A single-centre, open-label, randomised, phase II study on the maintenance of ovulation inhibition after intentional application errors during 84 days of treatment with MR-130A-01 contraceptive transdermal patch

The primary objective of this study is to investigate whether ovulation inhibition with MR-130A-01 is maintained despite intentional 24-hour and 48-hour application errors. This objective is clinically relevant for assessing the contraceptive efficacy and reliability of the transdermal contraceptive patch under conditions that simulate real-world usage patterns where application delays may occur.

The secondary objectives include:

• To evaluate ovulation inhibition properties of MR-130A-01 in the study population
• To evaluate ovarian activity, classified by the HSS during treatment with MR-130A-01 with scheduled application errors in comparison with regular application
• To determine the luteal phase adequacy in case of HSS 5 or 6
• To assess the effects of MR-130A-01 on the diameter of the largest FLS and endometrial thickness during treatment with scheduled application errors in comparison with regular application
• To evaluate the effect of MR-130A-01 on pituitary and ovarian hormone concentrations during treatment with scheduled application errors in comparison with regular application
• To describe the effect of scheduled application errors on systemic exposure during treatment with MR-130A-01
• To check treatment compliance
• To assess patch adhesion performance
• To assess overall safety and tolerability of MR-130A-01 as well as local tolerability of the transdermal therapeutic system
• To assess the bleeding pattern during treatment with MR-130A-01

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted exclusively of **healthy female subjects** aged **18 to 35 years** who were **post-menarcheal** and **premenopausal**. Participants were required to have a **body mass index** of at least 18.0 kg/m² and demonstrate good physical and mental health as determined through vital signs assessment, medical history review, and physical and gynecological examination. Women enrolled in the trial had **regular menstrual cycles** ranging from 21 to 35 days in duration, with an intact uterus and both ovaries visible on **transvaginal ultrasound** examination. An **ovulatory pre-treatment cycle** was confirmed by a progesterone concentration exceeding 10.0 nmol/L. Participants were required to be at least three months post-delivery, post-abortion, or post-lactation cessation at the time of screening. Throughout the study, participants consented to use reliable **non-hormonal contraceptive methods**, including male condoms, diaphragm, or heterosexual abstinence, unless they had undergone female sterilization or their sexual partner had been sterilized. The trial was conducted in a **vulnerable population** as designated in the study design.

This is a single-centre, open-label, randomised, **phase II study** evaluating the maintenance of **ovulation inhibition** following intentional application errors during treatment with a **contraceptive transdermal patch** containing **norelgestromin**. The investigational medicinal product, MR-130A-01, is a **transdermal system** designed for **transdermal use** and is classified as a synthetic progesterone. The trial employs an open-label design where participants and investigators are aware of the treatment assignment. The maximum treatment period is **84 days**.

The primary objective is to investigate whether ovulation inhibition is maintained despite intentional 24-hour and 48-hour application errors. The **primary endpoint** assesses ovulation incidence in cycles with regular application, in cycles with 24-hour application errors, and in cycles with 48-hour application errors. Ovulation is defined as a **Hoogland-Skouby score** of 5 or 6 in combination with positive **Landgren criterion**, which includes rupture or development into a **luteinized unruptured follicle** of a follicle-like structure greater than 13 mm, with concomitant **estradiol** concentrations exceeding 100 pmol/L, followed by a luteal phase with **progesterone** concentrations greater than 16.0 nmol/L for at least 5 days.

**Secondary endpoints** include overall ovulation incidence, ovulation incidence per treatment cycle, Hoogland-Skouby score determination for each treatment cycle, fulfilment of Landgren criterion in cycles with scores of 5 or 6, follicle-like structure diameter and endometrial thickness determined by **transvaginal ultrasonography**, and measurement of pituitary and ovarian hormone concentrations including **luteinizing hormone**, estradiol, and progesterone in serum. Additional assessments include plasma concentrations of **NGMN** and its metabolite **norgestrel** measured immediately before and at the end of scheduled patch-free windows and before application of new patches, adhesion scores evaluated by participants and site personnel, safety and tolerability through monitoring of **treatment-emergent adverse events**, safety clinical laboratory parameters, incidence of **application site reactions** with skin irritation scores, and bleeding pattern analysis including incidences of bleeding and spotting episodes.

