Acetaminophen + Ibuprofen for Patent Ductus Arteriosus

Recruiting at 8 trial locations

Overseen By Laura Thomas, MSc

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Mount Sinai Hospital, Canada

Must be taking: Ibuprofen

Disqualifiers: Chromosomal anomaly, Renal dysfunction, Hepatic dysfunction, others

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

Approved in 7 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 days

310 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new combination of ibuprofen and IV acetaminophen to treat a heart problem in very premature babies. These babies often don't respond well to just one drug, so using two drugs together might work better. The goal is to see if this combination is safer and more effective than using ibuprofen alone. Ibuprofen is commonly used to close the ductus arteriosus in premature newborns, and IV acetaminophen has shown effectiveness in similar treatments.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It is best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug combination of acetaminophen and ibuprofen for treating patent ductus arteriosus?

Research shows that ibuprofen is as effective as indomethacin in closing patent ductus arteriosus in preterm infants, with fewer side effects. This suggests that ibuprofen, a component of the drug combination, is effective for this condition. ^{1 2 3 4 5}

Is the combination of acetaminophen and ibuprofen generally safe for humans?

Ibuprofen, when taken at higher doses, has similar vascular risks to coxibs (a type of painkiller), but no specific safety data for the combination of acetaminophen and ibuprofen in humans is provided in the available research. ^{6 7 8 9 10}

How does the drug combination of acetaminophen and ibuprofen differ from other treatments for patent ductus arteriosus?

The combination of acetaminophen (paracetamol) and ibuprofen for treating patent ductus arteriosus (PDA) in preterm infants is unique because it aims to improve the closure rate of the ductus arteriosus compared to using ibuprofen alone. While ibuprofen is already effective for PDA, adding acetaminophen may enhance its effectiveness, offering a potentially better treatment option for this condition. ^{1 2 3 11 12}

Research Team

Amish Jain, MD PhD

Principal Investigator

MOUNT SINAI HOSPITAL

Eligibility Criteria

This trial is for extremely premature infants (born before 27 weeks) with a heart condition called PDA, where the duct fails to close after birth. Infants must not have had previous PDA treatment, except for indomethacin used to prevent bleeding in the brain. They should also have normal kidney and liver function and an adequate platelet count.

Inclusion Criteria

My baby was born before 27 weeks of pregnancy.

Permission given by the attending clinician to approach and then consent obtained from parents

I am set to start treatment with ibuprofen through IV or feeding tube.

Exclusion Criteria

Your liver is not working well, as shown by high levels of a liver enzyme called ALT.

Your platelet count is less than 50,000 per drop of blood.

I have been treated for PDA with drugs, except for indomethacin used to prevent brain bleeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either combination therapy with ibuprofen and acetaminophen or standard monotherapy with ibuprofen for PDA treatment

3 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including respiratory support, NEC, mortality, and BPD severity

Up to 250 days

Outcome Assessment

Assessment of PDA treatment success and other secondary outcomes

6-10 days post treatment initiation

Treatment Details

Interventions

• Acetaminophen Injection
• Ibuprofen

Trial Overview The study tests if giving Ibuprofen together with IV Acetaminophen is more effective than Ibuprofen alone for treating PDA in very early-born babies. The goal is to see if this combination can improve outcomes by acting on different pathways that keep the duct open.

Participant Groups

Group I: Combination Therapy Experimental Treatment 2 Interventions

Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates \< 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates \> 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days).

Group II: Standard Clinical Practice - Monotherapy Placebo Group 2 Interventions

Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates \< 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates \> 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo \[(0.9% saline IV q6h for 3 days).

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

Approved in United States as Advil for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Canada as Motrin for:

• Pain relief
• Fever reduction
• Inflammation

Approved in European Union as Nurofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Japan as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in China as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Switzerland as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Who Is Running the Clinical Trial?

