Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study)

This study will evaluate the safety, tolerability and PK-PD of, and to compare and contrast,
IV Ibuprofen with Caffeine and Ketorolac eye drops with Caffeine in ELGAN infants <28 weeks
GA for 14 days duration to treat and preferably prevent ROP associated with prematurity and
ELGAN. The specific aims of this trial are:

Aim 1: To establish the synergistic effect of local ophthalmic NSIADs and systemic caffeine
as optimal therapies for the attenuation and/or prevention of severe ROP. Hypothesis: Ocular
Ketorolac or systemic Ibuprofen potentiated with systemic Caffeine will prevent or diminish
the severity of ROP. We will: a) Evaluate the safety, tolerability, and efficacy of early
postnatal local ophthalmic NSIADs for prevention of severe ROP in ELGANs. b) Determine the
pharmacokinetics, pharmacodymanics and pharmacogenomics of NSAIDs potentiated with caffeine
for prevention of ROP.

Aim 2: To identify a "critical" number of arterial oxygen desaturations as a key risk factor
for severe ROP.

Hypothesis: A "critical" number of daily arterial oxygen desaturations during the first two
weeks of life is a key risk factor for severe ROP. We will: a) Further define the role of
VEGF, IGF, MMPs, and ROS in ROP and correlate the levels with the number of arterial oxygen
desaturations. b) Establish and identify whether increased serum VEGF in infants with severe
ROP is the diffusible isoform VEGF121. This isoform is formed from VEGF proteolysis by
plasmin and MMPs. MMPs also cleave Notch/Dll4, which acts as a regulator of VEGF signaling.

Aim 3: To determine whether infants at risk for severe ROP are haploinsufficient for the
delta-like ligand 4 (Dll4).

Hypothesis: ELGANs at risk for severe ROP will have different pattern of gene expression
specifically related to the Notch signaling pathway, as has been previously shown in animal
models. We will: a) Examine cord blood, cord tissue, and placental tissue to compare the gene
profile of VEGF and Notch signaling pathways among infants who develop severe ROP and those
who do not; and b) Determine whether NSAIDs and/or Caffeine will confer protective benefits
on Notch/Dll4 signaling and prevent the development of severe ROP.

This is a phase 2b, randomized, open label, multi-center, safety, tolerability and efficacy
study comparing 3 interventions for possible prevention of ROP. The trial will be conducted
in at least 8 investigational sites including the Neonatal networks (SUNY Downstate and the
Brooklyn-Queens Neonatal Network sites, SUNY Stony Brook), and Miller Children's Hospital,
Long Beach, CA. An independent DSMB will assess safety during the study. This study will
monitor for safety while on study drug and for 7 days after last dose of drug. An exploratory
study to determine the role of pharmacodynamic, drug concentrations (as surrogate of PK
profile) and pharmacogenomics will also be conducted in this patient population.

One hundred and twenty preterm infants (<28 weeks gestation; <1250 grams) between 0 and 72
hours of life will be randomized to receive either:

1. Caffeine citrate IV (20 mg/kg loading dose followed by 5 mg/kg/day maintenance dose)
plus placebo saline IV (1 ml/kg followed by 0.25 ml/kg) for 5 days plus sterile normal
saline (one drop two times a day) for 14 days (n=40);

2. Caffeine citrate as described in group 1 plus Ibuprofen (10 mg/kg loading dose followed
by low dose ibuprofen 2.5 mg/kg/day) for 5 days plus sterile normal saline (one drop two
times a day) for 14 days (n=40); and

3. Caffeine citrate plus saline IV placebo as described in group 1, and Ketorolac (Acuvail)
eye drops (one drop two times a day) for 14 days (n=40)

Inclusion Criteria:

- Neonates at high risk for ROP as outlined by the American Academy of Pediatrics,
Section on Ophthalmology; American Association for Pediatric Ophthalmology and
Strabismus; and American Academy of Ophthalmology (129) will be enrolled. Inclusion
criteria are:

1. all infants with a birth weight of less than 1250 grams;

2. all infants with a gestational age of 28 weeks or less; and

3. all infants who required oxygen therapy and ventilator support within the first 2
days of life.

Exclusion Criteria:

- Exclusion criteria are:

1. major congenital malformations and or chromosomal anomalies including
duct-dependent cardiac anomalies;

2. maternal antenatal NSAID exposure <72 hours before birth;

3. renal failure or oliguria defined as a urine flow rate <0.5 mL/kg/hour in the 8
hours prior to randomization. Anuria is acceptable if infant is less than 24
hours of life;

4. platelet count <75,000.mm3;

5. clinical bleeding such as oozing from puncture sites; and

6. participation in other clinical drug trials while subject participates in this
study and for 7 days after last dose of study drug.