A multicentre, single arm trial on contraceptive efficacy, safety and tolerability of LVDS (Levonorgestrel Vaginal Delivery System) during 13 cycles.

The primary objective of this multicentre, single-arm trial is to demonstrate the **contraceptive efficacy** of the Levonorgestrel Vaginal Delivery System (LVDS) over 13 cycles. This is clinically relevant as it addresses the need for effective pregnancy prevention methods, providing an alternative contraceptive option for women.

Secondary objectives include:

• To demonstrate the contraceptive efficacy of LVDS, further supporting its primary objective.
• To assess the **safety** and **tolerability** of LVDS, ensuring that the system is not only effective but also safe for long-term use.
• To evaluate the effect of LVDS on **bone mineral density** in adolescents aged 15-17 years, except in the Czech Republic and Germany, which is crucial for understanding the long-term implications of LVDS use in younger populations.

The clinical trial focuses on the **prevention of pregnancy** and involves a study population consisting exclusively of female subjects. Participants are sexually active, postmenarcheal, and premenopausal women at risk of pregnancy, including breastfeeding women. The age range for participants is between 15 and 17 years, provided that applicable laws allow for their consent to receive contraceptive services. The trial does not include male subjects. Participants are required to have a systolic blood pressure of ≤ 140 mm Hg and a diastolic blood pressure of ≤ 90 mm Hg, with controlled hypertension being permissible. The trial population includes women who have never used hormonal contraceptives, those who have had a hormonal contraceptive-free period, and those who switch directly from another hormonal contraceptive. Participants must be willing to use trial contraception for thirteen 28-day cycles and have intercourse in each cycle without the need for backup contraception. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **contraceptive efficacy**, safety, and tolerability of the Levonorgestrel Vaginal Delivery System (LVDS) over 13 cycles. This is a multicenter, single-arm trial focusing on the prevention of pregnancy. The trial will involve sexually active, postmenarcheal, and premenopausal female subjects, including breastfeeding women, who are at risk of pregnancy. Participants will be required to use the trial contraception for thirteen 28-day cycles. The trial is expected to run from May 2023 to December 2024, with an estimated duration of 364 days for each participant.

The trial will commence with an inclusion visit (Visit 1a), where eligibility criteria will be assessed. Participants must provide written informed consent and meet specific criteria, such as having regular menstrual cycles or having completed at least three menstrual cycles post-pregnancy. The inclusion visit will also ensure that participants are not involved in other clinical trials during the study period. Follow-up visits will be scheduled throughout the trial to monitor the primary endpoint, which is the overall Pearl Index in non-breastfeeding women aged 18 to 35 years. Secondary endpoints will include various efficacy and safety measures, such as adverse events, vital signs, and gynaecological examinations.

The end-of-study visit will conclude the trial, where final assessments will be conducted, including a comprehensive evaluation of the participant's health and any changes in bone mineral density for adolescents. Participants may be terminated early from the study if they fail to comply with the trial protocol, experience significant adverse events, or withdraw consent. The trial aims to provide robust data on the effectiveness and safety of the LVDS as a contraceptive method, contributing valuable insights into its use in the target population.

The clinical trial involves the use of an **experimental medication** known as the **Levonorgestrel Vaginal Delivery System 75**. This medication is designed as a **vaginal delivery system** and contains the active substance **levonorgestrel**, which is of chemical origin. The pharmaceutical form is specifically tailored for vaginal use, ensuring localized delivery of the active ingredient. The dosage of the system is set at a maximum daily dose of 75 micrograms, with a total maximum dose of 27.3 milligrams over the treatment period. The administration route is exclusively vaginal, and the treatment is intended to be used continuously for a maximum period of 364 days, corresponding to 13 menstrual cycles. The product is not formulated for pediatric use and is not classified as an orphan drug.

In this trial, no **non-experimental treatments** such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on assessing the contraceptive efficacy, safety, and tolerability of the Levonorgestrel Vaginal Delivery System. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of Exeltis France, and the product is identified by the sponsor product code CH211-75. The study aims to provide comprehensive data on the effectiveness of this contraceptive method over the specified duration.

The efficacy of the Levonorgestrel Vaginal Delivery System (LVDS) in this clinical trial will be assessed primarily through the **Pearl Index (PI)**, which is a standard measure of contraceptive effectiveness. The primary endpoint is the overall PI in non-breastfeeding women aged 18 to 35 years at the time of trial enrollment. Secondary efficacy endpoints include the overall PI in women aged ≤ 35 years and in women > 35 years, PI after correction for back-up contraception and sexual activity, and PI for method failure. Additionally, the pregnancy ratio will be evaluated using life table analysis.

Secondary safety and tolerability assessments will include monitoring adverse events, vital signs, physical and gynecological examinations, and various bleeding patterns. Clinical laboratory parameters such as hematology, biochemistry, including estradiol levels, TSH, and urinalysis, will also be evaluated. The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) will be used to assess the acceptability of the investigational product.

For adolescents aged 15-17 years, exploratory endpoints will focus on bone mineral density assessments, including changes in lumbar spine, femoral neck, total hip, and total body less head (TBLH) bone mineral density (BMD) and bone mineral content (BMC) as measured by DXA scans. These assessments will be conducted from baseline to specific visits during the trial.