Active Treatment vs Expectant Management for Patent Ductus Arteriosus

(PDA Trial)

Recruiting at 18 trial locations

Overseen By Matthew Laughon, MD, MPH

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: NICHD Neonatal Research Network

Disqualifiers: Cardiopulmonary compromise, Congenital heart disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 weeks postmenstrual age

836 Participants Needed

Trial Summary

What is the purpose of this trial?

Estimate the risks and benefits of active treatment versus expectant management of a symptomatic patent ductus arteriosus (sPDA) in premature infants.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications.

What data supports the idea that Active Treatment vs Expectant Management for Patent Ductus Arteriosus is an effective treatment?

The available research does not provide specific data on Active Treatment vs Expectant Management for Patent Ductus Arteriosus. Instead, it focuses on treatments for infective endocarditis, a different heart condition. Therefore, there is no direct evidence from the provided information to support the effectiveness of Active Treatment for Patent Ductus Arteriosus. ^{1 2 3 4 5}

What safety data exists for treatments of Patent Ductus Arteriosus?

The safety data for treatments of Patent Ductus Arteriosus (PDA) is limited and somewhat uncertain. The systematic review on dual therapy vs. monotherapy for PDA suggests that dual pharmacologic treatment may be more effective than monotherapy, but it does not specifically address safety data. The article on continued uncertainty highlights that despite many clinical trials, questions about the best treatment approach remain unanswered, partly due to changes in perinatal care and patient populations over time. The development of a common data model for active drug safety surveillance indicates efforts to enhance safety monitoring through analysis of multiple healthcare databases. However, specific safety data for PDA treatments, especially regarding adverse drug reactions in children, is not detailed in the provided research. ^{6 7 8 9 10}

Is the treatment for Patent Ductus Arteriosus generally safe in humans?

The research does not provide specific safety data for the treatments of Patent Ductus Arteriosus, but it highlights the need for more studies to understand the long-term effects and safety of these treatments in humans. ^{6 7 8 9 10}

Is Expectant Management a promising treatment for Patent Ductus Arteriosus?

Expectant Management, which involves waiting to see if the condition improves on its own, is promising because studies show it has similar outcomes to active treatments, like drugs or surgery, without increasing risks. This approach could be beneficial for preterm infants with Patent Ductus Arteriosus. ^{11 12 13 14 15}

How does the treatment for patent ductus arteriosus differ from other treatments?

The treatment for patent ductus arteriosus (PDA) in preterm infants can involve either active treatment, which includes medical or surgical interventions to close the ductus, or expectant management, which is a 'watch and wait' approach. Studies suggest that there is no significant difference in outcomes between these approaches, highlighting the need for further research to determine the best strategy for different subgroups of infants. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for premature infants aged between 48 hours and 21 days with a symptomatic patent ductus arteriosus (sPDA), which is a heart issue that's common in preemies. Infants must be born at gestational ages of 22 to less than 29 weeks. Those with serious heart or lung problems, other conditions affecting their health significantly, or any issues that might rule out participation are not eligible.

Inclusion Criteria

My baby is between 2 days and 3 weeks old.

My heart condition is classified as sPDA with a small or moderate size.

You have a specific heart condition called sPDA, which can be seen on an echocardiogram.

Exclusion Criteria

Any condition which, in the opinion of the investigator, would preclude enrollment

I have a known lung malformation.

I have a heart condition from birth, not including ASD or VSD.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active treatment with indomethacin or ibuprofen, or expectant management for symptomatic patent ductus arteriosus (sPDA)

Up to 36 weeks postmenstrual age

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of BPD, mortality, and other health outcomes

Up to 36 weeks postmenstrual age

Long-term Follow-up

Participants' growth and neurodevelopmental outcomes are assessed at 2 years corrected age

26 months corrected age

Treatment Details

Interventions

• Active Treatment
• Expectant Management

Trial Overview The study compares two approaches to treating sPDA in premature babies: 'Active Treatment' involves medical intervention to close the PDA, while 'Expectant Management' means monitoring the condition without immediate treatment unless it worsens.

Participant Groups

Group I: Active Treatment Group Active Control 1 Intervention

Infants assigned to the active treatment group will receive indomethacin or ibuprofen per their local site usual care dosing and schedule if the infant has a sPDA. The choice of indomethacin or ibuprofen will be left to the center, however, infants may only receive one or the other.

Group II: Expectant Management Group Active Control 1 Intervention

Infants assigned to the expectant management group will receive indomethacin or ibuprofen if cardiopulmonary compromise occurs.

