Evaluation of Ibuprofen and Paracetamol Co-administration for Patent Ductus Arteriosus Management in Extremely Low Gestational Age Neonates

The primary objective of the ACEDUCT Trial is to evaluate the clinical impact, efficacy, and safety of a combination regimen of **Ibuprofen** and intravenous **Acetaminophen** for the initial treatment course of patent ductus arteriosus (PDA) in extremely low gestational age neonates (ELGANs), compared to the current standard treatment of Ibuprofen alone. The primary goal is to reduce the incidence of bronchopulmonary dysplasia or death in ELGANs receiving pharmacotherapy for PDA by decreasing treatment failure with the use of the combination regimen. This is clinically relevant as it addresses significant morbidity and mortality associated with PDA in this vulnerable population.

Secondary objectives include examining the safety and impact of the combination regimen on other neonatal morbidities. This evaluation is crucial for understanding the broader implications of the treatment on neonatal health outcomes beyond the primary endpoints.

The clinical trial involves a total of **235 participants** diagnosed with **patent ductus arteriosus (PDA)**. The study population comprises preterm infants born at less than 27 weeks of gestational age, admitted to one of the designated neonatal intensive care units (NICUs). Both male and female subjects are included, and the trial specifically targets a vulnerable population of extremely low gestational age neonates (ELGANs). Participants were selected based on a confirmed diagnosis of PDA with a shunt size of at least 1.5 mm, as determined by echocardiography, and the decision to receive the first treatment course with either intravenous or enteral ibuprofen. The trial does not specify any particular lifestyle considerations such as diet or physical activity, given the age and health status of the participants. The selection process required permission from the attending clinician and consent from the parents. The study aims to assess the efficacy and safety of a combination treatment regimen of ibuprofen and intravenous acetaminophen compared to ibuprofen alone, with the primary objective of reducing the incidence of bronchopulmonary dysplasia or death in this vulnerable population.

The clinical trial is designed to evaluate the efficacy and safety of a combination treatment regimen involving **ibuprofen** and intravenous **paracetamol** for the management of **patent ductus arteriosus** (PDA) in extremely low gestational age neonates (ELGANs). This is a Phase 4, randomized, double-blind, controlled trial comparing the combination therapy to the standard treatment of ibuprofen alone. The trial is expected to run from July 2023 to March 2026, with participant involvement lasting up to three days, corresponding to the maximum treatment period.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as gestational age under 27 weeks, diagnosis of PDA with a diameter of at least 1.5 mm, and consent from parents. The inclusion visit will also involve baseline assessments and randomization. Follow-up visits will occur during the treatment period to monitor the primary outcome, which is a composite of pre-discharge mortality or any grade of bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. Secondary outcomes include PDA treatment success, renal or hepatic dysfunction, and other clinical parameters. The end-of-study visit will assess the final outcomes and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse effects, if the attending clinician deems it necessary, or if they withdraw consent. The trial aims to provide robust data on the potential benefits of the combination therapy in reducing the incidence of BPD or death in this vulnerable population, thereby informing future clinical practice for the treatment of PDA in ELGANs.

The clinical trial involves the administration of **Pedea 5 mg/ml solution for injection**, which contains the active substance **ibuprofen**. This medication is provided in a **solution for injection** form and is administered **intravenously**. The dosage is calculated based on the participant's weight, with a maximum daily dose of **20 mg/kg** and a total maximum dose of **40 mg/kg** over a treatment period of up to **3 days**. Ibuprofen is classified as a non-steroidal anti-inflammatory drug (NSAID) and is utilized in this study to evaluate its efficacy in combination with other treatments for patent ductus arteriosus (PDA) in extremely low gestational age neonates (ELGANs).

In addition to the experimental treatment, **Sodium Chloride 0.9% w/v Intravenous Infusion BP Solution for Infusion** is used as a comparator treatment. This solution, containing **sodium chloride**, is also administered **intravenously**. The pharmaceutical form is a **solution for infusion**, with a concentration of **0.9% w/v**. The maximum daily and total dose is **0.9% w/v**, administered over a period of up to **3 days**. Sodium chloride serves as an electrolyte solution, providing a standard-of-care therapy for maintaining fluid balance in the participants.

The trial also includes the administration of **Paracetamol 10mg/ml solution for infusion**, which contains the active substance **paracetamol**. This medication is provided in a **solution for infusion** form and is administered **intravenously**. The dosage is determined based on the participant's weight, with a maximum daily dose of **60 mg/kg** and a total maximum dose of **180 mg/kg** over a treatment period of up to **3 days**. Paracetamol is classified as an analgesic and is used in combination with ibuprofen to assess its impact on reducing treatment failure and improving duct-related outcomes in the study population.

The efficacy of the clinical trial titled "Co-administration of Acetaminophen with Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants – The ACEDUCT Trial" will be assessed using both primary and secondary endpoints. The primary endpoint is a composite outcome of pre-discharge mortality or any grade of **bronchopulmonary dysplasia (BPD)**, defined as the need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age. This will be measured to evaluate the reduction in the incidence of BPD or death in extremely low gestational age newborns (ELGANs) receiving pharmacotherapy for patent ductus arteriosus (PDA).

Secondary endpoints include several parameters: PDA treatment success, defined as PDA closure or becoming insignificant with a diameter of less than 1.5 mm; renal or hepatic dysfunction occurring within 7 days of treatment initiation; further exposure to PDA treatments; procedures for PDA closure; mortality; severity of BPD at 36 weeks postmenstrual age using Jensen’s criteria; necrotizing enterocolitis (NEC) stage 2A or higher; duration of invasive or non-invasive respiratory support; diuretic use during NICU stay; exposure to postnatal steroids; and sepsis during NICU stay. These endpoints will be assessed to provide a comprehensive evaluation of the treatment's efficacy and safety.