Acetaminophen + Ibuprofen for Patent Ductus Arteriosus

Recruiting at 9 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for patent ductus arteriosus (PDA), a heart issue in very premature babies, using a combination of acetaminophen (also known as paracetamol or Tylenol) and ibuprofen. The researchers aim to determine if this combination is more effective than ibuprofen alone, which often fails to succeed. Babies born before 27 weeks and diagnosed with PDA may qualify for this study. Participation offers a chance to contribute to finding a more effective treatment for this condition. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using either acetaminophen or ibuprofen to treat patent ductus arteriosus (PDA) in premature babies is generally safe. Studies have found both medications similarly effective in closing the PDA. No noticeable increase in serious side effects, such as death or bronchopulmonary dysplasia, has been observed with acetaminophen compared to ibuprofen.

However, ibuprofen can sometimes cause kidney problems, raising concerns. Acetaminophen might be a safer choice due to its typically fewer side effects. Researchers are testing a combination of acetaminophen and ibuprofen to determine if they work better together without increasing risks.

This trial is in a middle stage, indicating some evidence of safety, but more research is needed for confirmation. For those considering participation, the safety outlook is promising, but discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of acetaminophen and ibuprofen for treating patent ductus arteriosus (PDA) because it offers a potentially more effective approach than the standard monotherapy with ibuprofen alone. This combination therapy leverages acetaminophen's unique mechanism of action, which may enhance the closure of the ductus arteriosus in neonates, potentially improving outcomes where ibuprofen alone might not suffice. Moreover, this dual approach could expedite the treatment process, offering faster relief for infants with PDA.

What evidence suggests that this trial's treatments could be effective for patent ductus arteriosus?

This trial will compare the effectiveness of a combination therapy of acetaminophen and ibuprofen with standard clinical practice using ibuprofen alone for treating patent ductus arteriosus (PDA) in premature babies. Research has shown that acetaminophen, also known as paracetamol, may be more effective than ibuprofen in closing PDA. Some studies have found no major difference between using either medicine alone, but using both together might help avoid surgery. The combination reduces certain chemicals that keep the ductus open, making it a promising treatment for PDA in very premature babies. Early results suggest that using both medicines could lead to better outcomes by reducing the need for more invasive procedures. ^{1 2 3 4 6}

Who Is on the Research Team?

Amish Jain, MD PhD

Principal Investigator

MOUNT SINAI HOSPITAL

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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 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]

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]

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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11762024/

Comparison of the Effectiveness of Paracetamol and ... This study conclude that paracetamol is more effective than ibuprofen in closing patent ductus arteriosus (PDA) in preterm neonates.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5045561/

Comparison of Oral Acetaminophen Versus Ibuprofen in ... This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates.

3. publications.aap.org publications.aap.org/pediatrics/article/154/2/e2023065056/197778/Acetaminophen-for-Patent-Ductus-Arteriosus-and

Acetaminophen for Patent Ductus Arteriosus and Risk of ... Treatment with acetaminophen versus COX inhibitor alone for PDA was not associated with the composite outcome of death or BPD in extremely ...

4. accp1.onlinelibrary.wiley.com accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.2386

Pharmacokinetic and Pharmacodynamic Analysis of ... Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1355184125000626

Paracetamol versus ibuprofen as first-line treatment for ... The study findings indicated comparable primary closure rates between paracetamol and ibuprofen treatments (RR, 1.01; 95 % CI, 0.94–1.08; P = 0.78), although ...

6. nature.com nature.com/articles/s41372-024-02199-5

Response of the ductus arteriosus to acetaminophen or ... Acetaminophen and indomethacin are used for medical management of a patent ductus arteriosus. This study compared the efficacy of these agents in ELBW infants.