Evaluation of Perinatal Outcomes with Active Management Using Oxytocin, Dinoprostone, and Mifepristone in Pregnant Patients with Pre-labor Rupture of Membranes

The primary objective of this study is to evaluate whether **active management** of women with **premature rupture of membranes (PROM)**, specifically through early induction, reduces the newborn's need for respiratory support. This is clinically relevant as reducing the need for respiratory support can lead to improved neonatal outcomes and decrease the risk of complications associated with respiratory interventions.

The secondary objectives focus on the safety of active management by assessing the rate of stillbirths, the onset of infections in both the mother and fetus, and the length of hospitalization for the mother-infant dyads. Additionally, the study aims to reduce the use of antibiotic treatments in both mothers and newborns. These objectives are significant as they address potential risks and complications associated with PROM and aim to optimize maternal and neonatal health outcomes while minimizing unnecessary medical interventions.

The clinical trial involves **pregnant patients diagnosed with premature rupture of membranes (PROM)**. The study population is exclusively female, with participants aged 18 years and older. The trial does not include a vulnerable population. Participants were selected based on specific criteria, including a gestational age of 37 weeks or more, a negative rectovaginal GBS swab, and absent or poor uterine contractile activity six hours after PROM. Additionally, participants must have a cephalic presentation and the ability to provide informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized controlled** study to evaluate the effects of active management versus expectant management in pregnant patients diagnosed with **premature rupture of membranes (PROM)**. The trial is open-label and multicentric, involving multiple study sites. The primary objective is to assess whether early induction reduces the newborn's need for respiratory support. The trial is expected to commence recruitment on March 27, 2024, and conclude by March 27, 2026, with an estimated duration of two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as gestational age of at least 37 weeks, negative rectovaginal GBS swab, and the ability to provide informed consent. Following randomization, participants will be assigned to either the active management group, receiving **oxytocin** or **dinoprostone** for induction, or the expectant management group. The trial will include follow-up visits to monitor maternal and neonatal outcomes, with primary endpoints focusing on the need for neonatal ventilatory support, and secondary endpoints evaluating maternal and neonatal infections, among other parameters.

The expected length of participant involvement is approximately one day, corresponding to the maximum treatment period for the medicinal products used in the trial. Conditions that may lead to early termination from the study include the development of exclusion criteria or withdrawal of consent by the participant. The end-of-study visit will involve a comprehensive assessment of both maternal and neonatal health outcomes, ensuring all data is collected for final analysis. The trial's methodology and design are structured to provide robust data on the management of PROM, contributing valuable insights into maternal and neonatal care.

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy in the management of pre-labor rupture of membranes (PROM). The first medication is **oxytocin**, a hormone administered intravenously. The pharmaceutical form is identified as PHF00231MIG, and the maximum daily and total dose is 5 IU (international units). The treatment period is limited to one day. Oxytocin is utilized for its uterotonic properties to induce labor.

Another medication used in the trial is **dinoprostone**, a prostaglandin administered via a vaginal delivery system. The maximum daily and total dose is 10 mg, with a treatment period of one day. The device used for administration is a non-biodegradable polymeric system containing 10 mg of dinoprostone, which is CE marked. This formulation is designed to facilitate cervical ripening and labor induction.

**Misoprostol**, a synthetic analogue of prostaglandin E1, is also included in the study. It is administered orally, with a maximum daily and total dose of 200 µg. The pharmaceutical form is PHF00245MIG, and the treatment period is one day. Misoprostol is employed for its ability to induce labor by promoting uterine contractions.

A second formulation of **dinoprostone** is used, administered vaginally with a maximum daily and total dose of 3 mg. This formulation is delivered via a pre-filled syringe, which is CE marked, and is intended for use over a one-day treatment period. Like the other dinoprostone formulation, it is used to aid in cervical ripening and labor induction.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the protocol. The study does not include any non-experimental treatments such as standard-of-care therapy or placebo. The trial aims to assess the impact of these medications on the need for respiratory support in newborns following PROM.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the need for neonatal ventilatory support at delivery. This includes evaluating the requirement for free-flowing oxygen in an incubator, low flow oxygen (≤ 2 LPM), high flow oxygen (≥ 3 LPM), nasal continuous positive airway pressure (NCPAP) or other non-invasive ventilation (NIV), and mechanical ventilation. These parameters will be measured at the time of delivery to determine the immediate respiratory needs of the newborn.

Secondary endpoints will assess various maternal and neonatal outcomes. Intraamniotic infection will be evaluated by measuring maternal temperature, fetal tachycardia, maternal white blood cell count exceeding 15,000 per mm³, and the presence of purulent amniotic fluid during labor. Maternal infection will be monitored in mothers re-admitted to the hospital up to 42 days postpartum, with symptoms such as fever, purulent vaginal discharge, or surgical site infection being recorded. The length of hospital stay will serve as a proxy for maternal and newborn complications, and maternal antibiotic administration will be documented in terms of dosage and quality.

Neonatal infection will be defined by the presence of a pathogen in blood or cerebrospinal fluid cultures, with suspected infections based on clinical symptoms and abnormal laboratory markers, such as elevated C-reactive protein levels above 1.5 mg/dL. Neonatal pneumonia will be diagnosed through radiological evidence of persistent consolidation, cavitation, or pleural effusion, along with worsening gas exchange and at least three clinical or laboratory signs. Neonatal antibiotic administration will also be reported in terms of dosage and quality. Additionally, **tachysystole** is defined as more than five uterine contractions in 10 minutes and will be monitored as part of the secondary endpoints.