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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04447989
Recruitment Status : Recruiting
First Posted : June 25, 2020
Last Update Posted : June 21, 2022
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

Show Show detailed description

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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
Actual Study Start Date : May 27, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Safety

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. 32-44 weeks postmenstrual age
  4. Receiving respiratory support at enrollment:

    • If 32 0/7-35 6/7 weeks postmenstrual age: mechanical ventilation (high frequency or conventional)
    • If 36 0/7-44 6/7 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. Previous exposure to milrinone within 24 hours prior to randomization*
  6. Evidence of pulmonary hypertension or moderate/large patent ductus arteriosus (PDA) on the most recent echocardiogram performed within 14 days prior to randomization
  7. Known major congenital heart defect requiring medical or surgical intervention in the neonatal period
  8. Known allergy to sildenafil
  9. Known sickle cell disease
  10. Aspartate aminotransferase (AST) > 225 U/L < 72 hours prior to randomization
  11. Alanine aminotransferase (ALT) > 150 U/L < 72 hours prior to randomization
  12. 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

Locations
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United States, Arkansas
Arkansas Children's Research Institute Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Ankita Shukla, MD    501-364-7097    ashukla@uams.edu   
United States, Florida
South Miami Hospital Recruiting
Coral Gables, Florida, United States, 33146
Contact: Jorge Perez, MD    305-661-1515    jperezmd@kidzmedical.com   
University of Florida Jacksonville Shands Medical Center Active, not recruiting
Jacksonville, Florida, United States, 32209
United States, Georgia
Emory Children's Center Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shilpa Vyas-Read, MD    404-727-2401    svyasre@emory.edu   
United States, Illinois
Lurie Children's Hospital Recruiting
Chicago, Illinois, United States, 60611-2605
Contact: Megan Lagoski, MD    312-227-4190    mlagoski@luriechildrens.org   
United States, Louisiana
Ochsner Baptist Medical Center Recruiting
New Orleans, Louisiana, United States, 70115
Contact: Amanda England, MD    504-894-2619    amanda.england@ochsner.org   
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Kristen Leeman, MD    617-355-7909    kristen.leeman@childrens.harvard.edu   
United States, New York
University of Rochester School of Medicine Children's Hospital Recruiting
Rochester, New York, United States, 14642
Contact: Gloria Pryhuber, MD    585-507-8107    gloria_pryhuber@urmc.rochester.edu   
United States, North Carolina
University of NC at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Jennifer Talbert    984-974-7865    jtalbert@med.unc.edu   
Principal Investigator: Wesley Jackson, MD         
East Carolina University Recruiting
Greenville, North Carolina, United States, 27858
Contact: Ryan Moore, MD    252-744-4690    moorer15@ecu.edu   
United States, Ohio
Rainbow Babies and Childrens Hospital Recruiting
Cleveland, Ohio, United States, 44106
Contact: Stephanie Ford, MD    216-844-3387    stephanie.ford@uhhospitals.org   
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Leif Nelin, MD    614-355-6719    leif.nelin@nationwidechildrens.org   
United States, Tennessee
Vanderbilt Children's Hospital Recruiting
Nashville, Tennessee, United States, 37232-9544
Contact: Joern-Hendrik Weitkamp, MD    615-322-3476    hendrik.weitkamp@vumc.org   
United States, Virginia
University of Virginia Children's Hospital Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Michael McCulloch, MD    434-872-1143    mam3fk@virginia.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 21, 2022
Last Verified: June 2022
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