Retinopathy of Prematurity (ROP)
Conditions
Keywords
Retinopathy, Prematurity, Infant, Newborn, Diseases
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.
Interventions
DRUGmyo-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).
DRUGPlacebo
% glucose(dextrose)
Sponsors
National Eye Institute (NEI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Hours to 72 Hours
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD | 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 | 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 Bronchopulmonary Dysplasia (BPD) | 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 Type 2 or More Severe Retinopathy of Prematurity (ROP) | 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) | 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. |
| Number of Participants With Any Retinopathy of Prematurity (ROP) | 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)). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Days on Oxygen, Days on Ventilator | NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth | — |
| Hearing Loss | 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 | 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. |
| The Occurrence of Adverse Events and Serious Adverse Events | 7 days post study drug discontinuation | — |
| Cerebral Palsy | 22-26 Months Corrected Age | Cerebral palsy by severity category (absent/mild/moderate/severe). |
| Overall Health Status | 22-26 Months Corrected Age | Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses). |
| Vision Loss | 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.) |
| Necrotizing Enterocolitis (NEC) | 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 | 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 | 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) | 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 | 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 | 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) |
Countries
United States
Participant flow
Recruitment details
From April 2014 to September 2015, infants born before 28 weeks gestation and surviving \>12 hours were screened when admitted to one of the 18 NICHD NRN Centers (approximately 44 sites) in the United States and enrolled in the study if they met the eligibility criteria and consent was obtained before 72 hours postnatal age.
Participants by arm
| Arm | Count |
|---|---|
| Myo-Inositol 5% Injection Inositol (i.e 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. The medication is administered 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) begining within 12-72 hours of birth and continuing until the earliest of 34 weeks postmenstrual age (PMA), 10 weeks chronologic age, or the time of discharge. The doses are administered intravenously (IV) using syringe pump over 15-30 minutes until enteral feeds 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. | 317 |
| 5% Glucose(Dextrose) The placebo is 5% dextrose (5% glucose) in sterile water (D5W pyrogen and preservative free) United States Pharmacopoeia (USP) for IV infusion. The placebo is administered in the same dose (80 mg glucose/kg/day divided in 2 doses administered every 12 hours) and dispensed in the same manner (intravenously or enterally) as the inositol. | 321 |
| Total | 638 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 4 |
| Overall Study | Comfort Care | 0 | 1 |
| Overall Study | Discontinued Early Prior to Transfer | 3 | 2 |
| Overall Study | Infant Moved | 0 | 1 |
| Overall Study | Intolerance | 0 | 1 |
| Overall Study | Miscalculation of Final Dose Day | 0 | 3 |
| Overall Study | Non-compliance | 6 | 4 |
| Overall Study | Parent Decision | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Randomized not Treated | 4 | 2 |
| Overall Study | Redirection of Care | 0 | 2 |
| Overall Study | Study Suspension | 42 | 36 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Myo-Inositol 5% Injection | 5% Glucose(Dextrose) | Total |
|---|---|---|---|
| Age, Continuous | 25.9 weeks | 25.9 weeks | 25.9 weeks |
| Age, Customized AGE AT START OF STUDY THERAPY | 3 Days | 3 Days | 2.8 Days STANDARD_DEVIATION 0.8 |
| Age, Customized Gestational Age <26 weeks | 169 Participants | 170 Participants | 339 Participants |
| Age, Customized Gestational Age >=26 weeks | 148 Participants | 151 Participants | 299 Participants |
| ANTENATAL STEROIDS No | 36 Participants | 37 Participants | 73 Participants |
| ANTENATAL STEROIDS Unknown/Not Reported | 0 Participants | 1 Participants | 1 Participants |
| ANTENATAL STEROIDS Yes | 281 Participants | 283 Participants | 564 Participants |
| APGAR-5 MINUTE Test Result Available | 313 Participants | 316 Participants | 629 Participants |
| APGAR-5 MINUTE Test Result Not Available | 4 Participants | 5 Participants | 9 Participants |
| APGAR-5 MINUTE | 7 Units on a Scale | 6 Units on a Scale | 6 Units on a Scale |
| BIRTH WEIGHT | 740 Grams | 784.6 Grams STANDARD_DEVIATION 198.2 | 750 Grams |
| EARLY ONSET SEPSIS No | 310 Participants | 312 Participants | 622 Participants |
| EARLY ONSET SEPSIS Yes | 7 Participants | 9 Participants | 16 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 11 Participants | 6 Participants | 17 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black Not Hispanic or Latino | 119 Participants | 113 Participants | 232 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic or Latino | 38 Participants | 45 Participants | 83 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Other | 3 Participants | 11 Participants | 14 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Unknown/Not Reported | 13 Participants | 14 Participants | 27 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White Not Hispanic or Latino | 133 Participants | 132 Participants | 265 Participants |
| Region of Enrollment United States | 317 Participants | 321 Participants | 638 Participants |
| Sex: Female, Male Female | 159 Participants | 158 Participants | 317 Participants |
| Sex: Female, Male Male | 158 Participants | 163 Participants | 321 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 50 / 317 | 33 / 321 |
| other Total, other adverse events | 291 / 313 | 298 / 319 |
| serious Total, serious adverse events | 113 / 313 | 105 / 319 |
Outcome results
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.
