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

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.

Conditions

• Patent Ductus Arteriosus After Premature Birth

Interventions

DRUG

Acetaminophen Injection

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

DRUG

Ibuprofen 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)

OTHER

Sodium chloride 0.9% injection

Placebo- IV q6h for 3 days

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre

  collaborator OTHER

• McMaster Children's Hospital

  collaborator OTHER

• The Rotunda Hospital

  collaborator OTHER

• John Hunter Hospital

  collaborator OTHER_GOV

• Royal Alexandra Hospital

  collaborator OTHER

• Centre Hospitalier de l'Universite Laval (CHUL)

  collaborator UNKNOWN

• Royal North Shore Hospital

  collaborator OTHER

• Prince of Wales Hospital, Shatin, Hong Kong

  collaborator OTHER

• Mount Sinai Hospital, Canada

  lead OTHER

Principal Investigators

• Amish Jain, MD PhD · MOUNT SINAI HOSPITAL

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Max Age

27 Weeks

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-12-12

Primary Completion

2027-01-31

Completion

2027-04-30

Countries

• Australia
• Canada
• Hong Kong
• Ireland

Study Locations