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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
310
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 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- IV q6h for 3 days
John Hunter Hospital
Newcastle, New South Wales, Australia
ACTIVE_NOT_RECRUITINGRoyal North Shore Hospital
St Leonards, New South Wales, Australia
RECRUITINGRoyal Alexandra Hospital
Edmonton, Ontario, Canada
RECRUITINGMcMaster Children's Hospital
Hamilton, Ontario, Canada
RECRUITINGSunnybrook Health Sciences Centre
Toronto, Ontario, Canada
RECRUITINGMount Sinai Hospital
Toronto, Ontario, Canada
RECRUITINGCentre Hospitalier de l'Université Laval
Québec, Quebec, Canada
NOT_YET_RECRUITINGPrince of Wales Hospital
Shatin, NT, Hong Kong
NOT_YET_RECRUITINGThe Rotunda Hospital
Dublin, Ireland
ACTIVE_NOT_RECRUITINGComposite of pre-discharge mortality or any grade BPD
Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)
Time frame: 36 weeks PMA
PDA treatment success
Defined as PDA closure or becoming insignificant \[diameter \<1.5 mm\]
Time frame: 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
Time frame: Occurring within 7 days of treatment initiation
Further exposure to pharmacological PDA treatments
As per units' standard practice (not part of study procedures)
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
Surgical closure for PDA
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
Death during initial tertiary NICU stay
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
Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula \>2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation
Time frame: At 36 weeks PDM
NEC ≥ stage 2A
NEC ≥ stage 2A during NICU stay
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
Days of invasive or non invasive support during NICU say
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
Diuretic use for BPD treatment
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
Use for BPD treatment
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
Diagnosis of sepsis during NICU stay
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
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.