Patent Ductus Arteriosus After Premature Birth
Conditions
Keywords
Preterm Neonates, Patent Ductus Arteriosus, Echocardiography, Acetaminophen, Ibuprofen
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). The study will also evaluate the effects of combination regime vs. ibuprofen alone on neurodevelopmental outcomes at 18-30 months corrected age.
Interventions
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
DRUGIbuprofen 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)
Placebo- IV q6h for 3 days
Sponsors
Mount Sinai Hospital, Canada
Sunnybrook Health Sciences Centre
McMaster Children's Hospital
The Rotunda Hospital
John Hunter Hospital
Royal Alexandra Hospital
Centre de Recheche du Centre Hospitalier Université Laval
Royal North Shore Hospital
Prince of Wales Hospital, Shatin, Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Double-blinded
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
Eligibility
Sex/Gender
ALL
Age
No minimum to 27 Weeks
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| PDA treatment success | 6-10 days post treatment initiation | Defined as PDA closure or becoming insignificant \[diameter \<1.5 mm\] |
| 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 |
| 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) |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
Australia, Canada, Hong Kong, Ireland
Contacts
CONTACTLaura Thomas, MSc
PRINCIPAL_INVESTIGATORAmish Jain, MD PhD
MOUNT SINAI HOSPITAL
Outcome results
None listed