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