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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Patent Ductus Arteriosus After Premature Birth
• Intervention / Treatment: Drug: Acetaminophen Injection; Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen); Other: Sodium chloride 0.9% injection

• Study Type: Interventional
• Enrollment (Estimated): 310
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Thomas, MSc; Phone Number: 172060 416-586-4800; Email: laura.thomas@sinaihealth.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Recruiting
      • McMaster Children's Hospital
      • Principal Investigator: Amneet Sidhu, MD
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • SunnyBrook Health Sciences Centre
      • Principal Investigator: Dany Weisz, MD, MSc
      • Contact: Dany Weisz, MD, MSc
    • Toronto, Ontario, Canada, M5G 1X5
      • Recruiting
      • Mount Sinai Hospital
      • Principal Investigator: Amish Jain, MD PhD
• Ireland
  • Dublin, Ireland
    • Not yet recruiting
    • The Rotunda Hospital
    • Principal Investigator: Afif EL Khuffash, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combination Therapy; 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; 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; Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen); 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)
Placebo Comparator: Standard Clinical Practice - Monotherapy; 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); 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); Other: Sodium chloride 0.9% injection; Placebo- IV q6h for 3 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
PDA treatment success	Defined as PDA closure or becoming insignificant [diameter <1.5 mm]	6-10 days post treatment initiation
Renal or hepatic dysfunction	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	Occurring within 7 days of treatment initiation
Further exposure to pharmacological PDA treatments	As per units' standard practice (not part of study procedures)	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	Surgical closure for PDA	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	Death during initial tertiary NICU stay	From date of randomization until date of death (assessed up to a maximum of 250 days after randomization)
Severity of BPD at 36 weeks PDM using Jensen's criteria	Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation	At 36 weeks PDM
NEC ≥ stage 2A	NEC ≥ stage 2A during NICU stay	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
Duration (days) of invasive or non-invasive respiratory support	Days of invasive or non invasive support during NICU say	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
Need for diuretic use	Diuretic use for BPD treatment	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
Need for systemic steroids	Use for BPD treatment	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
Sepsis	Diagnosis of sepsis during NICU stay	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

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: Sunnybrook Health Sciences Centre; McMaster Children's Hospital; The Rotunda Hospital
• Investigators: Principal Investigator: Amish Jain, MD PhD, Mount Sinai Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2022
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 16, 2022
• First Submitted That Met QC Criteria: April 20, 2022
• First Posted (Actual): April 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Echocardiography; Ibuprofen; Acetaminophen; Preterm Neonates; Patent Ductus Arteriosus
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Heart Defects, Congenital; Cardiovascular Abnormalities; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Ductus Arteriosus, Patent; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Acetaminophen; Ibuprofen
• Other Study ID Numbers: CTO 1875

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No