Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study)

NCT ID: NCT02344225

Last Updated: 2020-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-01
• Study Completion Date: 2018-06-30

Brief Summary

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.

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)

Conditions

Retinopathy of Prematurity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Caffeine citrate

Intervention Type: DRUG

Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose)

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

Group Type: EXPERIMENTAL

Ibuprofen

Intervention Type: DRUG

Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days

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

Group Type: EXPERIMENTAL

Ketorolac

Intervention Type: DRUG

Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days

Interventions

Caffeine citrate

Caffeine citrate IV (20 mg/kg loading dose, 5 mg/kg/day maintenance dose)

Intervention Type: DRUG

Ibuprofen

Ibuprofen (10 mg/kg loading dose followed by low dose ibuprofen 2.5 mg/kg/day) for 5 days

Intervention Type: DRUG

Ketorolac

Ketorolac (Acuvail) eye drops (one drop two times a day) for 14 days

Intervention Type: DRUG

Other Intervention Names

Caffeine; Neoprofen; Acuvail

Eligibility Criteria

Inclusion Criteria

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

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.

• Maximum Eligible Age: 28 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Food and Drug Administration (FDA)

FED

Sponsor Role: collaborator

State University of New York - Downstate Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Khadija Sikriti

Clinical Trials Project Manager

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jacob V Aranda, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

SUNY Downstate Medical Center, University Hospital of Brooklyn

Locations

SUNY Downstate Medical Center/University Hospital of Brooklyn

Brooklyn, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1U54HD071594

Identifier Type: NIH

Identifier Source: secondary_id

View Link

349622

Identifier Type: -

Identifier Source: org_study_id