Evaluation of Menstrual Bleeding Patterns, Tolerability, and Compliance with Norgestimate and Ethinylestradiol in Italian Women Using Monophasic Oral Contraceptives

The primary objective of this study is to evaluate the **cycle control** in terms of breakthrough bleeding, specifically bleeding and/or spotting between cyclically regular onset of menses, in women using the monophasic oral contraceptive pill Effimia® (norgestimate 0.250 mg + ethinylestradiol 0.035 mg) in Italy. This is clinically relevant as it assesses the effectiveness and reliability of the contraceptive in maintaining regular menstrual cycles, which is a critical factor in contraceptive choice and user satisfaction.

Secondary objectives include:

• Evaluating cycle control in terms of frequency, duration, regularity, flow volume, and unscheduled bleeding and/or spotting.
• Assessing possible correlations between cycle irregularities and age, as well as the condition of being a starter or switcher of contraception.
• Evaluating the impact on sexual life.
• Assessing the impact on subjects affected by pre-treatment acne problems.
• Evaluating the impact on subjects with premenstrual syndrome (PMS).
• Assessing effects on lipid and glucose metabolism, hormonal parameters related to hyperandrogenism, and plasma coagulation parameters in a subgroup of 28 subjects.

The clinical trial focuses on evaluating the cycle control of the monophasic oral contraceptive pill **Effimia®** in a specific population. The study population comprises **healthy women** aged between 18 and 35 years, residing in Italy. Participants are required to have a good understanding of the Italian language to ensure comprehension of the informed consent and study instructions. The trial exclusively involves female subjects, with no male participants included. The sponsor has not provided information regarding the total number of participants. The study does not involve a vulnerable population. Participants are expected to adhere to the study protocol and provide written informed consent. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The primary medical condition under investigation is female contraception.

The clinical trial is a **prospective, open-label, non-comparative study** designed to evaluate the menstrual bleeding typology, tolerability, and compliance during a monophasic hormonal contraceptive treatment with **norgestimate** and **ethinylestradiol**. The trial is conducted in Italy and targets healthy women aged between 18 and 35 years who require contraception. The study aims to assess cycle control, specifically breakthrough bleeding, by calculating the intermenstrual spotting occurrence rate at the sixth cycle. The trial will also evaluate secondary endpoints such as frequency, duration, regularity, flow volume of menstrual bleeding, unscheduled bleeding, and other parameters like the Global Acne Grading System, Profile of Mood State, Female Sexual Function Index, and dysmenorrhea using the VAS scale. Compliance and contraception failure rate during the 6-month treatment period will also be assessed.

The trial is expected to last until December 31, 2024, with recruitment starting on July 5, 2023. Participants will be involved for a maximum of six months, corresponding to the treatment period with the oral contraceptive **Effimia**. The study includes several visits: an initial screening visit (V1) to confirm eligibility and obtain informed consent, followed by two follow-up visits (V2 and V3) to monitor progress and collect data on the primary and secondary endpoints. The end-of-study visit will coincide with the completion of the sixth cycle of treatment. Participants may be terminated early from the study if they become pregnant, fail to comply with the study protocol, or withdraw consent. The trial is not categorized as low intervention and is conducted as a phase 4 study, focusing on post-marketing surveillance to gather additional information on the drug's effect in a real-world setting.

The clinical trial involves the administration of the experimental medication **Effimia**, a monophasic oral contraceptive pill. Effimia contains two active substances: **ethinylestradiol** and **norgestimate**. The pharmaceutical form of Effimia is a tablet, with each tablet containing 0.250 mg of norgestimate and 0.035 mg of ethinylestradiol. The medication is administered orally. The dosing schedule involves a daily intake of one tablet, with a maximum daily dose of 0.25 mg of norgestimate. The treatment period is set for a maximum duration of six months. The medication is manufactured by ITALFARMACO S.P.A and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the cycle control, specifically breakthrough bleeding, during the use of Effimia. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted in a non-comparative, open-label manner, allowing for the assessment of menstrual bleeding typology, tolerability, and compliance in the study population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on evaluating **cycle control** by measuring the occurrence rate of breakthrough bleeding, defined as bleeding and/or spotting between cyclically regular onset of menses. This will be specifically assessed at the sixth cycle, with a comparison made within the group at Visit 3 (V3) relative to Baseline (V1).

Secondary endpoints include a comprehensive evaluation of cycle control parameters such as frequency, duration, regularity, flow volume (as determined by the subject), and unscheduled bleeding. These parameters will be compared within the group at Visit 2 (V2) and V3 against Baseline (V1). Additional secondary endpoints involve assessments using the Global Acne Grading System (GAGS), Profile of Mood State (POMS), Female Sexual Function Index (FSFI), and Dysmenorrhea measured by the Visual Analogue Scale (VAS). These will also be compared at V2 and V3 with respect to Baseline (V1).

Furthermore, compliance with the treatment regimen will be monitored, and the contraception failure rate during the 6-month treatment period will be calculated. This rate is defined as the proportion of women who become pregnant during the study, with reasons for any contraception failure being identified and documented. Metabolic and hormonal parameters will also be evaluated as part of the secondary endpoints.