The study population consists of healthy, post-menarcheal and **premenopausal women** aged 18 to 35 years with a **body mass index** of at least 18.0 kg/m² at screening. Participants must be in good physical and mental health as determined by vital signs, medical history, and physical and **gynaecological examination**. Eligible participants must have regular menstrual cycles between 21 and 35 days in duration with an intact uterus and ovaries, with both ovaries visible on transvaginal ultrasonography during screening. An **ovulatory pre-treatment cycle** confirmed by progesterone concentration greater than 10.0 nmol/L is required. Participants must be at least 3 months post-delivery, abortion, or cessation of lactation before screening. Participants must consent to use reliable non-hormonal contraceptive methods, including male condoms, diaphragm, or heterosexual abstinence throughout the study, unless the participant or sexual partner has undergone sterilization.

The trial involves a screening visit during which eligibility criteria are assessed through medical history, physical and gynaecological examination, transvaginal ultrasonography, and laboratory evaluations including progesterone concentration measurement. Following successful screening and confirmation of an ovulatory pre-treatment cycle, participants are randomised to treatment sequences. Study visits occur at scheduled intervals throughout the 84-day treatment period to assess ovulation status through transvaginal ultrasonography, collect blood samples for hormone concentration analysis, evaluate patch adhesion, monitor adverse events, and record bleeding patterns. Additional visits are scheduled to coincide with patch-free windows and application error periods to measure plasma concentrations of the active substance and its metabolite. An end-of-study visit is conducted to perform final safety assessments and collect concluding data.

Participant involvement extends from the screening phase through the 84-day treatment period and final follow-up assessments. The estimated recruitment start date is October 2025, with an estimated study completion date of September 2026. Conditions that may lead to early termination from the study include withdrawal of informed consent, development of medical conditions that compromise participant safety or study integrity, non-compliance with study procedures, protocol violations, or investigator discretion based on safety concerns or adverse events. Participants may voluntarily withdraw from the study at any time without prejudice to their medical care.

The experimental treatment investigated in this clinical trial is **MR-130A-01**, a contraceptive **transdermal system** containing **norelgestromin** as the active substance. Norelgestromin, also known as 17-deacylnorgestimate, is a synthetic progesterone. The product is manufactured by Mylan Pharmaceuticals Inc. and is classified as an integrated drug device combination, where the action of the medicinal substance is principal and not ancillary to the action of the medical device. The pharmaceutical form is a transdermal patch designed for **transdermal use**. The maximum treatment period is **84 days**. The study design involves intentional application errors of 24-hour and 48-hour durations to investigate whether **ovulation inhibition** is maintained despite such deviations from the intended application schedule. This open-label, randomised, phase II trial examines the maintenance of contraceptive efficacy under conditions simulating real-world application errors. The trial is conducted in a single centre with participants receiving the transdermal patch according to the study protocol, which includes planned deviations to assess the robustness of the contraceptive effect.

Efficacy will be assessed through evaluation of ovulation inhibition during treatment with the contraceptive transdermal patch. The primary endpoint is the incidence of **ovulation** in cycles with regular application, in cycles with 24-hour application errors, and in cycles with 48-hour application errors. Ovulation is defined as a Hoogland-Skouby score of 5 or 6 in combination with a positive Landgren criterion, which includes rupture or development into a luteinized unruptured follicle of a follicle-like structure greater than 13 mm, with concomitant **estradiol** concentrations exceeding 100 pmol/L and followed by a luteal phase with **progesterone** concentrations greater than 16.0 nmol/L for at least 5 days.

Secondary efficacy endpoints include overall ovulation incidence, ovulation incidence per treatment cycle, Hoogland-Skouby score determined for each treatment cycle, and fulfillment of the Landgren criterion in cycles with Hoogland-Skouby score 5 or 6. Follicle-like structure diameter and **endometrial thickness** will be determined by transvaginal ultrasonography. Pituitary and ovarian hormone concentrations will be measured in serum, including **luteinizing hormone**, estradiol, and progesterone. Plasma concentrations of norelgestromin and its metabolite **norgestrel** will be determined at specified timepoints: immediately before and at the end of one scheduled patch-free window once each per 24-hour and 48-hour application-error cycle, and immediately before application of a new patch once per regular-application cycle. Additional secondary endpoints include assessment of adhesion scores by participants and site personnel, bleeding pattern determined as incidences of bleeding and/or spotting episodes, number of observed days of bleeding and/or spotting, bleeding only and spotting only, and incidences of complete absence of bleeding or spotting.