Diuretic Therapy for Bronchopulmonary Dysplasia

(PRIMED Trial)

Not currently recruiting at 3 trial locations

Overseen By Anna Maria C. Hibbs, MD, MSCE

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Dexamethasone, Hydrocortisone, Long-acting diuretics

Disqualifiers: Congenital anomalies, Electrolyte imbalance, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a specific diuretic, furosemide (also known as Lasix), for premature babies with bronchopulmonary dysplasia (BPD), a chronic lung disease. Researchers aim to determine if babies respond well to this treatment and whether it offers long-term benefits. Eligible babies are born before 28 weeks, currently require breathing support, and are expected to remain in the hospital for at least 28 more days. The trial alternates between furosemide and a placebo to assess individual responses. This research could help determine if long-term diuretic treatment is beneficial. As a Phase 4 trial, the study focuses on understanding how this already FDA-approved and effective treatment benefits more patients.

Will I have to stop taking my current medications?

The trial requires that participants stop taking any longer-acting diuretics at least 5 days before enrollment. If you are currently on chronic diuretics, you will need to stop those as well. However, treatment with chronic steroids for adrenal insufficiency or cardiovascular instability is allowed.

What is the safety track record for furosemide?

Research has shown that furosemide, a commonly used water pill, poses some safety concerns for premature babies at risk for bronchopulmonary dysplasia (BPD). Studies have found that when babies took furosemide for up to four weeks, problems with their body's mineral balance increased. One study found that 92% of babies who received furosemide experienced side effects, such as dehydration or changes in blood chemistry.

Although furosemide is often used to help lower the risk of BPD or death in some cases, awareness of these possible side effects is important. Prospective trial participants should discuss the benefits and risks with healthcare providers. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using furosemide for bronchopulmonary dysplasia because it acts as a potent diuretic, helping to reduce fluid buildup in the lungs, which can ease breathing difficulties for infants with this condition. Unlike standard treatments that might take longer to show effectiveness, furosemide has the potential to deliver improvements in just a few days. Additionally, this trial's crossover design allows for a personalized approach, aiming to identify which patients are true responders, something that isn't typically explored with conventional therapies.

What evidence suggests that diuretic therapy might be an effective treatment for bronchopulmonary dysplasia?

Research has shown that furosemide can help treat bronchopulmonary dysplasia (BPD) in premature babies. One study found that increased use of furosemide reduced the likelihood of developing BPD and the combined risk of BPD or death. Furosemide also improves lung function, enhancing the lungs' ability to stretch and expand in these infants. However, side effects, such as imbalances in body salts, raise concerns, so careful monitoring is important. In this trial, participants will receive furosemide (plus potassium chloride) and a placebo (plus a placebo electrolyte solution) in different sequences to evaluate its potential benefits for infants with BPD. ^{1 2 3 6 7}

Who Is on the Research Team?

Anna Maria C. Hibbs, MD, MSCE

Principal Investigator

1. Rainbow Babies and Children's Hospital

Heather Kaplan, MD, MSCE

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for premature babies with a lung condition called bronchopulmonary dysplasia (BPD), who are expected to be hospitalized for at least 28 days, can eat enough, need extra oxygen, and were born before the 28th week of pregnancy. Babies on certain steroids or diuretics recently, those with specific blood test results or major birth defects aren't eligible.

Inclusion Criteria

<28 weeks gestation at birth

Receiving enteral feedings of 120 mL/kg/day or greater

Expected to be hospitalized for at least 28 days after enrollment

Exclusion Criteria

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

I haven't taken long-acting diuretics like hydrochlorothiazide in the last 5 days.

I am currently prescribed and taking diuretics regularly.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

N-of-1 Trial

Each individual N-of-1 trial will have 2 blocks where patients crossover between furosemide and placebo to determine short-term response

4 weeks

Multiple visits as per crossover design

Follow-up

Participants are monitored for safety and effectiveness after the N-of-1 trial

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Furosemide
• Placebo

Trial Overview

The PRIMED study tests if furosemide helps babies with BPD by comparing it against a placebo in an N-of-1 trial design. This means each baby will receive both the real medicine and a fake one at different times to see which works better for them individually.

