Bronchopulmonary Dysplasia
Conditions
Keywords
furosemide, ventilator-induced lung injury, lung injury, lung diseases, respiratory tract diseases, infant, premature diseases, newborn, diseases, diuretics
Brief summary
Babies who are born prematurely often develop a chronic lung disease called bronchopulmonary dysplasia (BPD). BPD puts babies at higher risk for problems with growth and development. Diuretics, such as furosemide, are frequently used in the management of early BPD). Many clinicians use informal trials of therapy to see if a baby responds to diuretics in the short-term before starting chronic diuretic therapy. Despite frequent use of diuretics, it is unclear how many babies truly respond to therapy and if there are long-term benefits of diuretic treatment. Designing research studies to figure this out has been challenging. The Pragmatic Research on Diuretic Management in Early BPD (PRIMED) study is a feasibility pilot study to help us get information to design a larger trial of diuretic management for BPD. Key questions this study will answer include: (1) Can we use an N-of-1 trial to determine whether a particular baby responds to furosemide? In an N-of-1 trial, a baby is switched between furosemide and placebo to compare that particular infant's response on and off diuretics. It is a more rigorous approach to the informal trials of therapy that are often conducted in clinical care. We hope to learn how many babies have a short-term response to furosemide ("responders"); (2) how many babies will still be on respiratory support at the end of the N-of-1 trial? This will help us determine how many patients would be eligible to randomize to chronic diuretic therapy in the second phase of the larger trail, and (3) if a baby is identified as a short-term responder, how many parents and physicians would be willing to randomize the baby to chronic diuretics (3 months) versus placebo in the longer trial?
Interventions
DRUGFurosemide (plus potassium chloride)
Furosemide is a loop diuretic that inhibits the reabsorption of sodium and chloride in the proximal and distal tubules as well as the loop of Henle. Participants will receive 2 mg/kg enteral furosemide daily during treatment periods when they receive study drug. To prevent hypokalemia and hypochloremia associated with furosemide use, participants will also receive 1 mg/kg of potassium chloride enterally twice per day when receiving furosemide. Each patient will have 8 days of total exposure to furosemide over the 16-day N-of-1 trial.
DRUGPlacebo (plus placebo electrolyte solution)
During treatment periods when participants receive placebo, they will receive a volume of sterile water equivalent to the study drug dose. Participants will also receive a placebo electrolyte solution equivalent to the volume of potassium chloride that would be given.
Sponsors
Children's Hospital Medical Center, Cincinnati
Rainbow Babies and Children's Hospital
Emory University
RTI International
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Masking description
Participant, care provider, investigator, outcomes assessor learn the order of furosemide and placebo administration at the end of their N-of-1 trial.
Intervention model description
The proposed pilot, feasibility study will enroll patients in a series of N-of-1 trials. Each individual N-of-1 trial will have 2 blocks. In each block patients will crossover between furosemide (plus potassium chloride) for 4 days and placebo (plus placebo electrolyte solution) for 4 days. Each patient will have 8 days of total exposure to furosemide over the 16-day N-of-1 trial.
Eligibility
Sex/Gender
ALL
Age
2 Weeks to 10 Weeks
Healthy volunteers
No
Inclusion criteria
1. \<28 weeks gestation at birth 2. Post-Menstrual Age (PMA) of 29-32 weeks gestation 3. Requiring invasive positive pressure respiratory support or NIPPV/NIMV and FiO2 ≥ 25% or requiring non-invasive positive pressure respiratory support (NCPAP≥ 5 cm H20, BiPhasic CPAP) and FiO2 ≥ 30%. 4. Receiving enteral feedings of 120 mL/kg/day or greater 5. Expected to be hospitalized for at least 28 days after enrollment
Exclusion criteria
1. Major congenital anomalies (e.g., known renal anomalies, congenital heart disease, congenital diaphragmatic hernia, or chromosomal anomalies) 2. In infants who had electrolyte testing in the week prior to enrollment, those with a serum creatinine \> 1.7 mg/dL, BUN \>50 mg/dL, Na \<125 mmoL/L, K ≤ 2.5 mmol/L, or Ca ≤ 6 mg/dL. Not having electrolyte testing in the week prior to enrollment is not an exclusion criterion. 3. Current treatment with Dexamethasone or hydrocortisone for respiratory failure. Treatment with chronic steroids for history of adrenal insufficiency or cardiovascular instability is not an exclusion criterion. 4. Treatment with any longer-acting diuretic (e.g., chlorothiazide, hydrochlorothiazide, acetazolamide) within 5 days of enrollment where exposure may result in carryover effects that confound the N-of-1 trial 5. Active order for standing, regularly scheduled diuretics (e.g., chronic diuretics) 6. Non-English speaking 7. Current treatment with ibuprofen or indocin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent of Enrolled Infants Who Completed the Full N-of-1 Trial, Remain on Respiratory Support at the Conclusion of the N-of-1 Trial, and Were Identified as a Responder | 23 Days |
| Percent of Providers Willing to Support Randomizing a Responder Infant | 30 Days |
Secondary
| Measure | Time frame |
|---|---|
| Percent of Enrolled Infants Completing Full N-of-1 Trial and Identified as Responder | 23 days |
| Percent of Enrolled Infants Completing Full N-of-1 Trial | 23 days |
| Percent of Enrolled Infants on Respiratory Support at the Conclusion of the N-of-1 Trial | 23 days |
| Rate of Chronic Diuretic Use Among Responders | 30 days |
| Rate of Chronic Diuretic Use Among Non-responders | 30 days |
| Percent of Parents Willing to Randomize Responder Infant | 30 days |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORHeather Kaplan, MD, MSCE
Children's Hospital Medical Center, Cincinnati
PRINCIPAL_INVESTIGATORAnna Maria Hibbs, MD, MSCE
1. Rainbow Babies and Children's Hospital
Participant flow
Recruitment details
Infant screening and enrollment took placed from 08/2023 to 08/2025 at 3 academic centers in the U.S. and their affiliate neonatal intensive care units.
Pre-assignment details
Infant screening occurred in continuous fashion once infant reached 29 weeks post-menstrual age; infants with high likelihood of eligibility could be consented and, then, assigned to the study arm/group only if meeting eligibility criteria.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 35 days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 | 0 / 16 |
| other Total, other adverse events | 18 / 19 | 14 / 18 | 12 / 16 |
| serious Total, serious adverse events | 1 / 19 | 1 / 18 | 0 / 16 |
Outcome results
None listed