Time frame: by 55 weeks PMA
Population: The analysis was performed on an intention to treat basis, including adjudicated ROP endpoints. Individuals for whom adjudicated ROP endpoints could not be obtained were treated as missing completely at random, and excluded from the primary analyses (4 Inositol and 1 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status | 91 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status | 66 Participants |
Comparison: The null hypothesis is there is no treatment effect on the development of severe ROP and mortality.p-value: 0.009595% CI: [1.08, 1.83]Robust Poisson
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))
Time frame: by 55 weeks PMA age
Population: The analysis was performed on an intention to treat basis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint | 50 Participants |
| 5% Glucose(Dextrose) | Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint | 33 Participants |
Comparison: The null hypothesis is there is no treatment effect on survival to ROP endpoint.p-value: 0.030695% CI: [1.03, 2.25]Robust Poisson regression
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)).
Time frame: by 55 weeks PMA
Population: The analysis was performed on an intention to treat basis. Individuals for whom ROP status could not be defined were treated as missing completely at random, and excluded from the analyses (50 Inositol and 35 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Any Retinopathy of Prematurity (ROP) | 171 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Any Retinopathy of Prematurity (ROP) | 183 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of ROPp-value: 0.746495% CI: [0.91, 1.14]Robust Poisson regression
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).
Time frame: 36 weeks PMA
Population: The analysis was performed on an intention to treat basis. Individuals for whom BPD outcome could not be obtained were treated as missing completely at random, and excluded from the analyses (45 Inositol and 33 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Bronchopulmonary Dysplasia (BPD) | 159 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Bronchopulmonary Dysplasia (BPD) | 165 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of BPD.p-value: 0.659995% CI: [0.91, 1.16]Robust Poisson regression
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.
Time frame: prior to 37 weeks PMA
Population: The analysis was performed on an intention to treat basis. Individuals who died prior to 37 weeks PMA for whom the cause(s) of death are unknown or individuals for whom BPD outcome could not be obtained were treated as missing completely at random, and excluded from the analyses (1 Inositol and 5 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD | 203 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD | 195 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of BPD or on mortality due to BDP.p-value: 0.388395% CI: [0.94, 1.17]Robust Poisson regression
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.
Time frame: by 28 days PMA
Population: The analysis was performed on an intention to treat basis. Individuals for whom severe IVH status could not be defined were treated as missing completely at random, and excluded from the analyses (6 Inositol and 4 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Severe Intraventricular Hemorrhage (IVH) | 51 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Severe Intraventricular Hemorrhage (IVH) | 50 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence severe IVH.p-value: 0.813395% CI: [0.74, 1.48]Robust Poisson regression
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).
Time frame: by 55 weeks PMA
Population: The analysis was performed on an intention to treat basis. Individuals for whom ROP status and/or type could not be defined were treated as missing completely at random, and excluded from the analyses (54 Inositol and 36 Placebo).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myo-Inositol 5% Injection | Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP) | 125 Participants |
| 5% Glucose(Dextrose) | Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP) | 142 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of Type 2 ROP or more severe ROP.p-value: 0.759895% CI: [0.83, 1.14]Robust Poisson regression
Other Pre-specified
Cerebral Palsy
Cerebral palsy by severity category (absent/mild/moderate/severe).
Time frame: 22-26 Months Corrected Age
Other Pre-specified
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
Other Pre-specified
Hearing Loss
Hearing loss requiring that hearing aids be prescribed.
Time frame: 22-26 Months Corrected Age
Other Pre-specified
Hearing Loss
Hearing loss as defined as never passing a hearing screening in one or both ears
Time frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
Isolated Gastrointestinal Perforation
judged not to be due to NEC
Time frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
Late Onset Sepsis
culture positive septicemia/bacteremia (≥72 hours of age) treated with antibiotics for ≥ 5 days or died before treatment was completed.
Time frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
Necrotizing Enterocolitis (NEC)
Stage II or worse, whether treated (medically or surgically) and if the infant survived (modified Bell's classification \[Walsh 1986\]).
Time frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
Neurodevelopment
Neurodevelopment at 22-26 months corrected age (i.e., 22-26 months past due date) using the Bayley Scales of Infant Development III.
Time frame: 22-26 months corrected age
Other Pre-specified
Overall Health Status
Overall health status per recall from the parent/guardian (including survival, re-hospitalizations, surgeries, ongoing medications, and chronic illnesses).
Time frame: 22-26 Months Corrected Age
Other Pre-specified
Patent Ductus Arteriosus (PDA)
Occurrence of clinically significant patent ductus arteriosus (PDA), and if received intervention with prostaglandin inhibitors, and/or surgery.
Time frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
Seizures
Seizures treated with an anticonvulsant for \>72 hours
Time frame: NRN infant status, i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
The Occurrence of Adverse Events and Serious Adverse Events
Time frame: 7 days post study drug discontinuation
Other Pre-specified
Total Days on Parenteral Nutrition
Total days on parenteral nutrition (including amino acids and/or lipids)
Time frame: NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Other Pre-specified
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.)
Time frame: 22-26 Months Corrected Age