Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study) (SPIPROP)

Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP STUDY)

Phase 2, open-label, randomized, multi-center studies in infants and premature infants are necessary to determine treatment and preventative strategies for ROP. This study was designed to: a) target infants at the highest risk of ROP in a large number of centers with variable rates of ROP (all stages and severe ROP or stage 3+); and b) assess whether caffeine plus systemic or ophthalmic NSAID will decrease ROP among infants most at risk for ROP. The study is designed to determine whether the novel treatment regimens are safe and potentially effective for ROP prevention and to obtain requisite data for the development of a Phase III efficacy/safety randomized blinded trial. Since caffeine is used extensively in NICUs as standard of care for ELGANs, no placebo group is included.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity
• Intervention / Treatment: Drug: Caffeine citrate; Drug: Ibuprofen; Drug: Ketorolac

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center/University Hospital of Brooklyn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Caffeine+Saline IV+Saline drops; Caffeine citrate IV (20 mg/kg loading dose, 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); Caffeine is the intervention	Drug: Caffeine citrate; Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose); Other Names: Caffeine
Experimental: Caffeine+Ibp IV+Saline drops; 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); Ibuprofen is the intervention	Drug: Ibuprofen; Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days; Other Names: Neoprofen
Experimental: Caffeine+Saline+Ketorolac drops; 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); Ketorolac is the intervention	Drug: Ketorolac; Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days; Other Names: Acuvail

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy as Measured by the Number of Participants Presenting With Retinopathy of Prematurity (ROP) and the Rate of Stages/Grade of ROP.	ROP (all grades) will be graded using International ROP Classification and severe ROP (Stage 3+ disease) or need for laser or Avastin The rate of mild (stage 1), moderate (stage 2) and severe ROP (stages >3) will be calculated as the number of infants diagnosed with ROP over the number of infants receiving retinal examinations. The study enrolled only 14 of the projected sample of 120, and the low enrollment did not allow meaningful analyses of efficacy and safety.	50 weeks PCA +/- 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events as a Measure of Safety and Tolerability	We did not reach the target number of participants needed to measure statistically reliable outcome measure. The secondary outcome measure included Intraventricular hemorrhage (Papile's criteria) and ocular examination for corneal lesions.	Eye examinations was done at standard of care through discharge and once, at 50 weeks PCA. All infants underwent routine eye examination by a pediatric ophthalmologist according to the International Classification for ROP

Collaborators and Investigators

• Sponsor: State University of New York - Downstate Medical Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Jacob V Aranda, MD, PhD, SUNY Downstate Medical Center, University Hospital of Brooklyn

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): June 30, 2018
• Study Completion (Actual): June 30, 2018

Study Registration Dates

• First Submitted: January 7, 2015
• First Submitted That Met QC Criteria: January 21, 2015
• First Posted (Estimate): January 22, 2015

Study Record Updates

• Last Update Posted (Actual): May 1, 2020
• Last Update Submitted That Met QC Criteria: April 21, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Retinal Diseases; Infant, Premature, Diseases; Retinopathy of Prematurity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Ketorolac; Ibuprofen; Caffeine; Caffeine citrate
• Other Study ID Numbers: 349622; 1U54HD071594 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO