Evaluation of the Impact of LF111 and Drospirenone on Bone Mineral Density in Adolescent and Adult Females Using Hormonal Contraceptives

The primary objective of this study is to evaluate the impact of **drospirenone** (DRSP) 3.5 mg chewable tablets and LF111 on **bone mineral density** (BMD) at the lumbar spine after 12 months (13 medication cycles) of investigation. This is compared to non-hormonal contraceptive methods. The clinical relevance of this objective lies in understanding the potential effects of hormonal contraceptives on bone health, which is crucial for the long-term skeletal health of adolescent and adult women.

Secondary objectives include:

• To further evaluate the impact of LF111 and DRSP 3.5 mg chewable tablets on BMD and bone turnover after 12 months (13 medication cycles) of investigation in comparison to non-hormonal contraceptive methods.
• To assess general safety and tolerability of LF111 and DRSP 3.5 mg chewable tablets in comparison to non-hormonal contraceptive methods.

The clinical trial involves a total of **422 participants** who are exclusively female, as the study focuses on the effects of oral contraception. The study population consists of females aged **14 to 45 years**, with a specific emphasis on those who have regular menstrual cycles and are postmenarcheal for at least two years and premenopausal. Participants aged 14 to 17 years are included only if they meet legal requirements for consent or assent to receive contraceptive services. The trial excludes male subjects and does not involve a vulnerable population. Participants are required to have a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 90 mmHg. Additionally, menstruation must have restarted for at least six months since the last pregnancy for those who were previously pregnant. The trial population was selected based on their willingness to use trial contraception for thirteen 28-day cycles or to use non-hormonal contraceptive methods for the duration of the trial. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the impact of **drospirenone** 3.5 mg chewable tablets on bone mineral density (BMD) at the lumbar spine in adolescent and adult women, compared to non-users of hormonal contraceptive methods. This is a multicenter, open-label, controlled study with a duration of 12 months, encompassing 13 medication cycles. The trial involves two cohorts: adolescents and adults, with the primary endpoint being the mean absolute change in lumbar spine (L1-L4) Z-score for adolescents and the mean percentage change in lumbar spine BMD for adults, both measured by dual-energy X-ray absorptiometry (DXA) from baseline to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, menstrual cycle regularity, and blood pressure. Eligible participants will be required to provide written informed consent or assent. The trial includes follow-up visits at 6 months and 12 months to monitor changes in body weight, body mass index (BMI), routine laboratory values, and serum estradiol levels in the hormonal treatment arm. Adverse events will also be recorded throughout the study duration.

The expected length of participant involvement is 12 months, with conditions for early termination including non-compliance with trial procedures, withdrawal of consent, or any adverse events that may compromise participant safety. The trial is not classified as low intervention and is categorized as a phase 4 study. Participants will be randomly assigned to either the drospirenone arm or the non-hormonal contraceptive arm, with the trial aiming to provide valuable insights into the effects of hormonal contraception on bone health.

The clinical trial involves the administration of **DROSPIRENONE**, a chemical-origin active substance, in the form of chewable tablets. Each tablet contains 3.5 mg of drospirenone. The pharmaceutical form is a tablet, and the route of administration is oral. Participants will receive a maximum daily dose of 4 mg, with a total maximum dose of 48 mg over the course of the study. The treatment period is set for 12 months, corresponding to 13 medication cycles. The study aims to evaluate the impact of drospirenone on bone mineral density (BMD) at the lumbar spine in adolescent and adult women. Compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** group, which will receive green tablets containing inactive ingredients such as lactose, maize starch, povidone, silica, colloidal anhydrous magnesium stearate, hypromellose, triacetin, polysorbate 80, titanium dioxide, indigo carmine, aluminium lake, and yellow iron oxide. The placebo tablets are designed to match the appearance of the active medication but contain no active pharmaceutical ingredients. The placebo is administered orally, following the same dosing schedule as the active treatment group, to ensure blinding and control within the study.

Efficacy in this clinical trial will be assessed by evaluating the impact of LF111 and **drospirenone** 3.5 mg chewable tablets on bone mineral density (BMD) at the lumbar spine after 12 months of investigation. The primary endpoints include the mean absolute change in lumbar spine (L1-L4) Z-score from baseline to 12 months for adolescents, and the mean percentage change in lumbar spine (L1-L4) BMD from baseline to 12 months for adults. These measurements will be conducted using dual-energy X-ray absorptiometry (DXA).

Secondary endpoints will include changes in body weight and body mass index (BMI), mean absolute and relative changes in routine laboratory values from baseline to 6 months and to 12 months, and mean absolute and relative changes in serum estradiol (E2) levels in the hormonal treatment arm from baseline to 6 months and to 12 months. Additionally, adverse events will be monitored throughout the trial. The efficacy parameters will be collected and analyzed at specified timepoints, including baseline, 6 months, and 12 months, to ensure comprehensive assessment of the treatment effects.