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

NCT05340582 | Recruiting Phase 2 DMC

• 1 other identifier: CTO 1875
• Study Type: interventional
• Target: 310
• Locations: 4 countries
• Sites: 9

Brief Summary

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).

Conditions

Patent Ductus Arteriosus After Premature Birth

Keywords

Preterm Neonates; Patent Ductus Arteriosus; Echocardiography; Acetaminophen; Ibuprofen

Outcome Measures

Primary Outcomes (1)

• Composite of pre-discharge mortality or any grade BPD

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

  36 weeks PMA

Secondary Outcomes (11)

• PDA treatment success

  6-10 days post treatment initiation

• Renal or hepatic dysfunction

  Occurring within 7 days of treatment initiation

• Further exposure to pharmacological PDA treatments

  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

• Procedure for PDA closure

  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

• Mortality

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

Study Arms (2)

Combination Therapy

EXPERIMENTAL

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).

Drug: Acetaminophen Injection; Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)

Standard Clinical Practice - Monotherapy

PLACEBO COMPARATOR

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).

Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen); Other: Sodium chloride 0.9% injection

Interventions

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

Combination Therapy

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)

Combination Therapy; Standard Clinical Practice - Monotherapy

Sodium chloride 0.9% injection OTHER

Placebo- IV q6h for 3 days

Standard Clinical Practice - Monotherapy

Eligibility Criteria

• Age: Up to 27 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Centre Hospitalier de l'Universite Laval (CHUL): collaborator
• Royal North Shore Hospital: collaborator
• Prince of Wales Hospital, Shatin, Hong Kong: collaborator
• Mount Sinai Hospital, Canada: lead
• Sunnybrook Health Sciences Centre: collaborator
• McMaster Children's Hospital: collaborator
• The Rotunda Hospital: collaborator
• John Hunter Hospital: collaborator
• Royal Alexandra Hospital: collaborator

Study Sites (9)

John Hunter Hospital

Newcastle, New South Wales, 2300, Australia

ACTIVE NOT RECRUITING

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

RECRUITING

Royal Alexandra Hospital

Edmonton, Ontario, T5H 3V9, Canada

RECRUITING

McMaster Children's Hospital

Hamilton, Ontario, L8N 3Z5, Canada

RECRUITING

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

RECRUITING

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

RECRUITING

Centre Hospitalier de l'Université Laval

Québec, Quebec, G1V 4G2, Canada

NOT YET RECRUITING

Prince of Wales Hospital

Shatin, NT, Hong Kong

NOT YET RECRUITING

The Rotunda Hospital

Dublin, Ireland

ACTIVE NOT RECRUITING

MeSH Terms

Conditions

Ductus Arteriosus, Patent

Interventions

Acetaminophen; Ibuprofen; Suspensions; Sodium Chloride

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Amish Jain, MD PhD

  MOUNT SINAI HOSPITAL

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Laura Thomas, MSc

CONTACT

416-586-4800; laura.thomas@sinaihealth.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Pragmatic, multicenter, double-blinded, placebo controlled, parallel, two-armed, superiority randomized trial comparing two treatment regimens for the first treatment course of PDA in ELGANs

Study Record Dates

• First Submitted: March 16, 2022
• First Posted: April 22, 2022
• Study Start: December 12, 2022
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): April 1, 2027
• Last Updated: December 4, 2025

Record last verified: 2025-11

Locations

IE (1); CA (5); HK (1); AU (2)