Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
AgeUp to 27
SponsorMount Sinai Hospital, Canada
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Acetaminophen Injection
DrugAcetaminophen 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)
DrugIbuprofen 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)
Sodium chloride 0.9% injection
Other interventionPlacebo- IV q6h for 3 days
Treatment groups
310 Participants
are divided into 2 treatment groupsGroup A: Combination TherapyExperimental treatment 2 interventions
Group B: Standard Clinical Practice - MonotherapyPlacebo comparator 2 interventions
Trial outcomes
Primary outcomes
1
Composite 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 PMASecondary outcomes
1
PDA treatment success
Defined as PDA closure or becoming insignificant \[diameter \<1.5 mm\]
Time frame
6-10 days post treatment initiation2
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 initiation3
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 randomization4
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 randomizationSponsors and contacts
Click on the lead sponsor to view all of their trials.
Mount Sinai Hospital, Canada
Lead sponsor
Sunnybrook Health Sciences Centre
Collaborator
McMaster Children's Hospital
Collaborator
The Rotunda Hospital
Collaborator
John Hunter Hospital
Collaborator
Royal Alexandra Hospital
Collaborator
Centre de Recheche du Centre Hospitalier Université Laval
Collaborator
Royal North Shore Hospital
Collaborator
Prince of Wales Hospital, Shatin, Hong Kong
Collaborator
Source ClinicalTrials.gov