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NCT Number: NCT05340582

Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants

Patent ductus arteriosus (PDA), the most common cardiovascular complication of prematurity, is associated with higher mortality and morbidities in extremely low gestational age neonates (ELGANs, < 27+0 weeks). Ibuprofen and acetaminophen, which act by reducing prostaglandin synthesis, are the most commonly used first and second line agents for PDA treatment across Canada. However, initial treatment failure with monotherapy is a major problem, occurring in >60% ELGANs. Treatment failure is associated with worsening rates of mortality and bronchopulmonary dysplasia (BPD), while early treatment success can achieve rates comparable to neonates without PDA. Treatment failure resulting in prolonged disease exposure is thought to be a major contributor. Recently, combination therapy with acetaminophen and ibuprofen has emerged as a new treatment regime. Acetaminophen exerts anti-prostaglandin effect through a different receptor site than ibuprofen, providing a biological rationale for their synergistic action.

The objective of this study is to evaluate the clinical impact, efficacy and safety of combination regime (Ibuprofen + IV Acetaminophen) for the first treatment course for PDA in ELGANs vs. Ibuprofen alone (current standard treatment).

The study will also evaluate the effects of combination regime vs. ibuprofen alone on neurodevelopmental outcomes at 18-30 months corrected age.

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Key information

Conditions

Patent Ductus Arteriosus After Premature Birth Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Ductus Arteriosus, Patent Heart Defects, Congenital Heart Diseases

Age range

Up to 27 week

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

John Hunter Hospital, Newcastle, New South Wales, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Preterm infants born <27+0 weeks gestational age
  • Permission given by the attending clinician to approach and then consent obtained from parents
  • Diagnosis of PDA ≥ 1.5 mm on echocardiography with unrestrictive predominantly left to right shunt
  • Designated to receive first treatment course with intravenous or enteral ibuprofen, as decided by the attending team.

Exclusion criteria

  • Chromosomal anomaly
  • Pre-treatment renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L
  • Pre-treatment hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L94
  • Platelet count <50,000 per microliter
  • Permission denied by the attending clinician to approach parents
  • Parental consent not available
  • Previous exposure to PDA medical treatment with any drug (prophylactic indomethacin use for prevention of intraventricular hemorrhage will not be considered as PDA treatment).

Treatment and study plan

Acetaminophen Injection

Drug

Acetaminophen injection solution 1000 mg/100 mL (10 mg/mL) latex-free plastic bag - dosage for this protocol is 15mg/kg/dose IV four times a day for 3 days

Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)

Drug

Ibuprofen is not a study drug - standard of care in participating NICUs in the standard clinical dose for neonates (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)

Sodium chloride 0.9% injection

Other

Placebo- IV q6h for 3 days

Primary outcomes

  1. Composite of pre-discharge mortality or any grade BPD

    Time frame: 36 weeks PMA

    Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)

Secondary outcomes

  1. PDA treatment success

    Time frame: 6-10 days post treatment initiation

    Defined as PDA closure or becoming insignificant [diameter <1.5 mm]

  2. Renal or hepatic dysfunction

    Time frame: Occurring within 7 days of treatment initiation

    Renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L; hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L

  3. Further exposure to pharmacological PDA treatments

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    As per units' standard practice (not part of study procedures)

  4. Procedure for PDA closure

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    Surgical closure for PDA

  5. Mortality

    Time frame: From date of randomization until date of death (assessed up to a maximum of 250 days after randomization)

    Death during initial tertiary NICU stay

  6. Severity of BPD at 36 weeks PDM using Jensen's criteria

    Time frame: At 36 weeks PDM

    Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation

  7. NEC ≥ stage 2A

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    NEC ≥ stage 2A during NICU stay

  8. Duration (days) of invasive or non-invasive respiratory support

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    Days of invasive or non invasive support during NICU say

  9. Need for diuretic use

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    Diuretic use for BPD treatment

  10. Need for systemic steroids

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    Use for BPD treatment

  11. Sepsis

    Time frame: From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

    Diagnosis of sepsis during NICU stay

Study contacts

Contact information is provided by the study sponsor or research team.

Laura Thomas, MSc

CONTACT

[email protected]

416-586-4800 ext. 172060

Sponsors and collaborators

Lead sponsor

Mount Sinai Hospital, Canada

Other

Collaborators

  • Centre de Recheche du Centre Hospitalier Université Laval
  • John Hunter Hospital
  • McMaster Children's Hospital
  • Prince of Wales Hospital, Shatin, Hong Kong
  • Royal Alexandra Hospital
  • Royal North Shore Hospital
  • Sunnybrook Health Sciences Centre
  • The Rotunda Hospital

Registry information

Official study title

Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants - The ACEDUCT Trial

Important dates

Study start
2022
Primary completion
2027
Study completion
2027
First posted
Apr 22, 2022
Registry last updated
Apr 6, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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