Pragmatic Research on Diuretic Management in Early BPD Pilot

Study Overview
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Brief Summary
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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?

Official Title
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Pragmatic Research on Diuretic Management in Early Bronchopulmonary Dysplasia (PRIMED) Pilot Study

Conditions
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Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Furosemide (plus potassium chloride)
* Drug: Placebo (plus placebo electrolyte solution)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: <28 weeks gestation at birth Post-Menstrual Age (PMA) of 30-32 weeks gestation Requiring positive pressure respiratory support (NCPAP≥ 5 cm H20, NIPPV/BiPhasic CPAP, or mechanical ventilation) Receiving FiO2 ≥ 30% Receiving enteral feedings of 120 mL/kg/day or greater Expected to be hospitalized for at least 28 days after enrollment Exclusion Criteria: Major congenital anomalies (e.g., known renal anomalies, congenital heart disease, congenital diaphragmatic hernia, or chromosomal anomalies) Serum creatinine > 1.7 mg/dL, BUN >50 mg/dL, Na <125 mmoL/L, K ≤ 2.5 mmol/L, or Ca ≤ 6 mg/dL in week prior to enrollment Treatment with a time-limited course of Dexamethasone or hydrocortisone within 10 days of enrollment. Exposure to a time-limited course dexamethasone or hydrocortisone for respiratory failure within 10 days of enrollment may result in carryover effects that confound the N-of-1 trial. Treatment with chronic steroids for adrenal insufficiency is not an exclusion criteria. Treatment with any diuretics within 7 days of enrollment. Exposure to diuretics within 7 days of enrollment may result in carryover effects that confound the N-of-1 trial. Non-English speaking

Ages Eligible for Study
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Minimum Age: 2 Weeks
Maximum Age: 10 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional 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 1 week and placebo (plus placebo electrolyte solution) for 1 week. Each patient will have 14 days of total exposure to furosemide over the 28-day N-of-1 trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: N-of-1 Trial<br>Each individual N-of-1 trial will have 2 blocks. In each block patients will crossover between furosemide (plus potassium chloride) for 1 week and placebo (plus placebo electrolyte solution) for 1 week. The total arm length (length of the N-of-1 Trial/Crossover) is 28 days. Patients may receive furosemide (plus potassium chloride) and placebo (plus placebo electrolyte solution) in one of four different treatment order sequences, however, treatment order will not be analyzed for the primary outcomes of feasibility/responder status. | Drug: Furosemide (plus potassium chloride)<br>* 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 14 days of total exposure to furosemide over the 28-day N-of-1 trial.<br>Drug: Placebo (plus placebo electrolyte solution)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |  | 35 Days | 
| Percent of providers willing to support randomizing a responder infant |  | 42 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of enrolled infants completing full N-of-1 trial and identified as responder |  | 35 days | 
| Percent of enrolled infants completing full N-of-1 trial |  | 35 days | 
| Percent of enrolled infants on respiratory support at the conclusion of the N-of-1 trial |  | 35 days | 
| Percent of parents willing to randomize responder infant |  | 42 days | 
| Rate of chronic diuretic use among responders (and non-responders) |  | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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furosemide, ventilator-induced lung injury, lung injury, lung diseases, respiratory tract diseases, infant, premature diseases, newborn, diseases, diuretics