PRIMED: Pragmatic Research on Diuretic Management in Early BPD Pilot

Sponsor

Children's Hospital Medical Center, Cincinnati (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05898022

Collaborator

Rainbow Babies and Children's Hospital (Other), Emory University (Other), RTI International (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Locations

Arm

Anticipated Duration (Months)

7.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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?

Condition or Disease	Intervention/Treatment	Phase
Bronchopulmonary Dysplasia	Drug: Furosemide (plus potassium chloride) Drug: Placebo (plus placebo electrolyte solution)	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

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 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.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)

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.

Primary Purpose:

Other

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Sep 30, 2025

Anticipated Study Completion Date :

Sep 30, 2025

Arms and Interventions

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 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) 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. 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.

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 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)

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.

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.

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Weeks to 10 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30303
2	RTI International	Durham	North Carolina	United States	27705
3	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
4	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

Children's Hospital Medical Center, Cincinnati
Rainbow Babies and Children's Hospital
Emory University
RTI International
National Heart, Lung, and Blood Institute (NHLBI)

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