Paracetamol vs. Ibuprofen in Preterm Infants With Hemodynamically Significant Patent Ductus Arteriosus: A Non-inferiority Randomized Clinical Trial Protocol

Abstract

Background: Currently, the first line treatment of persistent ductus arteriosus (PDA) is either indomethacin or ibuprofen. However, the potentially life-threatening side effects associated to their use have prompted physicians to look for alternative options. The incorporation of paracetamol as an alternative to ibuprofen in the management of PDA is still based on insufficient clinical evidence. Hence, more clinical trials are needed to establish a therapeutic role for paracetamol in the management of PDA that take into consideration short- and long-term safety and efficacy outcomes. Study Design: This is a non-inferiority, randomized, multicenter, double-blinded study to evaluate the efficacy, and safety of intravenous (IV) paracetamol vs. IV ibuprofen (standard treatment) for PDA in preterm patients with a gestational age ≤ 30 weeks. At baseline, patients will be randomized (1:1) to treatment with paracetamol or ibuprofen. The primary endpoint is closure of the ductus after the first treatment course. Secondary endpoints are related to effectiveness (need for a second treatment course, rescue treatment, reopening rate, time to definitive closure, need for surgical ligation), safety (early and long-term complications), pharmacokinetics, and pharmacodynamics, pharmacogenetics, pharmacoeconomics, and genotoxicity. Long-term follow-up to 24 months of corrected postnatal age will be performed using Bayley III neurodevelopmental scale. Trial Registration: ClinicalTrials.gov Identifier: NCT04037514. EudraCT: 2015-003177-14.

Keywords: ductus; efficacy; paracetamol; pharmacogenetics; pharmacokinetics; safety.

Figure 1

Diagram of study. (A) Birth; (B) diagnostic and randomization; The PARACETAMOL group will receive IV doses of 15 mg/kg administered every 6 h for 3 days (maximum two courses = 6 days of treatment). The IBUPROFEN group (control group) will receive an initial dose of IV 10 mg/kg followed by 5 mg/kg at 24 and 48 h (the three doses are considered a treatment course, maximum two courses). (C) Surgical close. (D) FOLLOW-UP: 40 weeks, 12 months, and 24 months.