Inositol to Reduce Retinopathy of Prematurity

Retinopathy of Prematurity (ROP) Clinical Trial

— INS-3  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01954082
• Other study ID #: NICHD-NRN-0053
• Secondary ID: U10HD021364U10HD
• Status: Terminated
• Phase: Phase 3
• Start date: April 17, 2014
• Est. completion date: December 31, 2016

Study information

• Verified date: March 2019
• Source: NICHD Neonatal Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 638
• Est. completion date: December 31, 2016
• Est. primary completion date: December 31, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 72 Hours

Eligibility

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).

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity
• Retinopathy of Prematurity (ROP)

Intervention

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).
• Placebo
% glucose(dextrose)

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Cincinnati Children's Medical Center	Cincinnati	Ohio
United States	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Research Institute at Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	RTI International	Durham	North Carolina
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	University of California - Los Angeles	Los Angeles	California
United States	Stanford University	Palo Alto	California
United States	Univeristy of Pennsylvania	Philadelphia	Pennsylvania
United States	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	University of Rochester	Rochester	New York

Sponsors (3)

Lead Sponsor	Collaborator
NICHD Neonatal Research Network	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Occurrence of Adverse Events and Serious Adverse Events		7 days post study drug discontinuation
Other	Necrotizing Enterocolitis (NEC)	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
Other	Isolated Gastrointestinal Perforation	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
Other	Late Onset Sepsis	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
Other	Patent Ductus Arteriosus (PDA)	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
Other	Seizures	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
Other	Total Days on Parenteral Nutrition	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
Other	Days on Oxygen, Days on Ventilator		NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other	Hearing Loss	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
Other	Neurodevelopment	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
Other	Vision Loss	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
Other	Hearing Loss	Hearing loss requiring that hearing aids be prescribed.	22-26 Months Corrected Age
Other	Cerebral Palsy	Cerebral palsy by severity category (absent/mild/moderate/severe).	22-26 Months Corrected Age
Other	Overall Health Status	Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses).	22-26 Months Corrected Age
Primary	Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status	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	Number of Participants With Bronchopulmonary Dysplasia (BPD)	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
Secondary	Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD	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
Secondary	Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint	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
Secondary	Number of Participants With Any Retinopathy of Prematurity (ROP)	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
Secondary	Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP)	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
Secondary	Number of Participants With Severe Intraventricular Hemorrhage (IVH)	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

External Links

•   NICHD NRN Website
•   NICHD Pregnancy & Perinatology Branch