Milrinone for Congenital Diaphragmatic Hernia

No longer recruiting at 18 trial locations

Overseen By Satyan Lakshminrusimha, M.D.

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: NICHD Neonatal Research Network

Must not be taking: Parenteral vasodilators

Disqualifiers: Hypertrophic cardiomyopathy, Cyanotic CHD, Bilateral CDH, Renal dysfunction, Intracranial bleed, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 72 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of milrinone in improving oxygen levels for newborns with congenital diaphragmatic hernia (CDH). CDH occurs when a hole in the diaphragm allows organs to move into the chest, affecting lung development and causing breathing problems. The study compares milrinone, which enhances heart pumping and widens blood vessels, against a placebo to assess its impact on lung and heart issues. Infants with CDH who require a breathing machine might be suitable for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if participants must stop taking their current medications. However, ongoing therapy with certain intravenous or subcutaneous pulmonary vasodilators is not allowed at the time of randomization, and starting these medications within the first 24 hours of the study drug is also not permitted.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that milrinone is often used in babies with congenital diaphragmatic hernia (CDH), despite limited safety data. Approximately 30% of these infants receive milrinone as part of their treatment. However, no studies have specifically tested its safety in this population.

The FDA has approved milrinone for other uses, indicating general safety. This pilot trial aims to determine its safety and effectiveness in improving oxygen levels in babies with CDH. Although milrinone is commonly used, its safety for this specific group remains uncertain. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CDH?

Unlike the standard treatments for congenital diaphragmatic hernia, which often focus on surgical repair and supportive care to manage symptoms, Milrinone offers a unique approach by enhancing heart function and improving blood flow. Researchers are excited about Milrinone because it works as a phosphodiesterase inhibitor, which helps relax and widen blood vessels, potentially improving oxygen delivery more effectively. This mechanism not only aims to stabilize the infants faster but may also reduce the reliance on invasive procedures, providing a promising new avenue for managing this challenging condition.

What evidence suggests that milrinone might be an effective treatment for congenital diaphragmatic hernia?

In this trial, participants will receive either milrinone or a placebo to evaluate its effectiveness for congenital diaphragmatic hernia (CDH). Research suggests that milrinone might improve oxygen levels in babies with CDH. It supports heart function by strengthening the heartbeat and aiding relaxation. Additionally, milrinone opens blood vessels in the lungs, which can help with breathing problems. Although often used to manage CDH, limited research specifically shows its effectiveness for these babies. Some studies indicate it might not significantly improve certain measures like oxygen levels or blood pressure in the lungs. However, it remains a treatment option due to its potential benefits for heart and lung function. ^{1 2 3 6 7}

Who Is on the Research Team?

Satyan Lakshminrusimha, M.D.

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

This trial is for newborns over 36 weeks gestation, weighing at least 2000g, diagnosed with congenital diaphragmatic hernia (CDH), experiencing severe lung and heart issues due to the hernia. They must be on mechanical ventilation but stable enough not to require certain emergency treatments or have specific heart conditions, bleeding in the brain, or genetic disorders that shorten life span.

Inclusion Criteria

I am on a breathing machine through a tube in my windpipe.

Your recent blood test shows that your blood is getting enough oxygen.

My oxygen saturation index is at least 5, based on the latest test within 12 hours.

Exclusion Criteria

My infant is on special medication for lung blood vessel issues or is on ECMO.

My infant has a specific type of heart defect present from birth.

My infant has a birth defect in both sides of the diaphragm.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Neonates receive milrinone or placebo infusion to test its efficacy in improving oxygenation

72 hours

Continuous monitoring during hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment, including clinical status and oxygenation response

12 months

Visits at discharge and 12 months of age

Long-term follow-up

Assessment of chronic lung disease and other long-term outcomes

56 days postnatal age or until discharge

What Are the Treatments Tested in This Trial?

Interventions

• Milrinone
• Placebo (5% Dextrose)

Trial Overview The study tests Milrinone's safety and effectiveness in improving oxygen levels in infants with CDH compared to a placebo. Infants will be randomly assigned to receive either Milrinone or a placebo solution intravenously while their oxygenation status is monitored.