How Is the Trial Designed?

Group I: N-of-1 Trial Experimental Treatment 2 Interventions

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.

Furosemide is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Lasix for:

• Hypertension
• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome

Approved in United States as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Acute pulmonary edema

Approved in Canada as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Hypertension

Approved in Japan as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome

Approved in China as Lasix for:

• Edema associated with congestive heart failure
• Liver cirrhosis
• Renal disease
• Nephrotic syndrome
• Hypertension

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Rainbow Babies and Children's Hospital

Collaborator

Trials

9

Recruited

4,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

RTI International

Collaborator

Trials

201

Recruited

942,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 37,693 infants born extremely premature (23-29 weeks gestational age), exposure to furosemide was linked to a significant decrease in the risk of bronchopulmonary dysplasia (BPD), with a reduction of 4.6 percentage points for every 10 percentage points increase in furosemide exposure days.

The study also found that increased furosemide exposure was associated with a lower combined risk of BPD or death, suggesting that furosemide may have a protective effect in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Furosemide Exposure and Prevention of Bronchopulmonary Dysplasia in Premature Infants. Greenberg, RG., Gayam, S., Savage, D., et al.[2023]

A survey of pediatric pulmonologists and neonatologists in Israel revealed significant variability in diuretic weaning strategies for outpatient preterm infants with bronchopulmonary dysplasia (BPD), indicating a lack of consensus in clinical practice.

Most healthcare providers expressed dissatisfaction with the current guidelines and data on diuretic use in BPD, highlighting the need for more research, including a larger controlled study to compare gradual tapering versus immediate discontinuation of diuretics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weaning Strategy of Diuretics in Outpatient Preterm Infants with Bronchopulmonary Dysplasia: A National Survey. Armoni Domany, K., Amirav, I., Sadot, E., et al.[2022]

Long-term oral diuretic therapy with spironolactone and chlorothiazide significantly improved pulmonary function in preterm infants with bronchopulmonary dysplasia, showing a 46% increase in dynamic pulmonary compliance and a 31% decrease in airway resistance during treatment.

While the diuretic group required less supplemental oxygen compared to the placebo group after 4 weeks, the overall duration of oxygen requirement did not differ between the two groups, and the pulmonary function improvements were not sustained after discontinuation of the diuretics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia. Kao, LC., Durand, DJ., McCrea, RC., et al.[2022]

Inhaled furosemide, administered as a single dose of 1 mg/kg, did not show any significant improvement in pulmonary mechanics in ventilator-dependent infants with severe bronchopulmonary dysplasia (BPD) based on a study of 9 infants.

The study measured pulmonary function before and after treatment, and results indicated no notable changes in dynamic compliance, dynamic resistance, or tidal volume, suggesting that inhaled furosemide may not be an effective treatment for improving lung function in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary effect of inhaled furosemide in ventilated infants with severe bronchopulmonary dysplasia. Kugelman, A., Durand, M., Garg, M.[2019]

In a study of 83 very preterm infants with bronchopulmonary dysplasia (BPD), furosemide treatment led to a rapid decrease in net fluid balance, indicating the development of diuretic tolerance within the first 24 hours of exposure.

Co-administration of thiazide diuretics did not affect the fluid balance response to furosemide, suggesting that tolerance occurs independently of thiazide use, highlighting the need for careful management of furosemide dosing in these infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretic Tolerance to Repeated-dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia. Bamat, NA., Huber, M., Shults, J., et al.[2023]

Bronchopulmonary dysplasia (BPD) is a serious lung disease affecting 5,000 to 10,000 preterm infants annually in the U.S., leading to long-term health issues, including cognitive and motor function impairments.

