Evaluation of Ceftriaxone Sodium, Clarithromycin, and Metronidazole in Reducing Neonatal Mortality in Threatened Late Miscarriage with Intact Membranes

The primary objective of this clinical trial is to **reduce neonatal mortality and severe morbidity** by prolonging pregnancies that are complicated by the threat of late miscarriage with intact membranes. This is clinically relevant as it aims to improve outcomes for both the mother and the neonate in high-risk pregnancies, potentially decreasing the incidence of adverse neonatal events and improving survival rates.

Secondary objectives include:

• Prolongation of pregnancy
• Prolongation of the latency period between randomization and delivery
• Reduction of **chorioamnionitis**
• Reduction of postpartum endometritis and maternal sepsis
• Improvement of neonatal outcomes based on the primary composite judgment criterion

These secondary objectives are significant as they focus on extending the gestational period, reducing maternal and neonatal infections, and enhancing overall neonatal health outcomes, which are critical factors in managing pregnancies at risk of late miscarriage.

The clinical trial involves **pregnant women** with singleton pregnancies who are hospitalized for threatened late miscarriage with intact membranes. The study population is exclusively female, with participants being over 18 years of age. The trial focuses on a vulnerable population, specifically those between 18 0/7 and 23 6/7 weeks of gestation, as defined by specific ultrasound criteria. Participants must have a living fetus at the time of inclusion and must not experience regular and painful uterine contractions. Additionally, an adequate understanding of the French language and affiliation with social security are required. The sponsor has not provided information regarding the total number of participants. The trial aims to reduce neonatal mortality and severe morbidity by prolonging pregnancies complicated by the threat of late miscarriage with intact membranes.

The clinical trial is designed as an open, multiple-center, **randomized**, and controlled study aimed at evaluating the efficacy of a combination of antibiotics in reducing neonatal mortality and severe morbidity in pregnancies complicated by the threat of late miscarriage with intact membranes. The trial will involve pregnant women with singleton pregnancies who are hospitalized for threatened late miscarriage, defined by specific criteria such as a cervix ≤10 mm or protrusion of the amniotic sac, as observed through transvaginal ultrasound or speculum examination. The study will commence with a screening visit to confirm eligibility based on inclusion criteria, including maternal age over 18 years, absence of regular and painful uterine contractions, and adequate understanding of the French language.

Participants will be randomly assigned to receive either the investigational treatment or a control, with the investigational treatment comprising **ceftriaxone sodium** administered as a solution for injection, and **clarithromycin** and **metronidazole** administered orally in the form of film-coated tablets. The maximum treatment period for ceftriaxone sodium is six days, while clarithromycin and metronidazole can be administered for up to seven days. The primary endpoint of the trial is a composite criterion that includes late miscarriage, perinatal mortality, and severe neonatal morbidity before hospital discharge. Secondary endpoints will assess individual components of the composite criterion, such as bronchopulmonary dysplasia and sepsis.

The trial is expected to last until March 2028, with recruitment starting in October 2024. Participants will be involved in the study for the duration of their treatment period, with follow-up visits scheduled to monitor outcomes and assess any adverse events. An end-of-study visit will be conducted to collect final data and ensure participant safety. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent by the participant. The trial aims to provide valuable insights into the potential benefits of antibiotic therapy in prolonging pregnancies and improving neonatal outcomes in cases of threatened late miscarriage.

The clinical trial involves the administration of **Ceftriaxone Viatris 1 g**, a **poudre pour solution injectable**. This experimental medication is formulated as a **solution for injection** and contains the active substance **ceftriaxone sodium**. The medication is administered via injection, with a maximum daily dose of 1 gram. The treatment period for this medication is limited to a maximum of 6 days. The pharmaceutical product is manufactured by Viatris Sante and is authorized for use in France under the marketing authorization number NL25364.

Another experimental medication used in the trial is **Clarithromycine EG 500 mg**, available as **comprimés pelliculés** or **film-coated tablets**. The active substance in this medication is **clarithromycin**. It is administered orally, with a maximum daily dose of 1.5 grams. The treatment duration for this medication is up to 7 days. This product is manufactured by Clonmel Healthcare Ltd. and holds the marketing authorization number MA1045/04502 in Malta.

The trial also includes the administration of **Métronidazole Arrow 500 mg**, provided as **comprimé pelliculé sécable** or **film-coated tablets**. The active substance is **metronidazole**, and the medication is administered orally. The maximum daily dose is 1 gram, with a treatment period extending up to 7 days. This pharmaceutical product is produced by Arrow Generiques and is authorized in France with the marketing authorization number NL 49493.

All medications in this trial are of chemical origin and are not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study.

The efficacy of the clinical trial titled "Echec-MAT - A combination of antibiotics to improve neonatal mortality and morbidity for pregnancies complicated with previable labour and intact membranes" will be assessed using a composite primary endpoint. This endpoint includes the occurrence of late miscarriage, perinatal mortality, and/or severe neonatal morbidity before hospital discharge. Specific conditions considered under severe neonatal morbidity are **bronchopulmonary dysplasia**, sepsis proven by blood culture, intraventricular hemorrhage ≥ Grade 3, periventricular leukomalacia ≥ Grade 2, and necrotizing enterocolitis at stage ≥ 2 according to Bell's classification.

Secondary endpoints will evaluate each component of the composite criterion individually. These include neonatal mortality and late miscarriage, bronchopulmonary dysplasia diagnosed at discharge or at a corrected age of 36 6/7 weeks of gestation, sepsis diagnosed by clinical signs and positive blood culture, intraventricular hemorrhage ≥ Grade 3 and/or periventricular leukomalacia diagnosed by repeated transfontanellar ultrasounds, and necrotizing enterocolitis ≥ Stage 2 using Bell's classification. The trial aims to reduce neonatal mortality and severe morbidity by prolonging pregnancies complicated by the threat of late miscarriage with intact membranes.