Evaluation of Differential Effects of Combined Oral Contraceptives Drospirenone/Estetrol and Ethinylestradiol/Levonorgestrel on Brain Structure and Function

The primary objective of this study is to determine whether the combined hormonal contraceptives **Estetrol/drospirenone** (E4/DRSP) and **ethinylestradiol/levonorgestrel** (EE/LNG) exhibit differential effects on brain structure and function. This is clinically relevant as it may provide insights into the neurological impacts of these contraceptive formulations, potentially influencing contraceptive choice based on neurological health considerations.

Secondary objectives include evaluating the change in quality of life and assessing alterations in depressive and anxiety symptoms. These objectives are important for understanding the broader psychological and emotional effects of these contraceptives, which can impact overall patient well-being and satisfaction with contraceptive use.

The clinical trial focuses on the effects of combined hormonal **contraceptives** on brain structure and function. The study population consists exclusively of **female** participants, aged between 18 and 35 years, who are essentially healthy and in need of contraception. Participants are required to have a regular menstrual cycle, defined as occurring every 25 to 31 days. The trial does not include any vulnerable populations. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the need for participants to be sexually active, aligning with the study's focus on contraception. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the effects of two combined oral contraceptives on brain structure and function. The trial will compare the effects of **drospirenone and estetrol** with **ethinylestradiol and levonorgestrel**. The primary objective is to assess changes in brain metrics such as grey matter volume, white matter integrity, and resting state activity. Secondary endpoints include changes in the **DRSP score**, quality of life, and symptoms of depression and anxiety. The trial is expected to commence recruitment on February 1, 2024, and conclude by December 31, 2025, with a maximum treatment period of 12 months for each participant.

Participants will be required to attend several study visits throughout the trial. The initial visit will be a screening visit to confirm eligibility, which includes being a healthy woman aged 18-35 with a regular menstrual cycle and in need of contraception. Following successful screening, participants will be randomized to receive one of the two contraceptive regimens. Subsequent visits will be scheduled to monitor treatment effects and collect data on the primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted.

Participant involvement is expected to last up to 12 months, with regular follow-up visits to ensure compliance and monitor any adverse effects. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent by the participant. The trial is structured to maintain scientific rigor and ensure the safety and well-being of all participants throughout its duration.

The clinical trial involves the administration of two **combined oral contraceptives** to evaluate their effects on brain structure and function. The first experimental medication is a combination of **drospirenone** and **estetrol**. This medication is administered in an oral pharmaceutical form, with a maximum daily dose of 1 mg and a total maximum dose of 84 mg over a treatment period of 12 months. The route of administration is oral, and the medication is not a pediatric formulation. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.

The comparator treatment in this trial is a combination of **levonorgestrel** and **ethinylestradiol**. Similar to the experimental medication, this treatment is also administered orally, with a maximum daily dose of 1 mg and a total maximum dose of 84 mg over a 12-month period. The pharmaceutical form is consistent with the experimental medication, and it is also not intended for pediatric use. Participant compliance with the dosing regimen will be closely monitored to ensure adherence to the study protocol.

Both medications are classified as contraceptives and are chemically derived. The trial is designed as a randomized, double-blind, longitudinal study to compare the effects of these two hormonal contraceptives on the brain. The study aims to determine if there are differential impacts on brain structure and function between the two treatment groups. Participants will be monitored for adherence to the dosing schedule, and any deviations will be documented as part of the compliance monitoring process.

Efficacy in this clinical trial will be assessed by evaluating both primary and secondary endpoints. The primary endpoint focuses on the change from baseline to treatment in brain structure and function, specifically measuring alterations in grey matter volume, grey matter surface and gyrification, white matter integrity and connectivity using Diffusion Tensor Imaging (DTI), as well as resting state activity and reactivity during emotion processing. These parameters will provide insights into the differential effects of the combined hormonal contraceptives, estetrol/drospirenone (E4/DRSP) and ethinylestradiol/levonorgestrel (EE/LNG), on brain structure and function.

Secondary endpoints include changes in the **DRSP** score, which assesses premenstrual symptoms, as well as changes in Quality of Life and in depressive and anxiety symptoms from baseline to treatment. These secondary measures will be collected to provide a comprehensive understanding of the impact of the contraceptives beyond their primary effects on brain structure and function. The trial will employ validated scales and imaging techniques to ensure accurate and reliable data collection and analysis. The schedule for these assessments will be aligned with the trial's timeline, ensuring that data is collected at appropriate intervals to capture the treatment effects over the course of the study.