Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study)

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Brief Title

Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP Study)

Official Title

Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP STUDY)

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)
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Efficacy as Measured by the Number of Participants Presenting With Retinopathy of Prematurity (ROP) and the Rate of Stages/Grade of ROP.

Secondary Outcome

 Number of Participants With Adverse Events as a Measure of Safety and Tolerability

Condition

Retinopathy of Prematurity

Intervention

Caffeine citrate

Study Arms / Comparison Groups

 Caffeine+Saline IV+Saline drops
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

14

Start Date

January 1, 2015

Completion Date

June 30, 2018

Primary Completion Date

June 30, 2018

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - 28 Weeks

Accepts Healthy Volunteers

No

Contacts

Jacob V Aranda, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02344225

Organization ID

349622

Secondary IDs

1U54HD071594

Responsible Party

Principal Investigator

Study Sponsor

State University of New York - Downstate Medical Center

Collaborators

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

Study Sponsor

Jacob V Aranda, MD, PhD, Principal Investigator, SUNY Downstate Medical Center, University Hospital of Brooklyn


Verification Date

April 2020