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

Approved in United States as Active Treatment for:

• Symptomatic Patent Ductus Arteriosus (sPDA) in Premature Infants

Approved in European Union as Active Treatment for:

• Symptomatic Patent Ductus Arteriosus (sPDA) in Premature Infants

Approved in Canada as Active Treatment for:

• Symptomatic Patent Ductus Arteriosus (sPDA) in Premature Infants

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

Outpatient parenteral antibiotic treatment (OPAT) for infective endocarditis (IE) showed a significantly lower one-year mortality rate of 8% compared to 42% for hospital-based antibiotic treatment (HBAT), indicating OPAT's effectiveness as a treatment option.

Despite only 21.7% of patients meeting the restrictive IDSA criteria for OPAT, the study found no increased risk of mortality or readmission for those who did not meet these criteria, suggesting that the criteria should be expanded to allow more patients access to OPAT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort. Pericà S, JM., Llopis, J., González-Ramallo, V., et al.[2020]

In a study of 67 patients with active infective endocarditis who underwent surgery, culture-negative endocarditis was identified as a significant independent predictor of poor late survival and increased risk of complications after surgery.

The study found that while the overall operative mortality was 17.8%, the majority of adverse events, including reoperations and deaths, occurred within the first two years post-surgery, highlighting the need for close monitoring during this period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical results for active endocarditis with prosthetic valve replacement: impact of culture-negative endocarditis on early and late outcomes. Murashita, T., Sugiki, H., Kamikubo, Y., et al.[2022]

Outpatient parenteral antibiotic therapy (OPAT) for infective endocarditis (IE) is becoming more common, but there is a lack of controlled studies proving its effectiveness compared to traditional inpatient therapy.

The authors suggest stricter patient selection criteria for OPAT, recommending inpatient care or daily follow-ups during the first two weeks of treatment when complications are most likely, and considering OPAT only during the later phases when risks are lower.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient selection criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. Andrews, MM., von Reyn, CF.[2022]

In a pediatric outpatient parenteral antibiotic therapy (OPAT) program, providers spent 54 hours on nonreimbursable care coordination activities, which helped prevent 10 emergency room visits and 2 hospital readmissions for patients with complex infections.

The care coordination efforts led to increased healthcare utilization, including 16 additional subspecialist visits and 13 primary care visits, highlighting the importance of these activities in improving patient outcomes beyond what is captured through standard billing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilizing a Modified Care Coordination Measurement Tool to Capture Value for a Pediatric Outpatient Parenteral and Prolonged Oral Antibiotic Therapy Program. Vaz, LE., Farnstrom, CL., Felder, KK., et al.[2022]

Surgical treatment for active valvular infectious endocarditis in 142 patients showed a hospital mortality rate of 15.5%, indicating a significant risk during the immediate postoperative period.

Over an average follow-up of 3.5 years, the total survival rate was 74.4%, with 76.8% of discharged patients experiencing good long-term outcomes, suggesting that surgery can be an effective intervention for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Possibilities of cardiac surgery in the treatment of active valvular infectious endocarditis]. Tsukerman, GI., Dubrovskiĭ, VS., Zhadovskaia, VM., et al.[2017]

Despite extensive research involving nearly 5000 infants in clinical trials, there remains significant uncertainty about the best treatment strategies for patent ductus arteriosus (PDA) due to evolving clinical practices and patient demographics.

The article highlights the need for updated research designs that reflect current perinatal care advancements and the characteristics of today's more premature patient population to address ongoing clinical management challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continued uncertainty regarding treatment of patent ductus arteriosus in premature infants and the role of clinical trials. Juszczak, E., Gupta, S.[2021]

In a meta-analysis of 470 patients from five studies, dual pharmacotherapy for patent ductus arteriosus (PDA) resulted in a higher ductal closure rate of 67% compared to 58% for monotherapy, indicating greater efficacy for the combination treatment.

The analysis showed a statistically significant odds ratio of 1.97 (p = 0.023) favoring dual therapy, suggesting it may be a more effective approach, although further large-scale randomized controlled trials are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Therapy vs. Monotherapy for the Patent Ductus Arteriosus: A Systematic Review. Hammerman, C., Bin-Nun, A., Abdaljalil, H., et al.[2022]

The report emphasizes the importance of designing prospective observational studies with clear hypotheses and causal inference goals to effectively inform health policy decisions, especially in comparative effectiveness research.

To enhance the credibility and relevance of these studies, researchers should consider using robust design strategies, such as inception cohorts and new user designs, and ensure transparency in their study protocols, including registration on public platforms before execution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Berger, ML., Dreyer, N., Anderson, F., et al.[2022]

The study developed a common data model (CDM) that successfully transformed data from over 43 million individuals, allowing for systematic and comparable analyses of drug safety across different healthcare databases.