Mount Sinai Hospital, Canada

Lead Sponsor

Trials

210

Recruited

70,700+

John Hunter Hospital

Collaborator

Trials

8

Recruited

1,700+

Royal Alexandra Hospital

Collaborator

Trials

20

Recruited

9,300+

Centre Hospitalier de l'Universite Laval (CHUL)

Collaborator

Trials

3

Recruited

780+

Royal North Shore Hospital

Collaborator

Trials

42

Recruited

7,900+

Prince of Wales Hospital, Shatin, Hong Kong

Collaborator

Trials

55

Recruited

21,700+

Sunnybrook Health Sciences Centre

Collaborator

Trials

693

Recruited

1,569,000+

McMaster Children's Hospital

Collaborator

Trials

43

Recruited

19,900+

The Rotunda Hospital

Collaborator

Trials

12

Recruited

4,300+

Findings from Research

Ibuprofen (IBU) was found to be as effective as indomethacin (IND) in closing patent ductus arteriosus (PDA) in extremely low-birthweight infants, with no significant differences in closure rates or the need for surgical ligation between the two treatments.

IBU demonstrated a better safety profile regarding short-term renal function, as indicated by higher urine volume and lower levels of urinary L-type fatty acid binding protein compared to IND, suggesting less renal impairment in infants treated with IBU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence on renal function of ibuprofen treatment for patent ductus arteriosus in extremely low birthweight infants. Nishizaki, N., Matsuda, A., Yoneyama, T., et al.[2020]

A meta-analysis of nine trials involving 566 preterm infants found that ibuprofen (IBU) and indomethacin (INDO) are equally effective in closing patent ductus arteriosus (PDA), with no significant difference in efficacy (P = 0.70).

However, ibuprofen was associated with significantly lower increases in serum creatinine levels and higher urine output compared to indomethacin, indicating better renal safety and less adverse effects on organ blood flow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. Thomas, RL., Parker, GC., Van Overmeire, B., et al.[2018]

Current ibuprofen dosing regimens for treating patent ductus arteriosus (PDA) may be inadequate, and simulations suggest that a new regimen could improve efficacy and safety.

The proposed regimen starts with an initial dose of 18 mg/kg followed by 4 mg/kg every 12 hours, which maintains effective drug levels while reducing peak concentrations, and should be adjusted to 5 mg/kg every 12 hours after 96 hours of postnatal age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns. Flint, RB., Ter Heine, R., Spaans, E., et al.[2019]

The study found that the currently recommended intravenous ibuprofen dose regimen of 10-5-5 mg/kg is effective in closing the patent ductus arteriosus (PDA) in preterm infants with a postmenstrual age (PMA) of 27-29 weeks, achieving an 80% closure rate with minimal adverse effects.

For infants with a PMA of less than 27 weeks, a higher dose regimen of 20-10-10 mg/kg may improve closure rates, but this needs further investigation for safety and tolerability due to increased renal adverse effects observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. Desfrere, L., Zohar, S., Morville, P., et al.[2022]

In a study of 60 preterm infants with significant patent ductus arteriosus (PDA), ibuprofen (IBU) showed similar efficacy to indomethacin (IND) in closing PDA, with closure rates of 50% for IBU and 46.7% for IND, indicating that both treatments are effective options.

IBU was associated with a significantly lower incidence of acute kidney injury, as indicated by serum creatinine increases greater than 0.3 mg/dL, occurring in 35.7% of IBU patients compared to 84.2% in the IND group, suggesting that IBU may be a safer alternative for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is ibuprofen superior to indomethacin for patent ductus arteriosus in Japanese preterm infants? Matsumura, S., Masutani, S., Oshima, A., et al.[2021]

Sofosbuvir has a significant interaction with amiodarone, leading to a risk of severe bradycardia, highlighting the need for caution when these drugs are used together.

SGLT2 inhibitors are associated with risks of diabetic ketoacidosis and bone fractures, indicating important safety considerations for patients using these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance update]. Dao, K., Chtioui, H., Rothuizen, LE., et al.[2016]

In 2006, several drugs were associated with significant safety concerns, including cardiovascular events linked to erythropoietins and macular edema associated with rosiglitazone, highlighting the need for careful monitoring by prescribers.

