Trial Outcomes & Findings for Inositol to Reduce Retinopathy of Prematurity (NCT NCT01954082)

NCT ID: NCT01954082

Last Updated: 2019-03-22

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

638 participants

Primary outcome timeframe

by 55 weeks PMA

Results posted on

2019-03-22

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	317	321
Overall Study Treated	313	319
Overall Study COMPLETED	249	264
Overall Study NOT COMPLETED	68	57

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Study Suspension	42	36
Overall Study Adverse Event	10	4
Overall Study Intolerance	0	1
Overall Study Non-compliance	6	4
Overall Study Physician Decision	2	0
Overall Study Parent Decision	1	0
Overall Study Withdrawal by Subject	0	1
Overall Study Discontinued Early Prior to Transfer	3	2
Overall Study Redirection of Care	0	2
Overall Study Miscalculation of Final Dose Day	0	3
Overall Study Comfort Care	0	1
Overall Study Infant Moved	0	1
Overall Study Randomized not Treated	4	2

Baseline Characteristics

Age at start of study therapy is only available for infants who started treatment (313 Inositol and 319 Placebo).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Myo-Inositol 5% Injection n=317 Participants 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.	5% Glucose(Dextrose) n=321 Participants 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.	Total n=638 Participants Total of all reporting groups
Age, Continuous	25.9 weeks n=317 Participants	25.9 weeks n=321 Participants	25.9 weeks n=638 Participants
Age, Customized Gestational Age · <26 weeks	169 Participants n=317 Participants	170 Participants n=321 Participants	339 Participants n=638 Participants
Age, Customized Gestational Age · >=26 weeks	148 Participants n=317 Participants	151 Participants n=321 Participants	299 Participants n=638 Participants
Age, Customized AGE AT START OF STUDY THERAPY	3 Days n=313 Participants • Age at start of study therapy is only available for infants who started treatment (313 Inositol and 319 Placebo).	3 Days n=319 Participants • Age at start of study therapy is only available for infants who started treatment (313 Inositol and 319 Placebo).	3 Days n=632 Participants • Age at start of study therapy is only available for infants who started treatment (313 Inositol and 319 Placebo).
Sex: Female, Male Female	159 Participants n=317 Participants	158 Participants n=321 Participants	317 Participants n=638 Participants
Sex: Female, Male Male	158 Participants n=317 Participants	163 Participants n=321 Participants	321 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · Asian	11 Participants n=317 Participants	6 Participants n=321 Participants	17 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · Black Not Hispanic or Latino	119 Participants n=317 Participants	113 Participants n=321 Participants	232 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · Hispanic or Latino	38 Participants n=317 Participants	45 Participants n=321 Participants	83 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · Other	3 Participants n=317 Participants	11 Participants n=321 Participants	14 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · White Not Hispanic or Latino	133 Participants n=317 Participants	132 Participants n=321 Participants	265 Participants n=638 Participants
Race/Ethnicity, Customized Race/Ethnicity · Unknown/Not Reported	13 Participants n=317 Participants	14 Participants n=321 Participants	27 Participants n=638 Participants
Region of Enrollment United States	317 Participants n=317 Participants	321 Participants n=321 Participants	638 Participants n=638 Participants
BIRTH WEIGHT	740 Grams n=317 Participants	765 Grams n=321 Participants	750 Grams n=638 Participants
ANTENATAL STEROIDS No	36 Participants n=317 Participants	37 Participants n=321 Participants	73 Participants n=638 Participants
ANTENATAL STEROIDS Yes	281 Participants n=317 Participants	283 Participants n=321 Participants	564 Participants n=638 Participants
ANTENATAL STEROIDS Unknown/Not Reported	0 Participants n=317 Participants	1 Participants n=321 Participants	1 Participants n=638 Participants
EARLY ONSET SEPSIS No	310 Participants n=317 Participants	312 Participants n=321 Participants	622 Participants n=638 Participants
EARLY ONSET SEPSIS Yes	7 Participants n=317 Participants	9 Participants n=321 Participants	16 Participants n=638 Participants
APGAR-5 MINUTE Test Result Available	313 Participants n=317 Participants	316 Participants n=321 Participants	629 Participants n=638 Participants
APGAR-5 MINUTE Test Result Not Available	4 Participants n=317 Participants	5 Participants n=321 Participants	9 Participants n=638 Participants
APGAR-5 MINUTE	7 Units on a Scale n=317 Participants	6 Units on a Scale n=321 Participants	6 Units on a Scale n=638 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=313 Participants 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.	5% Glucose(Dextrose) n=320 Participants 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.
Number of Participants With Unfavorable Outcome, Defined as Severe Retinopathy of Prematurity (ROP) or Death Prior to Reaching Acute/Final ROP Status	91 Participants	66 Participants

SECONDARY outcome

Timeframe: 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).

BPD is defined as supplemental oxygen required to maintain an oxygenation saturation of \>90% at 36 weeks postmenstrual age (PMA) (NICHD physiologic definition).

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=272 Participants 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.	5% Glucose(Dextrose) n=288 Participants 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.
Number of Participants With Bronchopulmonary Dysplasia (BPD)	159 Participants	165 Participants

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=316 Participants 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.	5% Glucose(Dextrose) n=316 Participants 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.
Number of Participants With Bronchopulmonary Dysplasia (BPD) or Death From BPD	203 Participants	195 Participants

SECONDARY outcome

Timeframe: by 55 weeks PMA age

Population: The analysis was performed on an intention to treat basis.

Defined as death from any cause following randomization through primary study follow-up (up to 55 weeks postmenstrual age (PMA))

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=317 Participants 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.	5% Glucose(Dextrose) n=321 Participants 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.
Number of Participants With All Cause Death Before Retinopathy of Prematurity (ROP) Endpoint	50 Participants	33 Participants

SECONDARY outcome

Timeframe: 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).

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)).

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=267 Participants 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.	5% Glucose(Dextrose) n=286 Participants 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.
Number of Participants With Any Retinopathy of Prematurity (ROP)	171 Participants	183 Participants

SECONDARY outcome

Timeframe: 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).

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).

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=263 Participants 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.	5% Glucose(Dextrose) n=285 Participants 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.
Number of Participants With Type 2 or More Severe Retinopathy of Prematurity (ROP)	125 Participants	142 Participants

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Myo-Inositol 5% Injection n=311 Participants 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.	5% Glucose(Dextrose) n=317 Participants 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.
Number of Participants With Severe Intraventricular Hemorrhage (IVH)	51 Participants	50 Participants

Other events: 298 other events

Deaths: 33 deaths

Serious adverse events

Other adverse events

Additional Information

Dale Phelps

University of Rochester

Phone: (585) 275-2972

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigators must adhere to the Neonatal Research Network Publication policies.
Publication restrictions are in place

Restriction type: OTHER