WOMEN&More: Prospective phase III multi-center open-label study of the efficacy, safety, and acceptability of mifepristone 50 mg once-weekly as a contraceptive

The primary objective of this study is to evaluate the **efficacy**, safety, and acceptability of mifepristone 50 mg administered once weekly as a contraceptive. This is clinically relevant as it aims to provide an alternative contraceptive method that could potentially offer improved compliance and user satisfaction compared to daily oral contraceptives.

Secondary objectives include:

• Exploration of pregnancy outcomes, which is important for understanding the effectiveness and potential implications of the contraceptive method on reproductive health.
• Exploration of temporary increased liver functions, which is crucial for assessing the safety profile of mifepristone and its impact on liver health.

The clinical trial focuses on the **efficacy**, safety, and acceptability of mifepristone 50 mg once-weekly as a contraceptive. The study population consists exclusively of **female** participants aged 18 to 35 years, who are in good general health with a body mass index (BMI) of less than 35 kg/m². Participants are required to have a menstrual cycle of 21-35 days if not using hormonal contraceptives, and those who have used Depo-Provera must have experienced at least three cycles of 21-35 days after cessation. The trial does not include a vulnerable population, and only individuals who understand and speak Dutch or English are eligible. Participants must be willing to use mifepristone as their sole method of contraception for 12 months and engage in unprotected vaginal heterosexual intercourse with a non-sterilized partner at least once a month. They are also required to fill in a daily diary via a study app and complete online questionnaires five times throughout the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **phase III** multi-center open-label study designed to evaluate the efficacy, safety, and acceptability of **mifepristone** 50 mg administered once weekly as a contraceptive. The trial will involve participants aged 18-35 who meet specific inclusion criteria, such as having a **BMI** less than 35 kg/m² and being willing to use mifepristone as the sole method of contraception for 12 months. The study is expected to commence recruitment on February 1, 2025, and conclude by February 1, 2030, with a total duration of approximately five years.

Participants will be required to attend several study visits throughout the trial. The initial visit will serve as a screening to confirm eligibility based on the inclusion criteria. Following successful screening, participants will be enrolled and begin the treatment phase, which will last for 12 months. During this period, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including assessments of endometrial thickness and liver function tests. The primary endpoint is the occurrence of pregnancy during treatment, measured by the Overall Pearl Index. Secondary endpoints include assessments of endometrial changes, liver function, and acceptability factors such as user failure and side effects.

The end-of-study visit will occur at the conclusion of the 12-month treatment period, where final assessments will be conducted, and data will be collected on any pregnancies that occurred during the study. Participants are expected to adhere to the study protocol, including taking the oral medication as prescribed and completing daily diaries and online questionnaires. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial is not classified as a low-intervention study, and participants are required to understand and speak Dutch or English to ensure effective communication and adherence to the study requirements.

The clinical trial involves the administration of **Mifepristone**, an experimental medication, which is being evaluated for its efficacy, safety, and acceptability as a contraceptive. The pharmaceutical form of the medication is a **tablet**, with each tablet containing 50 mg of the active substance, **mifepristone**. The medication is administered orally, with a dosing schedule of once-weekly administration. The maximum daily and total dose is 50 mg, and the treatment period extends up to 52 weeks. The active substance, mifepristone, is of chemical origin and is classified under the ATC code G03XB01. The trial is conducted under the auspices of Leiden University Medical Center.

In addition to the experimental treatment, the study may involve the use of **uterotonica** as a non-experimental treatment. Uterotonica are agents that induce contraction or greater tonicity of the uterus and may be used as a standard-of-care therapy in the context of this trial. The administration of uterotonica will be in accordance with standard medical practice and will not interfere with the primary objective of evaluating mifepristone as a contraceptive.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the once-weekly administration of mifepristone. Compliance monitoring will be conducted through regular follow-up visits and participant self-reporting. The trial is designed to assess the long-term use of mifepristone over a period of up to 52 weeks, with a focus on its contraceptive efficacy and safety profile.

The efficacy of the clinical trial will be assessed primarily through the **Overall Pearl Index**, which measures the occurrence of pregnancy during treatment due to user and method failure. This primary endpoint will provide a quantitative evaluation of the contraceptive effectiveness of mifepristone 50 mg administered once weekly. Secondary endpoints will include a range of parameters to further evaluate the efficacy and acceptability of the treatment. These include the proportion of participants with endometrial thickness greater than 15 mm, irregular cystic appearance of the endometrium on ultrasound, and liver function abnormalities such as ALT and AST elevation three times above normal levels or bilirubin two times above normal levels. Additionally, the trial will assess user acceptability through factors such as user failure, depression, sexual functioning, use of antidepressants, weight changes, bleeding profile, side effects, and overall acceptability. The trial will also document the proportion of participants opting for an abortion or continuing the pregnancy, with outcomes such as miscarriages, ectopic pregnancies, preterm labor, growth restriction, and congenital abnormalities being registered. The data collection will be conducted through scheduled visits and compliance with the study protocol, including the use of a study app for daily diary entries and online questionnaires. The trial is designed to ensure comprehensive data collection and analysis to evaluate the efficacy and acceptability of mifepristone as a contraceptive method.