Bronchopulmonary Dysplasia
Conditions
Brief summary
Describe the safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia and determine preliminary effectiveness and pharmacokinetics (PK) of sildenafil. Funding Source - FDA Office of Orphan Products Development (OOPD).
Detailed description
This will be a multi-center, randomized, placebo-controlled, sequential dose escalating, double masked, safety data study of sildenafil in premature infants. This is a Phase II study design, premature infants (inpatient in neonatal intensive care units) will be randomized in a dose escalating approach 3:1 (sildenafil: placebo) into 3 cohorts with escalating doses of sildenafil. There will be 40 randomized and dosed participants in each cohort for a total of up to 120 participants. Cohort 1 sildenafil dose will be 0.125 mg/kg q 8 hours IV or 0.25 mg/kg q 8 hours enteral. Cohort 2 sildenafil dose will be 0.5 mg/kg q 8 hours IV or 1.0 mg/kg q 8 hours enteral. Cohort 3 sildenafil dose will be 1 mg/kg q 8 hours IV or 2 mg/kg q 8 hours enteral.
Interventions
DRUGSildenafil
Infants will be randomized using a 3:1 scheme to receive sildenafil or placebo.
OTHERPlacebo
Infants randomized to the placebo group will receive the equivalent volume of dextrose 5% for IV use or enteral use (if receiving enteral study drug).
Sponsors
University of North Carolina, Chapel Hill
Duke University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
The Emmes Company, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Days to 28 Days
Healthy volunteers
No
Inclusion criteria
* Receiving positive airway pressure (nasal continuous airway pressure, nasal intermittent positive pressure ventilation, or nasal cannula flow \> 1LPM) or mechanical ventilation (high frequency or conventional) * \<29 weeks gestational age at birth * 7-28 (inclusive) days postnatal age at time of randomization
Exclusion criteria
* Currently receiving vasopressors * Currently receiving inhaled nitric oxide * Baseline mean arterial pressure \< gestational age (in weeks) plus postnatal age (in weeks) within 2 hours of sildenafil administration * Known allergy to sildenafil * Known sickle cell disease * Aspartate Aminotransferase (AST) \> 225 U/L \< 72 hours prior to randomization * Alanine Aminotransferase (ALT) \> 150 U/L \< 72 hours prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Determined by Adverse Event Experienced by Participants | Nonserious AEs were collected through Day 14 post last intervention; SAEs through Day 28. Retinopathy of prematurity was assessed through discharge/transfer, up to 575 days after first treatment. | Description of safety of sildenafil in premature infants and assessed by frequency and incidence of adverse events (AEs) and serious adverse events. Both non-serious and serious adverse events were collected from the time of informed consent through Day 14 after the last study intervention. Serious adverse events were additionally collected through 28 days after the last study intervention. Retinopathy of prematurity (ROP), whether serious or non-serious, was collected through hospital discharge or transfer; hospitalization duration varied based on clinical course, the longest duration was up to 575 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution | Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration. | Volume of distribution was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment. |
| Clearance | Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration. | Clearance was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment. |
| Half-Life | Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration. | Half-life was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment. |
| Area Under the Curve (AUC) | Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration. | Exposure, as measured by area under the plasma concentration-time curve (AUC), was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment. |
| Peak Plasma Concentration | Pharmacokinetic samples were collected after any dose following completion of 7 days of study drug administration through Day 28 of study drug administration. | Maximum plasma concentration (Cmax) was estimated for participants receiving active study drug using a population pharmacokinetic model. Pharmacokinetic samples were collected after approximately 7 days on study drug at protocol-defined time points (0-15 minutes, 30-60 minutes, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, within 15 minutes prior to the next dose, and 16-24 hours after the last dose) through 28 days of treatment. |
| Change in Moderate-severe BPD or Death | From the first day of study drug administration to the end of study drug administration, up to 28 days | Moderate-severe bronchopulmonary dysplasia (BPD) or death risk will be defined by the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) BPD outcome estimator. https://neonatal.rti.org/. The outcome measure is a reduction in moderate-severe BPD or death risk from day 1 of study drug to end of study drug administration. The BPD outcome estimator uses the following to calculate risk of BPD: Gestational age, Birth weight, Sex, Maternal Race/EthnicitylmPostnatal day, Ventilation type, Fraction of Inspired Oxygen The NICHD NRN BPD estimator calculates the risk of BPD (none, mild, moderate, severe) or death by postnatal day, as a percentage. For this protocol, outcomes will be dichotomized as none-mild vs. moderate-severe-death. Risk estimates will be recorded on days 7, 14, 21, and 28 of the study drug period, using the day closest to the participants postnatal age. For infants older than 28 days, the day 28 estimate will be applied. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORMatthew M Laughon, MD, MPH
University of North Carolina, Chapel Hill
Participant flow
Pre-assignment details
In total, 109 individuals provided informed consent. Three were not randomized and therefore did not receive study intervention, 106 participants were consented and randomized to a study arm/group (started).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 26.2 Weeks STANDARD_DEVIATION 1.5 |
| Age, Customized Post Natal Age | 20.6 Days STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 36 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 1 / 30 | 2 / 16 | 1 / 26 |
| other Total, other adverse events | 27 / 30 | 27 / 30 | 14 / 16 | 21 / 26 |
| serious Total, serious adverse events | 3 / 30 | 8 / 30 | 2 / 16 | 2 / 26 |
Outcome results
None listed