Comparison of Oxytocin and Prostaglandins for Labor Induction in Women with Unfavorable Cervix Post-Cervical Ripening: A Multicenter Non-Inferiority Trial

The primary objective of this study is to demonstrate that, among women with an **unfavorable cervix** after a first cervical ripening, the induction of labor with **oxytocin** does not increase the risk of **caesarean delivery** compared to repeating cervical ripening with **prostaglandins**. This is clinically relevant as it addresses the safety and efficacy of labor induction methods, potentially impacting clinical decision-making and patient outcomes.

Secondary objectives include: - Demonstrating that induction of labor with oxytocin, compared to repeated cervical ripening, is associated with a reduced time to delivery, shorter length of stay, and increased satisfaction among women. - Showing that maternal and neonatal morbidity are similar for both strategies. - Evaluating that inducing labor with oxytocin is not clinically inferior in terms of caesarean delivery rate and is not more expensive (economic non-inferiority) compared to repeated cervical ripening in women with an unfavorable cervix after a first cervical ripening.

The clinical trial focuses on the **labor induction** of women with an unfavorable cervix after 24 hours of cervical ripening. The study population consists exclusively of female participants, specifically pregnant women aged 18 years and older. These women are at a term of 37+0 weeks of gestation or more, with a singleton cephalic pregnancy. The gestational age is estimated from the first trimester ultrasound conducted between 11+0 and 13+6 weeks of gestation. Participants must have a medical indication for labor induction following a previous pharmacological or mechanical cervical ripening of 24 hours, and a Bishop score of 6 or less at inclusion. All participants are required to provide written informed consent and must be holders of a French health insurance policy. The sponsor has not provided information regarding the total number of participants in the trial. The trial population was selected based on these specific criteria, ensuring a focus on a vulnerable population that requires careful consideration during the study.

The clinical trial is designed as a **randomized**, non-inferiority controlled study to evaluate the efficacy of **oxytocin** versus **prostaglandins** for labor induction in women with an unfavorable cervix after 24 hours of cervical ripening. The primary objective is to determine if labor induction with oxytocin does not increase the risk of caesarean delivery compared to repeating cervical ripening with prostaglandins. The trial is expected to run from September 28, 2021, to November 28, 2025, with participant involvement lasting up to 1 day, corresponding to the maximum treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being a pregnant woman aged 18 or older, with a singleton cephalic pregnancy at a term of 37+0 weeks of gestation, and a Bishop score of 6 or less. Written informed consent and French health insurance coverage are also required. The primary endpoint is the rate of caesarean delivery, while secondary endpoints include time from intervention to delivery, maternal satisfaction, and various maternal and neonatal morbidity outcomes.

Study visits will include follow-up assessments to monitor the intervention's effects and any adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary post-trial care is arranged. Conditions that may lead to early termination from the study include withdrawal of consent or any medical condition that contraindicates continued participation. The trial employs a double-blind methodology to ensure unbiased results, with participants randomly assigned to receive either oxytocin or prostaglandins. The trial's design and procedures adhere to rigorous scientific standards to ensure the validity and reliability of the findings.

The clinical trial involves the use of several treatments for labor induction in women with an unfavorable cervix. The **experimental medication** is **OXYTOCIN**, marketed as OXYTOCINE PANPHARMA 5 UI/1 ml, solution injectable. This medication is administered as a **solution for injection** via the **intravenous route**. The maximum daily dose is 10 units, with a total maximum dose of 10 units over a treatment period of one day. The active substance, oxytocin, is a protein of non-chemical origin, and the product is manufactured by PANPHARMA.

One of the **comparator treatments** is **MISOPROSTOL**, marketed as ANGUSTA 25 microgrammes, comprime. This medication is provided in **tablet form** and is administered **orally**. The maximum daily dose is 200 milligrams, with a total maximum dose of 200 milligrams over a one-day treatment period. The active substance, misoprostol, is of chemical origin, and the product is manufactured by NORGINE B.V.

Another **comparator treatment** is **DINOPROSTONE**, marketed as PROPESS 10 mg, système de diffusion vaginal. This medication is delivered via a **vaginal delivery system**. The maximum daily dose is 10 milligrams, with a total maximum dose of 10 milligrams over a one-day treatment period. The active substance, dinoprostone, is of chemical origin, and the product is manufactured by FERRING S.A.S.

The final **comparator treatment** is also **DINOPROSTONE**, marketed as PROSTINE E2 2 mg/3 g, gel vaginal. This medication is provided as a **vaginal gel**. The maximum daily dose is 6 milligrams, with a total maximum dose of 6 milligrams over a one-day treatment period. The active substance, dinoprostone, is of chemical origin, and the product is manufactured by PFIZER HOLDING FRANCE.

All treatments are administered under controlled conditions, with compliance monitored throughout the trial. The trial aims to compare the efficacy of oxytocin with prostaglandins in reducing the risk of caesarean delivery after cervical ripening.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of **caesarean delivery**, regardless of the indication for the procedure. This will serve as the main measure to determine the non-inferiority of labor induction with oxytocin compared to repeated cervical ripening with prostaglandins in women with an unfavorable cervix after initial cervical ripening.

Secondary endpoints will provide additional insights into the efficacy and safety of the interventions. These include the time from intervention to delivery in hours, delivery within 12 hours, maternal satisfaction, and the need for induction with oxytocin in the control group. Other secondary measures include the indication for caesarean delivery, instrumental delivery, and the need for oxytocin augmentation. Maternal and neonatal safety outcomes such as uterine hyperstimulation, suspicion of per-partum infection, post-partum hemorrhage, and neonatal morbidity indicators like birth trauma and hypoxic ischemic encephalopathy will also be evaluated.

The trial will also assess economic outcomes, specifically the proportion of incremental cost-effect pairs that fall within the non-inferiority area for various economic non-inferiority margins, maintaining a constant clinical non-inferiority margin of 7%. These efficacy parameters will be collected and analyzed throughout the trial duration, with specific timepoints and methods for measurement not detailed in the provided data.