TT, Harmon HM, Watterberg KL, Hintz SR; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Relationships between retinopathy of prematurity without ophthalmologic intervention and neurodevelopment and vision at 2 years. Pediatr Res. 2021 Oct 22:10.1038/s41390-021-01778-y. doi: 10.1038/s41390-021-01778-y. Online ahead of print.

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT01954082
• Other Study ID Numbers: 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 )
• First Posted: October 1, 2013
• Results First Posted: September 26, 2018
• Last Update Posted: March 22, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• 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/

• 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:

Retinopathy; Prematurity; Infant, Newborn, Diseases

Additional relevant MeSH terms:

Retinal Diseases; Retinopathy of Prematurity; Premature Birth; Obstetric Labor, Premature; Infant, Premature, Diseases; Eye Diseases; Obstetric Labor Complications; Pregnancy Complications; Infant, Newborn, Diseases; Inositol; Vitamin B Complex; Vitamins; Micronutrients; Physiological Effects of Drugs