Clincosm LogoSign in Get a demo

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

Sponsor
Christoph P Hornik, MD MPH (Other)
Overall Status
Recruiting
CT.gov ID
NCT04447989
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH), University of North Carolina, Chapel Hill (Other)
120
Enrollment
14
Locations
6
Arms
30.2
Anticipated Duration (Months)
8.6
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

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
Phase 2

Detailed Description

Screening/Baseline

Research staff will document informed consent from the parent/guardian for all participants who satisfy eligibility criteria. The following information will be recorded in the case report form (eCRF) from the clinical medical record:

  1. Participant demographics, including birth weight and gestational age at birth

  2. Maternal race/ethnicity

  3. Medical history

  4. Physical examination, including actual weight

  5. All mean arterial pressure (MAP) obtained in the 24 hours before the first dose

  6. Concomitant medications (within 24 hours prior to start of study drug)

  7. Respiratory assessment

  8. Laboratory evaluations

  9. Echocardiogram: If performed per local standard of care < 14 days prior to start of study drug, a study-specific echocardiogram need not be repeated. If not performed per local standard of care < 14 days prior to start of study drug, an echocardiogram will be required to confirm eligibility.

  10. Cardiac catheterization reports, if performed per local standard of care < 14 days prior to start of study drug.

  11. Adverse events following initial study-specific procedure

Treatment Period

The treatment period will include Days 1-28 or last day of study drug if early withdrawal of study drug. The following information will be collected and recorded while the participant is on study drug:

  1. Actual weight on study Days 7 (± 1 day), 14 (± 1 day), 21 (± 1 day), and 28 (± 1 day) of study drug administration

  2. Date, time, amount, and route of study drug dose

  3. All concomitant medications

  4. MAP

  1. All MAP values obtained 24 hours after the first dose of study drug regardless of administration route.

  2. MAP values will be obtained at a minimum at the following time points i. Prior to the first dose of study drug or dose escalation: 2 hours (± 5 minutes), 1 hour (± 5 minutes), and 15 minutes (± 5 minutes) ii. If administration route is IV:

  1. During and following the first dose of study drug or dose escalation: MAP at start of infusion, every 15 minutes (± 5 minutes) during infusion, at end of infusion (inclusive of flush) (± 5 minutes), at 15 and 30 minutes (± 5 minutes) after end of infusion, hourly (± 15 minutes) for 4 hours, and once in the remaining 2 hours prior to the next dose.

  2. For subsequent IV doses, the lowest valid MAP value should be recorded daily while on study drug.

  1. If the administration route is enteral:

  1. During and following the first dose of study drug or dose escalation: MAP at start of enteral administration, then every 15 minutes (± 5 minutes) for 90 minutes (1.5 hours), then every 30 minutes (± 5 minutes) for 60 minutes (1 hour), then hourly (± 15 minutes) for 4 hours, then once in the remaining 2 hours prior to the next dose.

  2. For subsequent enteral doses, the lowest valid MAP value should be recorded daily while on study drug.

  3. Respiratory assessment, weekly

  4. Laboratory evaluations, at least every other week

  5. Echocardiograms and cardiac catheterization reports, if performed per local standard of care

  6. Pharmacokinetic (PK) sampling (after Day 7)

  7. Adverse events

Weaning Period (Cohorts 2 and 3)

The weaning period will begin following Day 28 of study drug or, following the last day of study drug if participant was withdrawn from study drug prior to Day 28 and the dose escalated to ≥ 0.5 mg/kg IV or ≥ 1 mg/kg enteral.

The following information will be collected and recorded while the participant is weaning from study drug:

  1. Date, time, amount and route of study drug dose

  2. MAP (the lowest MAP value on last day of wean should be recorded).

  3. Respiratory assessment on last day of wean

  4. Echocardiogram and cardiac catheterization reports, if performed per local standard of care

  5. Adverse events

Follow-up Period

The follow-up period will include Days 1-28 after the last study drug dose; last study drug dose may occur prior to Day 28 for those participants who withdraw from study drug early; on Day 28 for those participants who complete the full treatment period; or after last weaning dose for those participants who require weaning. The following information will be reported in electronic data capture system (EDC) at Day 1 (+ 2 days) and 14 (± 2days) of the follow-up period (or days closest to and after Day 1 and 14, if >1 assessment is available), except for MAP, adverse events (AEs), and serious adverse events (SAEs) (which will be reported from Days 1-28 post last study drug dose) and standard of care echocardiograms or cardiac catheterization reports:

  1. Physical examination, including actual weight

  2. MAP (the lowest valid MAP value on follow-up Day 1, 14, 21, and 28 should be recorded).

  3. Respiratory assessment

  4. Laboratory evaluations

  5. Echocardiogram on follow-up Day 1 (+2 days). If performed per local standard of care, a study-specific echocardiogram need not be repeated. If not performed per local standard of care on Day 1 (+2 days) of the follow-up period, an echocardiogram will need to be performed.

  6. Echocardiograms and cardiac catheterization reports, if performed per local standard of care (during follow-up Days 1-28)

  7. Adverse events and SAEs (during follow-up Days 1-28)

Final Study Assessment

Final study assessment will occur at the time of discharge or transfer. The following information will be collected:

  1. Physical examination, including actual weight

  2. Respiratory assessment

  3. Echocardiogram and cardiac catheterization reports, if performed per local standard of care on the day of discharge or transfer or up to 2 days prior.

  4. Global rank

  5. Discharge information A. Discharge or transfer B. Death C. Duration of hospitalization

  6. Record if treatment for retinopathy of prematurity (ROP) was required

Study Design

Study Type:
Interventional
Anticipated 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.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
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

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 Names:
  • Revatio

    		•
    Placebo Comparator: Cohort 1, placebo

    Placebo (IV or enteral) every 8 hours for 28 days

    Drug: Placebo
    dextrose 5%
    Other Names:
  • 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 Names:
  • Revatio

    		•
    Placebo Comparator: Cohort 2, placebo

    Placebo (IV or enteral) every 8 hours for 28 days

    Drug: Placebo
    dextrose 5%
    Other Names:
  • 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 Names:
  • Revatio

    		•
    Placebo Comparator: Cohort 3, placebo

    Placebo (IV or enteral) every 8 hours for 28 days

    Drug: Placebo
    dextrose 5%
    Other Names:
  • Dextrose 5%

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Safety based upon incidence of hypotension [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 [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 [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 [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 [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 [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 [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 29 Weeks
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arkansas Children's Research Institute Little Rock Arkansas United States 72202
    2 South Miami Hospital Coral Gables Florida United States 33146
    3 University of Florida Jacksonville Shands Medical Center Jacksonville Florida United States 32209
    4 Emory Children's Center Atlanta Georgia United States 30322
    5 Lurie Children's Hospital Chicago Illinois United States 60611-2605
    6 Ochsner Baptist Medical Center New Orleans Louisiana United States 70115
    7 Boston Children's Hospital Boston Massachusetts United States 02115
    8 University of Rochester School of Medicine Children's Hospital Rochester New York United States 14642
    9 University of NC at Chapel Hill Chapel Hill North Carolina United States 27599
    10 East Carolina University Greenville North Carolina United States 27858
    11 Rainbow Babies and Childrens Hospital Cleveland Ohio United States 44106
    12 Nationwide Children's Hospital Columbus Ohio United States 43205
    13 Vanderbilt Children's Hospital Nashville Tennessee United States 37232-9544
    14 University of Virginia Children's Hospital Charlottesville Virginia United States 22908

    Sponsors and Collaborators

    • Christoph P Hornik, MD MPH
    • National Heart, Lung, and Blood Institute (NHLBI)
    • University of North Carolina, Chapel Hill

    Investigators

    • Principal Investigator: Christoph Hornik, MD, Duke UMC
    • Principal Investigator: Matt Laughon, MD, UNC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Christoph P Hornik, MD MPH, Associate Professor of Pediatrics, Duke University
    ClinicalTrials.gov Identifier:
    NCT04447989
    Other Study ID Numbers:
    • Pro00104901
    • 1R61HL147833-01
    First Posted:
    Jun 25, 2020
    Last Update Posted:
    Jun 21, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Bronchopulmonary Dysplasia
    Sildenafil Citrate

    Study Results

    No Results Posted as of Jun 21, 2022