How Is the Trial Designed?

Group I: Milrinone Experimental Treatment 1 Intervention

Milrinone infusion at 0.33µg/kg/min. The dose of the study drug will be increased to 0.66 µg/kg/min if oxygenation index (OI) remains ≥ 10 without any evidence of hypotension (as defined by the protocol) two hours after initiation of study drug. Infusion will be continued until the OI decreases to \< 7. The maximum duration of study drug infusion is 72 hours.

Group II: 5% dextrose (D5W) Placebo Group 1 Intervention

An equivalent volume of 5% dextrose (D5W) will be used for infants randomized to the placebo arm.

Milrinone is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Primacor for:

• Acute heart failure
• Cardiogenic shock

Approved in Canada as Milrinone for:

• Acute heart failure
• Cardiogenic shock

Approved in European Union as Milrinone for:

• Acute heart failure

Who Is Running the Clinical Trial?

NICHD Neonatal Research Network

Lead Sponsor

Trials

62

Recruited

209,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Out of 1787 reported adverse drug reactions (ADRs) over 11 years, 103 (5.85%) were in pediatric patients, with serious ADRs being more common in younger children, particularly newborns and infants.

The most frequent ADRs were nervous system disorders, primarily linked to antineoplastics and immunodulators, highlighting the need for careful monitoring and reporting, especially since medication errors were noted in 7.8% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital. López-Valverde, L., Domènech, È., Roguera, M., et al.[2021]

Ceftriaxone is associated with a high incidence of gastrointestinal disorders (37.4%) and serious adverse drug reactions (ADRs) such as immune hemolytic anemia and biliary pseudolithiasis in pediatric patients, with 5717 patients studied across 112 trials.

Immune hemolytic anemia, particularly in children with sickle cell disease, can lead to severe outcomes, including death, highlighting the need for caution when prescribing ceftriaxone to this vulnerable group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of ceftriaxone in paediatrics: a systematic review. Zeng, L., Wang, C., Jiang, M., et al.[2020]

Adverse drug reactions (ADRs) in children can significantly impact their health, with incidence rates estimated between 0.6% and 19.9%, and up to 6% of pediatric hospital admissions being linked to ADRs.

Efforts by pharmacovigilance centers aim to enhance the reporting and documentation of ADRs in children, which is crucial for understanding the relationship between drug use and clinical reactions, ultimately leading to safer and more effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse drug reactions in children]. Jaffan, L., Läer, S.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5704584/

Milrinone in congenital diaphragmatic hernia – a randomized ... We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ≥36 weeks postmenstrual age (PMA) with CDH.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02951130

Milrinone in Congenital Diaphragmatic Hernia Milrinone is commonly used during the management of CDH although no randomized trials have been performed to test its efficacy. Thirty percent of infants with ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30708393/

Is Milrinone Effective for Infants with Mild-to-Moderate ... Conclusion: In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular ...

4. nature.com nature.com/articles/s41372-025-02226-z

Golden hour management of infants with congenital ... Despite increased disease severity, survival improved over time, from 71% (2008–2013) to 82% (2014–2018) and 83% (2019–2023), p = 0.02 for trend ...

5. omicsdi.org omicsdi.org/dataset/biostudies-literature/S-EPMC5704584

Milrinone in congenital diaphragmatic hernia - a ... Survival to discharge was 71%. Discussion:CDH is an orphan disease with high mortality with few randomized trials evaluating postnatal ...

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/30/NCT02951130/ICF_000.pdf

Milrinone in Congenital Diaphragmatic Hernia This initial pilot study will help us to understand how milrinone works to help the heart and lungs give oxygen to the tissues and other organs in infants with ...

7. wjps.bmj.com wjps.bmj.com/content/7/2/e000790

Hemodynamic management of congenital diaphragmatic ... 49 Currently, milrinone is used in 17% of CDH cases within the Neonatal Research Network. Ongoing research (NCT02951130) aims to assess whether ...