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

Patent Ductus Arteriosus After Premature Birth Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05340582
• Other study ID #: CTO 1875
• Status: Recruiting
• Phase: Phase 2
• Start date: December 12, 2022
• Est. completion date: December 2026

Study information

• Verified date: March 2024
• Source: Mount Sinai Hospital, Canada
• Contact: Laura Thomas, MSc
• Phone: 416-586-4800
• Email: laura.thomas[@]sinaihealth.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 310
• Est. completion date: December 2026
• Est. primary completion date: May 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 27 Weeks

Eligibility

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).

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Patent Ductus Arteriosus After Premature Birth
• Premature Birth

Intervention

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
• 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

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Ireland	The Rotunda Hospital	Dublin

Sponsors (4)

Lead Sponsor	Collaborator
Mount Sinai Hospital, Canada	McMaster Children's Hospital, Sunnybrook Health Sciences Centre, The Rotunda Hospital

Countries where clinical trial is conducted

Canada,  Ireland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	PDA treatment success	Defined as PDA closure or becoming insignificant [diameter <1.5 mm]	6-10 days post treatment initiation
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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