Pragmatic Research on Diuretic Management in Early BPD Pilot (PRIMED)

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

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?

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: Placebo (plus placebo electrolyte solution); Drug: Furosemide (plus potassium chloride)

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University, Rainbow Babies and Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: N-of-1 Trial; 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. The total arm length (length of the N-of-1 Trial/Crossover) is 16 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: Placebo (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.; Drug: Furosemide (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.

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome 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
Percent of parents willing to randomize responder infant	30 days
Rate of chronic diuretic use among responders (and non-responders)	30 days

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Emory University; RTI International; Rainbow Babies and Children's Hospital
• Investigators: Principal Investigator: Heather Kaplan, MD, MSCE, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Anna Maria Hibbs, MD, MSCE, 1. Rainbow Babies and Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2023
• Primary Completion (Actual): July 10, 2025
• Study Completion (Actual): December 12, 2025

Study Registration Dates

• First Submitted: June 1, 2023
• First Submitted That Met QC Criteria: June 1, 2023
• First Posted (Actual): June 12, 2023

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: furosemide; lung injury; lung diseases; respiratory tract diseases; infant; newborn; diuretics; ventilator-induced lung injury; premature diseases; diseases
• Additional Relevant MeSH Terms: Wounds and Injuries; Pathologic Processes; Infant, Premature, Diseases; Infant, Newborn, Diseases; Thoracic Injuries; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Lung Diseases; Disease; Respiratory Tract Diseases; Lung Injury; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Sulfur Compounds; Organic Chemicals; Amides; Aniline Compounds; Amines; Sulfonamides; Sulfanilamides; Sulfones; Furosemide
• Other Study ID Numbers: 2021-0120; R34HL158586-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No