Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants

Mount Sinai Hospital, Canada

Status and phase: Enrolling; Phase 2

Conditions: Patent Ductus Arteriosus After Premature Birth

Treatments: Other: Sodium chloride 0.9% injection; Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen); Drug: Acetaminophen Injection

Study type: Interventional

Funder types: Other

Identifiers

NCT05340582

CTO 1875

Details and patient eligibility

About

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).

Enrollment: 310 estimated patients

Sex: All

Ages: Under 27 weeks old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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310 participants in 2 patient groups, including a placebo group

Combination Therapy

Experimental group

Description:

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).

Treatment:

Drug: Acetaminophen Injection

Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)

Standard Clinical Practice - Monotherapy

Placebo Comparator group

Description:

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).

Treatment:

Drug: Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)

Other: Sodium chloride 0.9% injection