The article reviews the literature on nebulized furosemide as a potential treatment for BPD, highlighting its safety and efficacy in managing this condition, although no single intervention currently exists to fully prevent or treat BPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nebulized furosemide in the treatment of bronchopulmonary dysplasia in preterm infants. Sahni, J., Phelps, SJ.[2021]

In a study of 3252 infants over 442,341 subject-days, chronic exposure to diuretics was linked to increased use of sodium chloride (NaCl) and potassium chloride (KCl) in infants developing severe bronchopulmonary dysplasia (sBPD).

Thiazide diuretics led to higher electrolyte use compared to loop diuretics, and adding potassium-sparing diuretics only slightly reduced KCl use, suggesting that the effects of different diuretic classes on electrolyte balance may need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children's hospitals. Nelin, TD., Lorch, S., Jensen, EA., et al.[2023]

Inhaled furosemide at doses of 1 and 2 mg/kg has shown to improve pulmonary function in preterm neonates with acute respiratory distress and potential bronchopulmonary dysplasia, without significant adverse effects.

Current studies only evaluated the effects of a single dose and monitored outcomes for a short duration (2 to 4 hours), indicating a need for further research to establish optimal dosing and long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerosolized furosemide in the treatment of acute respiratory distress and possible bronchopulmonary dysplasia in preterm neonates. Pai, VB., Nahata, MC.[2017]

In a study of 9,457 preterm infants, those who received diuretics for at least 7 days showed an increased likelihood of needing supplemental oxygen at home, indicating that diuretic use did not improve pulmonary outcomes as hoped.

The literature review revealed that while some studies noted short-term improvements in lung mechanics with diuretic use, there was no consistent evidence of benefits in oxygenation, highlighting the need for more randomized controlled trials to assess long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postnatal diuretics, weight gain and home oxygen requirement in extremely preterm infants. Williams, EE., Gunawardana, S., Donaldson, NK., et al.[2023]

In a study of over 107,000 premature infants, 37% were exposed to diuretics, primarily furosemide, despite the lack of FDA approval for this use, indicating a significant off-label prescription trend.

The study found that while many infants were not on mechanical ventilation when starting diuretics, adverse events occurred at a rate of 42 per 1,000 infant-days, with thrombocytopenia being the most common laboratory abnormality, raising concerns about the safety of diuretic use in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretic exposure in premature infants from 1997 to 2011. Laughon, MM., Chantala, K., Aliaga, S., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6486845/

Furosemide Exposure and Prevention of ...

More days of furosemide exposure between postnatal day 7 and 36 weeks was associated with decreased risk of BPD and a combined outcome of BPD or death.

2.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0022347625001696

Furosemide Safety in Preterm Infants at Risk for ...

Our study showed that up to 4 weeks of furosemide given to preterm infants at high risk for BPD was associated with an increase in electrolyte abnormalities.

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3608485/

Variation in the Use of Diuretic Therapy for Infants With ...

A Cochrane systematic review of 6 trials found that although furosemide improves pulmonary compliance, minute ventilation, and oxygen requirement in infants ...

4.

jpeds.com

jpeds.com/article/S0022-3476(25)00169-6/abstract

Furosemide Safety in Preterm Infants at Risk for ...

We found 293 AEs in 74 of 80 (93%) infants, including 223 AEs among 56 of 61 (92%) infants who received furosemide and 70 AEs among 18 of 19 (95 ...

5.

frontiersin.org

frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.820259/full

Pharmacotherapy in Bronchopulmonary Dysplasia: What Is ...

Lung compliance, pulmonary resistance, and tidal volume improved significantly 30 min to 4 h after a 1 mg/kg dose of nebulized furosemide without associated ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02527798

NCT02527798 | Safety of Furosemide in Premature Infants ...

Moderate-severe BPD or death risk was defined by the NICHD Neonatal Research Network (NRN) BPD outcome estimator which provides an estimate of the risk of BPD ( ...

7.

scholars.duke.edu

scholars.duke.edu/publication/1674906

Furosemide Safety in Preterm Infants at Risk for ...

RESULTS: We found 293 AEs in 74 of 80 (93%) infants, including 223 AEs among 56 of 61 (92%) infants who received furosemide and 70 AEs among 18 of 19 (95%) ...