Co-administration of Acetaminophen with Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants
- Conditions
- Patent Ductus Arteriosus After Premature Birth
- Interventions
- Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)Other: Sodium chloride 0.9% injection
- Registration Number
- NCT05340582
- Lead Sponsor
- Mount Sinai Hospital, Canada
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 310
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Combination Therapy Acetaminophen Injection 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). Combination Therapy Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen) 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). Standard Clinical Practice - Monotherapy Sodium chloride 0.9% injection 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). Standard Clinical Practice - Monotherapy Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen) 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).
- Primary Outcome Measures
Name Time Method Composite of pre-discharge mortality or any grade BPD 36 weeks PMA Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)
- Secondary Outcome Measures
Name Time Method Need for systemic steroids 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 Use for BPD treatment
Duration (days) of invasive or non-invasive respiratory support 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 Days of invasive or non invasive support during NICU say
PDA treatment success 6-10 days post treatment initiation Defined as PDA closure or becoming insignificant \[diameter \<1.5 mm\]
Severity of BPD at 36 weeks PDM using Jensen's criteria At 36 weeks PDM Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula \>2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation
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 Surgical closure for PDA
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 As per units' standard practice (not part of study procedures)
NEC ≥ stage 2A 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 NEC ≥ stage 2A during NICU stay
Sepsis 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 Diagnosis of sepsis during NICU stay
Renal or hepatic dysfunction Occurring within 7 days of treatment initiation 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
Mortality From date of randomization until date of death (assessed up to a maximum of 250 days after randomization) Death during initial tertiary NICU stay
Need for diuretic use 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 Diuretic use for BPD treatment
Trial Locations
- Locations (9)
John Hunter Hospital
🇦🇺Newcastle, New South Wales, Australia
Royal North Shore Hospital
🇦🇺St Leonards, New South Wales, Australia
Royal Alexandra Hospital
🇨🇦Edmonton, Ontario, Canada
McMaster Children's Hospital
🇨🇦Hamilton, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Mount Sinai Hospital
🇨🇦Toronto, Ontario, Canada
Centre Hospitalier de l'Université Laval
🇨🇦Quebec, Canada
Prince of Wales Hospital
🇭🇰Shatin, NT, Hong Kong
The Rotunda Hospital
🇮🇪Dublin, Ireland