Other notable adverse reactions included serious complications from aprotinin, long-term use of linezolid, and congenital anomalies linked to paroxetine and lamotrigine, emphasizing the importance of understanding the safety profiles of medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. Livio, F., Buclin, T., Biollaz, J.[2013]

A new algorithm consisting of 13 items was developed to more accurately identify adverse drug reactions (ADRs) in critically ill newborns in NICUs, showing higher validity and reliability compared to the existing Naranjo algorithm.

The new algorithm achieved a weighted kappa of 0.76 and an intraclass correlation coefficient of 0.62, indicating it is a better tool for detecting ADRs than the Naranjo algorithm, which had lower scores of 0.31 and 0.43, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An algorithm to detect adverse drug reactions in the neonatal intensive care unit. Du, W., Lehr, VT., Lieh-Lai, M., et al.[2021]

In a study of 200 neonates in a newborn intensive care unit, 30% experienced adverse drug reactions (ADRs), with 14.7% classified as major and life-threatening.

The most common major and moderate ADRs included respiratory depression and cardiac arrhythmias, while minor ADRs often involved hematologic and metabolic issues, highlighting the need for careful monitoring of drug use in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidemiology of adverse drug reactions in the newborn. Aranda, JV., Portuguez-Malavasi, A., Collinge, JM., et al.[2006]

In a quality improvement project at the Children's Mercy NICU, a bedside monitoring tool was implemented to assess adverse drug reactions (ADRs) in patients receiving specific medications, leading to the identification of 28 potential ADRs, significantly more than previously reported.

The study found that the neonatal-specific Du score was more effective than the Naranjo score in characterizing ADRs, highlighting the need for improved detection and reporting of ADRs in the NICU population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving Recognition and Reporting of Adverse Drug Reactions in the NICU: A Quality Improvement Project. Cammack, B., Oschman, A., Lewis, T.[2022]

In a pilot study involving 24 preterm infants, the combination of intravenous ibuprofen and paracetamol showed a trend towards a higher closure rate of hemodynamically significant patent ductus arteriosus (hsPDA) compared to ibuprofen and placebo (83% vs. 42%).

No adverse effects were reported from adding paracetamol to ibuprofen, suggesting that it may be a safe option, but further larger studies are needed to confirm its efficacy in promoting hsPDA closure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding Paracetamol to Ibuprofen for the Treatment of Patent Ductus Arteriosus in Preterm Infants: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Hochwald, O., Mainzer, G., Borenstein-Levin, L., et al.[2019]

In a study of 255 preterm infants with significant patent ductus arteriosus (PDA), high-dose ibuprofen was found to be more effective than oral paracetamol for closing the ductus, achieving closure in 71.7% of cases compared to only 37.9% with paracetamol.

The study indicated that paracetamol is a less effective option for managing PDA in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants, with particularly low closure rates in ELBW infants (13%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral ibuprofen is superior to oral paracetamol for patent ductus arteriosus in very low and extremely low birth weight infants. Lu, J., Li, Q., Zhu, L., et al.[2022]

References

1. Australia pubmed.ncbi.nlm.nih.gov

The influence on renal function of ibuprofen treatment for patent ductus arteriosus in extremely low birthweight infants. [2020]

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

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns. [2019]

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

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. [2022]

5. Australia pubmed.ncbi.nlm.nih.gov

Is ibuprofen superior to indomethacin for patent ductus arteriosus in Japanese preterm infants? [2021]

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

[Pharmacovigilance update]. [2016]

7. Switzerland pubmed.ncbi.nlm.nih.gov

[Pharmacovigilance and teratovigilance]. [2013]

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

An algorithm to detect adverse drug reactions in the neonatal intensive care unit. [2021]

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

Epidemiology of adverse drug reactions in the newborn. [2006]

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

Improving Recognition and Reporting of Adverse Drug Reactions in the NICU: A Quality Improvement Project. [2022]

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

Adding Paracetamol to Ibuprofen for the Treatment of Patent Ductus Arteriosus in Preterm Infants: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. [2019]

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

Oral ibuprofen is superior to oral paracetamol for patent ductus arteriosus in very low and extremely low birth weight infants. [2022]