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

Overview

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.

Interventions

• 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)
• Other Sodium chloride 0.9% injection
  Placebo- IV q6h for 3 days

Primary outcome measures

• Composite of pre-discharge mortality or any grade BPD [Time frame: 36 weeks PMA]

Secondary outcome measures (11)

• PDA treatment success [Time frame: 6-10 days post treatment initiation]
• Renal or hepatic dysfunction [Time frame: Occurring within 7 days of treatment initiation]
• 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]
• 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]
• Mortality [Time frame: 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 [Time frame: At 36 weeks PDM]
• 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]
• 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]
• 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]
• 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]
• 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]

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Canada · 5 centers

• Royal Alexandra Hospital — Edmonton
• McMaster Children's Hospital — Hamilton
• Sunnybrook Health Sciences Centre — Toronto
• Mount Sinai Hospital — Toronto
• Centre Hospitalier de l'Université Laval — Québec

Australia · 2 centers

• John Hunter Hospital — Newcastle
• Royal North Shore Hospital — St Leonards

Hong Kong · 1 center

• Prince of Wales Hospital — Shatin

Ireland · 1 center

• The Rotunda Hospital — Dublin

Identifiers

NCT: NCT05340582 · CTO 1875

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