Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

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Brief Title

Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

Official Title

Safety of Sildenafil in Premature Infants With Severe Bronchopulmonary Dysplasia

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).
    

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

           B. 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.

           iii. 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.

        5. Respiratory assessment, weekly

        6. Laboratory evaluations, at least once a week

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

        8. Pharmacokinetic (PK) sampling (after Day 7[)

        9. 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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Safety based upon incidence of hypotension

Secondary Outcome

 Volume of Distribution

Condition

Bronchopulmonary Dysplasia of Newborn

Intervention

Sildenafil

Study Arms / Comparison Groups

 Cohort 1, sildenafil
Description:  Sildenafil (0.5 mg/kg IV or 1 mg/kg enteral) every 8 hours for 28 days

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

120

Start Date

May 2021

Completion Date

December 2023

Primary Completion Date

December 2023

Eligibility 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.
      

Gender

All

Ages

N/A - 29 Weeks

Accepts Healthy Volunteers

No

Contacts

Christoph Hornik, MD, 919-668-8115, [email protected]



Administrative Informations


NCT ID

NCT04447989

Organization ID

Pro00104901

Secondary IDs

1R61HL147833-01

Responsible Party

Sponsor-Investigator

Study Sponsor

Christoph P Hornik, MD MPH

Collaborators

 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Christoph Hornik, MD, Principal Investigator, Duke UMC


Verification Date

June 2020