Clinical trial NCT01954082: Inositol to Reduce Retinopathy of Prematurity
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Retinopathy of Prematurity (ROP)
Keywords: Retinopathy
Prematurity
Infant, Newborn, Diseases
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Eye Institute (NEI)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2013-10-01
Enrollment: 638
Sex: ALL
Minimum age (years): 12
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility 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).

Primary outcomes:
measure: Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status
timeFrame: by 55 weeks PMA
Secondary outcomes:
measure: Number of Participants With Bronchopulmonary Dysplasia (BPD)
timeFrame: 36 weeks PMA
measure: Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD
timeFrame: prior to 37 weeks PMA
measure: Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint
timeFrame: by 55 weeks PMA age
measure: Number of Participants With Any Retinopathy of Prematurity (ROP)
timeFrame: by 55 weeks PMA
measure: Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP)
timeFrame: by 55 weeks PMA
measure: Number of Participants With Severe Intraventricular Hemorrhage (IVH)
timeFrame: by 28 days PMA
Other outcomes:
measure: The Occurrence of Adverse Events and Serious Adverse Events
timeFrame: 7 days post study drug discontinuation
measure: Necrotizing Enterocolitis (NEC)
timeFrame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Isolated Gastrointestinal Perforation
timeFrame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Late Onset Sepsis
timeFrame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Patent Ductus Arteriosus (PDA)
timeFrame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Seizures
timeFrame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Total Days on Parenteral Nutrition
timeFrame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Days on Oxygen, Days on Ventilator
timeFrame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Hearing Loss
timeFrame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Neurodevelopment
timeFrame: 22-26 months corrected age
measure: Vision Loss
timeFrame: 22-26 Months Corrected Age
measure: Hearing Loss
timeFrame: 22-26 Months Corrected Age
measure: Cerebral Palsy
timeFrame: 22-26 Months Corrected Age
measure: Overall Health Status
timeFrame: 22-26 Months Corrected Age
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Univeristy of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
Study officials:
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C Walsh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Barbara J Stoll, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Kurt Schibler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Greg Sokol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Kathleen A Kennedy, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Ronald N Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Edward F Bell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Dale L Phelps, MD
role: STUDY_DIRECTOR
affiliation: University of Rochester
name: Carl T D'Angio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Mercy Hospital Kansas City
name: William Truog, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute at Nationwide Children's Hospital
name: Pablo Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Uday Devaskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas at Southwestern
name: Myra Wyckoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Kristi L Watterberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Barbara Schmidt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. 2023 Nov;94(5):1720-1730. doi: 10.1038/s41390-021-01778-y. Epub 2021 Oct 22.