Milrinone for Congenital Diaphragmatic Hernia

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

66 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if milrinone, a medicine that helps the heart and lungs, can improve oxygen levels in newborns with severe lung and heart problems due to CDH. These babies often don't get better with usual treatments. The goal is to see if milrinone can safely help these babies breathe easier. Milrinone is used in up to 30% of CDH infants across the United States, but no studies have tested its effectiveness or safety in these newborns.

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.

What data supports the effectiveness of the drug Milrinone for treating congenital diaphragmatic hernia?

Milrinone is used in infants with congenital diaphragmatic hernia (CDH) to help improve heart function and blood flow in the lungs. It has been shown to improve oxygenation in some cases of pulmonary hypertension (high blood pressure in the lungs) associated with CDH, although no large studies have confirmed its effectiveness specifically for CDH. ^{1 2 3 4 5}

Is Milrinone generally safe for use in humans?

The provided research articles do not contain specific safety data for Milrinone or its other names like Primacor or Placebo (5% Dextrose) in humans. Therefore, no relevant safety information is available from these sources. ^{6 7 8 9 10}

How does the drug Milrinone differ from other treatments for congenital diaphragmatic hernia?

Milrinone is unique because it works by increasing the heart's ability to pump blood and relaxing blood vessels, which can help improve oxygen delivery in patients with congenital diaphragmatic hernia. This mechanism of action is different from other treatments that may not directly target heart function and blood vessel relaxation. ^{11 12 13 14 15}

Research Team

Satyan Lakshminrusimha, M.D.

Principal Investigator

University of California, Davis

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia? [2020]

4. Germany pubmed.ncbi.nlm.nih.gov

Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Treatment of premature infants with pulmonary hypertension and right ventricular dysfunction with milrinone: a case series. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital. [2021]

7. Norway pubmed.ncbi.nlm.nih.gov

Safety in paediatric clinical trials--a 7-year review. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Safety of ceftriaxone in paediatrics: a systematic review. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Adverse drug reactions in children]. [2013]

10. Italy pubmed.ncbi.nlm.nih.gov

[Adverse drug reactions in childhood. A drug surveillance study in Sicily]. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. [2014]

12. United States pubmed.ncbi.nlm.nih.gov

Outpatient vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening and labor induction postterm: a randomized controlled study. [2016]

13. Germany pubmed.ncbi.nlm.nih.gov

[Treatment of the unstable bladder in children with the anticholinergic agent propiverin hydrochloride (mictonorm/mictonets)]. [2012]

14. Germany pubmed.ncbi.nlm.nih.gov

[Metaraminol in therapy of various forms of priapism]. [2013]

15. England pubmed.ncbi.nlm.nih.gov

Intracavernosal metaraminol for treatment of intraoperative penile erection. [2019]