Evaluation of Tailored Antibiotic and Steroid Therapy Based on IL-6 in Amniotic Fluid for Prolonging Pregnancy in Preterm Premature Rupture of Membranes

The primary objective of the study is to evaluate whether a **tailored antibiotic and steroid therapy** based on the interleukin-6 (IL-6) value in amniotic fluid, obtained through amniocentesis in patients with preterm premature rupture of membranes (PPROM), is associated with the prolongation of pregnancy compared to standard treatment. This is clinically relevant as prolonging pregnancy in cases of PPROM can potentially improve maternal and neonatal outcomes by reducing the risks associated with preterm birth.

Secondary objectives include:

• Evaluating the latency period from premature rupture of membranes to birth.
• Assessing the incidence of **chorioamnionitis** and **funisitis**.
• Determining short-term adverse maternal outcomes.
• Investigating short-term neonatal outcomes.
• Exploring the microbiome of the mother and newborn as an optional outcome.

The clinical trial involves a study population of **female** participants aged 18 years and older, specifically focusing on those experiencing **preterm premature rupture of membranes** (pPROM) during pregnancy. The trial does not include male participants, and the population is not considered vulnerable. Participants are selected based on confirmed pPROM, as verified by the Amnisure test or clinical examination, and are within the gestational age range of 22+0 to 33+6 weeks. The study is limited to those with a singleton pregnancy and an otherwise uncomplicated pregnancy until the occurrence of pPROM. All participants have provided signed informed consent. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of a **tailored antibiotic and steroid therapy** in patients with preterm premature rupture of membranes (pPROM) compared to standard treatment. This trial is a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to commence on March 1, 2025, and conclude by March 1, 2028, with the primary objective of assessing whether the tailored therapy prolongs pregnancy beyond seven days from the rupture of membranes to delivery.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), confirmed pPROM, and a singleton pregnancy between 22+0 and 33+6 weeks. Following the screening, participants will be randomized to receive either the tailored therapy or standard treatment. The study will include follow-up visits to monitor the latency to birth, incidence of chorioamnionitis and funisitis, and short-term maternal and neonatal outcomes. The end-of-study visit will occur after delivery to assess the primary and secondary endpoints, including the microbiome in the mother and newborn as an optional outcome.

The expected length of participant involvement is from the time of pPROM diagnosis until delivery, with the primary endpoint being the latency of pregnancy of more than seven days. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize various medicinal products, including **betamethasone sodium phosphate** administered via intramuscular injection and antibiotics such as **gentamicin sulfate** and **ampicillin sodium** administered through intravenous infusion, ensuring comprehensive treatment coverage. The study aims to improve maternal and neonatal outcomes while reducing unnecessary antibiotic use.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone**, with the active substance **betamethasone sodium phosphate**, is administered as an intramuscular injection. The maximum daily dose is 12 mg, with a total maximum dose of 24 mg over a treatment period of up to 2 days. This corticosteroid is utilized for its anti-inflammatory properties.

**Gentamicin**, containing the active substances **betamethasone valerate** and **gentamicin sulfate**, is delivered via intravenous infusion. The maximum daily dose is 400 mg, with a total maximum dose of 2800 mg over a 7-day treatment period. This antibiotic is used for its efficacy against a broad range of bacterial infections.

**Benzylpenicillin**, comprising **benzylpenicillin procaine**, **benzathine benzylpenicillin**, and **benzylpenicillin potassium**, is also administered through intravenous infusion. The maximum daily dose is 17 IU, with a total maximum dose of 125 IU over a 10-day treatment period. This antibiotic is effective in treating various bacterial infections.

**Clarithromycin**, with the active substance **demeclocycline hydrochloride**, is administered orally. The maximum daily dose is 1 g, with a total maximum dose of 10 g over a 10-day treatment period. This antibiotic is used for its broad-spectrum antibacterial activity.

**Magnesium sulfate** is administered via intravenous infusion for neuroprotection. The maximum daily and total dose is 16 g, administered over a single day. This treatment is used for its neuroprotective effects in specific clinical scenarios.

**Ampicillin and beta-lactamase inhibitor**, containing **ampicillin sodium**, **sulbactam sodium**, and **lidocaine hydrochloride**, is delivered through intravenous infusion. The maximum daily dose is 12 g, with a total maximum dose of 84 g over a 7-day treatment period. This antibiotic combination is used to enhance the efficacy of ampicillin against beta-lactamase-producing bacteria.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to evaluate the efficacy of these tailored therapeutic regimens in patients with preterm premature rupture of membranes, focusing on pregnancy prolongation and improved maternal and neonatal outcomes.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the latency of pregnancy, defined as the duration of more than 7 days from the occurrence of premature rupture of membranes to delivery. This will be measured to determine the effectiveness of the tailored antibiotic and steroid therapy based on the **IL-6** value in amniotic fluid, compared to standard treatment.

Secondary endpoints include latency to birth, incidence of chorioamnionitis and funisitis, short-term adverse maternal outcomes, short-term neonatal outcomes, and the microbiome in mother and newborn as an optional outcome. These parameters will provide a comprehensive assessment of the treatment's impact on both maternal and neonatal health.