Using the CDM, analyses of drug effects, such as those related to rofecoxib and acute myocardial infarction, produced consistent results, demonstrating its effectiveness in enhancing drug safety surveillance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and evaluation of a common data model enabling active drug safety surveillance using disparate healthcare databases. Reisinger, SJ., Ryan, PB., O'Hara, DJ., et al.[2022]

In a systematic review of 17 studies involving children, the incidence of adverse drug reactions (ADRs) in hospitalized children was found to be 9.53%, with severe reactions accounting for 12.29%, highlighting the significant risk of ADRs in this population.

The study revealed that 2.09% of pediatric hospital admissions were due to ADRs, with 39.3% of these being life-threatening, indicating a critical need for improved drug safety monitoring and preventive strategies in pediatric healthcare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of adverse drug reactions in paediatric in/out-patients: a systematic review and meta-analysis of prospective studies. Impicciatore, P., Choonara, I., Clarkson, A., et al.[2023]

Routine early treatment to close the ductus arteriosus in preterm infants is not beneficial, indicating that a more tailored approach is necessary.

There is a need for better diagnostic tools and clinical trials to identify which infants would benefit from later ductal closure, as current management strategies are inconsistent and require further evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Learning to live with patency of the ductus arteriosus in preterm infants. Benitz, WE.[2011]

In a study of 68 premature infants weighing less than 1,500 g with patent ductus arteriosus (PDA), medical treatment was found to fail in 67.6% of cases for those with large PDAs (≥2 mm), indicating a high need for surgical intervention.

Primary surgical closure of large PDAs was associated with lower rates of bronchopulmonary dysplasia (BPD) and no surgery-related mortality, suggesting it may be a safer and more effective option for reducing long-term complications in these vulnerable infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary surgical closure should be considered in premature neonates with large patent ductus arteriosus. Ko, SM., Yoon, YC., Cho, KH., et al.[2021]

A meta-analysis of 7 randomized controlled trials found no significant difference in all-cause mortality or adverse clinical outcomes between expectant management and active treatment for patent ductus arteriosus (PDA) in preterm infants.

The study suggests a need for larger, double-blinded trials to better define the role of expectant management, particularly in high-risk subgroups, to clarify treatment strategies for PDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expectant management of patent ductus arteriosus for preterm infants: A meta-analysis of randomized controlled trials. Cheema, HA., Majeed, Z., Hayat, T., et al.[2023]

This systematic review aims to evaluate the effectiveness and safety of pharmacotherapeutic options (indomethacin, ibuprofen, and acetaminophen) for managing patent ductus arteriosus (PDA) in preterm infants, focusing on the primary outcome of PDA closure failure and various secondary outcomes related to neonatal health.

The study will utilize a Bayesian network meta-analysis to compare treatment effects across different interventions, which will help clarify the best therapeutic options and potentially reduce uncertainty in clinical practice for managing PDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: a protocol for a systematic review and network meta-analysis. Mitra, S., Florez, ID., Tamayo, ME., et al.[2019]

In a 1-year follow-up of a clinical trial involving premature infants with patent ductus arteriosus, three management strategies showed no significant differences in long-term health outcomes, indicating that all strategies may be equally effective.

While initial treatment with indomethacin led to more bleeding episodes during hospitalization, and usual medical therapy with surgery as backup resulted in higher rates of retrolental fibroplasia, these issues did not translate into significant differences in health at one year of age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical course to 1 year of age in premature infants with patent ductus arteriosus: results of a multicenter randomized trial of indomethacin. Peckham, GJ., Miettinen, OS., Ellison, RC., et al.[2019]

References

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

Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort. [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

Surgical results for active endocarditis with prosthetic valve replacement: impact of culture-negative endocarditis on early and late outcomes. [2022]

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

Patient selection criteria and management guidelines for outpatient parenteral antibiotic therapy for native valve infective endocarditis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Utilizing a Modified Care Coordination Measurement Tool to Capture Value for a Pediatric Outpatient Parenteral and Prolonged Oral Antibiotic Therapy Program. [2022]

5. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Possibilities of cardiac surgery in the treatment of active valvular infectious endocarditis]. [2017]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Continued uncertainty regarding treatment of patent ductus arteriosus in premature infants and the role of clinical trials. [2021]

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

Dual Therapy vs. Monotherapy for the Patent Ductus Arteriosus: A Systematic Review. [2022]

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

Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Development and evaluation of a common data model enabling active drug safety surveillance using disparate healthcare databases. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Incidence of adverse drug reactions in paediatric in/out-patients: a systematic review and meta-analysis of prospective studies. [2023]

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

Learning to live with patency of the ductus arteriosus in preterm infants. [2011]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Primary surgical closure should be considered in premature neonates with large patent ductus arteriosus. [2021]

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

Expectant management of patent ductus arteriosus for preterm infants: A meta-analysis of randomized controlled trials. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: a protocol for a systematic review and network meta-analysis. [2019]

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

Clinical course to 1 year of age in premature infants with patent ductus arteriosus: results of a multicenter randomized trial of indomethacin. [2019]