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Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia (SILDI-SAFE)

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ClinicalTrials.gov Identifier: NCT04447989
Recruitment Status : Not yet recruiting
First Posted : June 25, 2020
Last Update Posted : June 25, 2020
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Information provided by (Responsible Party):
Christoph P Hornik, MD MPH, Duke University

Brief Summary:
This is a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study of sildenafil in premature infants (inpatient in Neonatal Intensive Care Units (NICUs)) with severe bronchopulmonary dysplasia (BPD).

Condition or disease Intervention/treatment Phase
Bronchopulmonary Dysplasia of Newborn Drug: Sildenafil Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Premature infants with severe BPD (inpatient in neonatal intensive care units) will be randomized in a dose escalating approach 3:1 (sildenafil: placebo) sequentially, into each of 3 cohorts. There will be approximately 40 randomized and dosed participants in each cohort for a total of up to 120 participants.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Study drug (sildenafil or placebo) will be prepared in the pharmacy by the unblinded pharmacist. Treatment cohort will be randomly assigned electronically and communicated to the pharmacist via the study portal. All other study staff and the patients/parents will be blinded to the treatment assignment.
Primary Purpose: Treatment
Official Title: Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia
Estimated Study Start Date : May 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Cohort 1, sildenafil
Sildenafil (0.5 mg/kg IV or 1 mg/kg enteral) every 8 hours for 28 days
Drug: Sildenafil
Sildenafil citrate injection or powder for suspension
Other Name: Revatio

Placebo Comparator: Cohort 1, placebo
Placebo (IV or enteral) every 8 hours for 28 days
Drug: Placebo
dextrose 5%
Other Name: Dextrose 5%

Active Comparator: Cohort 2, sildenafil
Sildenafil (1 mg/kg IV or 2 mg/kg enteral) every 8 hours for 28 days
Drug: Sildenafil
Sildenafil citrate injection or powder for suspension
Other Name: Revatio

Placebo Comparator: Cohort 2, placebo
Placebo (IV or enteral) every 8 hours for 28 days
Drug: Placebo
dextrose 5%
Other Name: Dextrose 5%

Active Comparator: Cohort 3, sildenafil
Sildenafil (2 mg/kg IV or 4 mg/kg enteral) every 8 hours for 28 days
Drug: Sildenafil
Sildenafil citrate injection or powder for suspension
Other Name: Revatio

Placebo Comparator: Cohort 3, placebo
Placebo (IV or enteral) every 8 hours for 28 days
Drug: Placebo
dextrose 5%
Other Name: Dextrose 5%




Primary Outcome Measures :
  1. Safety based upon incidence of hypotension [ Time Frame: Through 28 days post last dose of study drug ]

    Safety as determined by incidence of hypotension experienced by the participants through 28 days post last dose of study drug.

    Hypotension will be defined as any clinically significant low blood pressure event deemed by the treating physician to require intervention with a fluid bolus or the initiation or escalation of inotropic, vasopressor, or systemic steroid therapy with the specific intent to raise blood pressure.



Secondary Outcome Measures :
  1. Volume of Distribution [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
    Volume of distribution [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]

  2. Clearance [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
    Clearance [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]

  3. Half-life [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
    Half-life [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]

  4. Area Under the Curve [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
    Area Under the Curve [ Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]

  5. Peak Plasma Concentration [ Time Frame: Blood samples will be collected after any dose following the completion of 7 days (168 hours) of study drug administration. ]
    Peak Plasma Concentration [Time Frame: 8 hr. dosing: time frame: 0-15 min, 30-60 min, 1-2 hr, 2-3 hr, 3-4 hr, 4-5 hr, within 15 min prior to next dose, and 16-24 hrs. after last dose.]


Other Outcome Measures:
  1. Global rank [ Time Frame: Through study completion, 28 days after the last dose of study drug ]
    Clinically significant events ranked in order of decreasing perceived severity. Each participant will receive a rank based upon the lowest ranking (worst) endpoint as defined in the statistical analysis plan that they experienced during the study.



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Ages Eligible for Study:   up to 29 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Documented informed consent from parent or guardian, prior to study procedures
  2. < 29 weeks gestational age at birth
  3. 32-40 weeks postmenstrual age
  4. Receiving respiratory support at enrollment:

    • If 32-36 weeks postmenstrual age: mechanical ventilation (high frequency or conventional)
    • If > 36-40 weeks postmenstrual age: mechanical ventilation (high frequency or conventional) OR continuous positive airway pressure (CPAP)

Note: Criteria 3 and 4 define severe BPD for the purposes of this study

CPAP is defined as any of the following:

  • Nasal cannula > 2 liters per minute (LPM)
  • Nasal continuous positive airway pressure (NCPAP)
  • Nasal intermittent positive pressure ventilation (NIPPV)
  • Noninvasive neurally adjusted ventilatory assist (NAVA)
  • Any other device designed to provide positive pressure through a nasal device (e.g., RAM cannula, etc.)

Exclusion Criteria:

  1. Previous enrollment and dosing in this study, protocol number (NHLBI-2019-SIL), "Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (BPD)"
  2. Previous exposure to sildenafil within 7 days prior to randomization*
  3. Previous exposure to vasopressors within 24 hours prior to randomization*
  4. Previous exposure to inhaled nitric oxide within 24 hours prior to randomization
  5. Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on the most recent echocardiogram performed within 14 days prior to randomization
  6. Known major congenital heart defect requiring medical or surgical intervention in the neonatal period
  7. Known allergy to sildenafil
  8. Known sickle cell disease
  9. Aspartate aminotransferase (AST) > 225 U/L < 72 hours prior to randomization
  10. Alanine aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization
  11. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study.

    • Participant will be reassessed prior to dosing to reconfirm eligibility criteria.

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): NCT04447989


Contacts
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Contact: Project Leader 919-668-8115 mary.bailey@duke.edu
Contact: Project Leader 919-668-8282 Jacqueline.Huvane@duke.edu

Sponsors and Collaborators
Christoph P Hornik, MD MPH
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Investigators
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Principal Investigator: Christoph Hornik, MD Duke UMC
Principal Investigator: Matt Laughon, MD UNC
Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Christoph P Hornik, MD MPH, Associate Professor of Pediatrics, Duke University
ClinicalTrials.gov Identifier: NCT04447989    
Other Study ID Numbers: Pro00104901
1R61HL147833-01 ( U.S. NIH Grant/Contract )
First Posted: June 25, 2020    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to make IPD available to other researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bronchopulmonary Dysplasia
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents