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Trial record 22 of 48 for:    necrotizing enterocolitis | NIH

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

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ClinicalTrials.gov Identifier: NCT02344225
Recruitment Status : Completed
First Posted : January 22, 2015
Last Update Posted : October 31, 2018
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
Khadija Sikriti, State University of New York - Downstate Medical Center

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.

Condition or disease Intervention/treatment Phase
Retinopathy of Prematurity Drug: Caffeine citrate Drug: Ibuprofen Drug: Ketorolac Phase 2

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  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Synergistic Pharmacologic Intervention for Prevention of ROP (SPIPROP STUDY)
Study Start Date : January 2015
Actual Primary Completion Date : June 30, 2018
Actual Study Completion Date : June 30, 2018

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: Acuvail




Primary Outcome Measures :
  1. Efficacy as measured by the number of participants presenting with Retinopathy of Prematurity (ROP) and the rate of stages/grade of ROP. [ Time Frame: 50 weeks PCA +/- 7 days ]
    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. 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.


Secondary Outcome Measures :
  1. Number of participants with Adverse Events as a measure of Safety and Tolerability. [ Time Frame: Daily for 2 weeks (while on study) ]
    Safety/tolerability as measured by renal, gastrointestinal and liver function along with hematologic parameters. Renal function will be determined by: a) Urine output (ml/kg/hr) daily; b) serum electrolyes,creatinine and blood urea nitrogen as per standard of care; and c) daily fluid requirement. Gastrointestinal function will be determined by daily assessment for: a) necrotizing enterocolitis (NEC) Bell's criteria; b) GI bleeding; c) trophic feeding; d) time to full feeds (100 ml/kg/day); and e) time to discontinue total parenteral nutrition. Liver function studies done weekly as standard of care will include a) serum bilirubin total/direct; b) AST, ALT, alkaline phosphatase. Hematologic parameters: done as per standard of care include platelets, hemoglobin, hematocrit, white blood count.

  2. Safety as measured by occurrence of intraventricular hemorrhage, corneal lesions or perinventricular leucomalacia. [ Time Frame: Daily for 2 weeks (while on study) ]
    Includes intraventricular hemorrhage (Papile's criteria), Perinventricular leucomalacia by sonogram as per standard of care, and ocular examination for: corneal lesions. Daily examination by the neonatal staff of the cornea for haziness or other lesions confirmed by an ophthalmologist at least once a week or whenever an AE occurs will be done. Corneal lesions or haziness will require prompt discontinuation of the ophthalmic study eye drops.



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Ages Eligible for Study:   up to 28 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02344225


Locations
United States, New York
SUNY Downstate Medical Center/University Hospital of Brooklyn
Brooklyn, New York, United States, 11203
Sponsors and Collaborators
State University of New York - Downstate Medical Center
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

Responsible Party: Khadija Sikriti, Clinical Trial Manager, State University of New York - Downstate Medical Center
ClinicalTrials.gov Identifier: NCT02344225     History of Changes
Other Study ID Numbers: 349622
1U54HD071594 ( U.S. NIH Grant/Contract )
First Posted: January 22, 2015    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Retinopathy of Prematurity
Retinal Diseases
Eye Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Citric Acid
Ibuprofen
Ketorolac
Ketorolac Tromethamine
Caffeine
Caffeine citrate
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Purinergic P1 Receptor Antagonists
Purinergic Antagonists