Clinical trial NCT05340582: Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants
Official title: Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants - The ACEDUCT Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Patent Ductus Arteriosus After Premature Birth
Keywords: Preterm Neonates
Patent Ductus Arteriosus
Echocardiography
Acetaminophen
Ibuprofen
Lead sponsor: Mount Sinai Hospital, Canada
Sponsor class: OTHER
Collaborators: name: Sunnybrook Health Sciences Centre
name: McMaster Children's Hospital
name: The Rotunda Hospital
name: John Hunter Hospital
name: Royal Alexandra Hospital
name: Centre Hospitalier de l'Universite Laval (CHUL)
name: Royal North Shore Hospital
name: Prince of Wales Hospital, Shatin, Hong Kong
First posted: 2022-04-22
Enrollment: 310
Sex: ALL
Maximum age (years): 27
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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
Primary purpose: TREATMENT

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).


Eligibility criteria: 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).

Primary outcomes:
measure: Composite of pre-discharge mortality or any grade BPD
timeFrame: 36 weeks PMA
Secondary outcomes:
measure: PDA treatment success
timeFrame: 6-10 days post treatment initiation
measure: Renal or hepatic dysfunction
timeFrame: Occurring within 7 days of treatment initiation
measure: Further exposure to pharmacological PDA treatments
timeFrame: 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
measure: Procedure for PDA closure
timeFrame: 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
measure: Mortality
timeFrame: From date of randomization until date of death (assessed up to a maximum of 250 days after randomization)
measure: Severity of BPD at 36 weeks PDM using Jensen's criteria
timeFrame: At 36 weeks PDM
measure: NEC ≥ stage 2A
timeFrame: 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
measure: Duration (days) of invasive or non-invasive respiratory support
timeFrame: 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
measure: Need for diuretic use
timeFrame: 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
measure: Need for systemic steroids
timeFrame: 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
measure: Sepsis
timeFrame: 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
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Ontario
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Quebec
country: Canada
facility: Centre Hospitalier de l'Université Laval
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
state: NT
city: Dublin
country: Ireland
facility: The Rotunda Hospital
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Amish Jain, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: