Inositol to Reduce Retinopathy of Prematurity

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.

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).