Evaluation of Vaginal Progesterone for Luteal Phase Support in Enhancing Live Birth Rates in Infertility Patients Undergoing Frozen-Thawed IVF Natural Cycles

The primary objective of this study is to evaluate the efficacy of **vaginal progesterone** as luteal phase support in improving live birth rates in women undergoing frozen/thawed in-vitro fertilization natural cycles (FET-NC). The study aims to determine if progesterone support is superior to no support and, if proven superior, to compare the effectiveness of 7 weeks versus 3 weeks of progesterone treatment. This is clinically relevant as optimizing luteal phase support could enhance live birth outcomes in assisted reproductive technologies.

Secondary objectives include:

• Comparing treatment groups regarding pregnancy outcomes, including biochemical, clinical, ongoing, and term pregnancy rates, as well as rates of miscarriage, termination of pregnancy, and ectopic pregnancy.
• Evaluating perinatal and obstetric outcomes between treatment groups.
• Assessing self-reported side effects and adverse events across treatment groups.
• Analyzing cost-effectiveness of the treatment regimens.
• Investigating the effect of S-progesterone levels before FET on the likelihood of achieving live birth and other secondary pregnancy outcomes.

The clinical trial focuses on **infertility** and involves a study population exclusively composed of female participants. The age range for participants is between 18 and 43 years, with a body mass index (BMI) between 18.5 and 35. Participants are required to have regular menstrual cycles lasting between 24 to 35 days. The trial population was selected based on specific criteria, including the ability to understand written and spoken Swedish, English, or Arabic, and the provision of informed consent. The study targets women who are planned for a frozen embryo transfer in a natural cycle (FET-NC) with a blastocyst. The sponsor has not provided information regarding the total number of participants. The trial does not include male subjects and involves a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **vaginal progesterone** as luteal support in improving live birth rates in women undergoing frozen/thawed in-vitro fertilization natural cycles. This is a multicenter, open, randomized trial comparing the outcomes of luteal phase support with vaginal progesterone against no support. The trial aims to determine if 7 weeks of progesterone treatment is superior to 3 weeks in terms of live birth per woman. The study is expected to run from April 21, 2021, to January 31, 2026, with participant involvement lasting up to 7 weeks, depending on the treatment group assignment.

Participants will be randomly assigned to receive either Cyclogest 400 mg pessary or Lutinus 100 mg vaginal tablet, both containing the active substance **progesterone**, or no treatment. The trial includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, BMI, and regular menstrual cycles, followed by treatment visits where the administration of the study drug will be monitored. Follow-up visits will assess primary and secondary endpoints, including live birth, biochemical pregnancy, and other obstetric outcomes. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are addressed.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The primary endpoint is the live birth rate, while secondary endpoints include various pregnancy and perinatal outcomes, as well as cost-effectiveness and progesterone levels in blood samples. The trial is not categorized as low intervention and is classified as a Phase IV study, focusing on the real-world application of the treatment. The study is conducted in accordance with ethical guidelines, ensuring informed consent and participant safety throughout the trial duration.

The clinical trial involves the administration of **Cyclogest 400 mg vagitorium**, which contains the active substance **progesterone**. This medication is formulated as a **pessary** and is intended for **vaginal use**. The maximum daily dose is 800 mg, with a total maximum dose of 39,200 mg over a treatment period of up to 7 days. The medication is manufactured by Gedeon Richter PLC and is chemically derived. Participants are required to adhere to the dosing schedule to ensure compliance, which will be monitored throughout the trial.

Another treatment used in the trial is **Lutinus 100 mg vaginaltabletter**, also containing **progesterone** as the active ingredient. This medication is provided in the form of a **vaginal tablet** and is administered via the **vaginal route**. The maximum daily dose for Lutinus is 300 mg, with a total maximum dose of 14,700 mg over a 7-day treatment period. The product is manufactured by Ferring Läkemedel AB and is of chemical origin. Participant compliance with the dosing regimen will be closely monitored to ensure the integrity of the trial results.

Both treatments are being evaluated for their efficacy in providing luteal phase support in women undergoing frozen/thawed in-vitro fertilization natural cycles. The trial aims to determine if vaginal progesterone is superior to no luteal phase support in terms of live birth rates, and if a 7-week treatment duration is more effective than a 3-week duration. No non-experimental treatments, such as standard-of-care therapy or placebo, are being used in this study.

Efficacy in this clinical trial will be assessed primarily through the endpoint of live birth per woman undergoing frozen embryo transfer in a natural cycle (FET-NC). The trial aims to determine if luteal phase support with vaginal **progesterone** is superior to no support, and if a 7-week treatment duration is more effective than a 3-week duration. Secondary endpoints include a range of pregnancy-related outcomes such as biochemical pregnancy, clinical pregnancy, ongoing pregnancy, term pregnancy, miscarriage, ectopic pregnancy, termination of pregnancy, intrauterine fetal death, and perinatal death. Additionally, perinatal outcomes like birth weight, gestational age, preterm birth, low birth weight, stillbirth, and birth defects will be evaluated. Obstetric outcomes such as hypertensive disorders of pregnancy, placenta previa, placenta abruption, and postpartum hemorrhage will also be assessed. Cost-effectiveness and **progesterone** levels in blood samples from day LH+3 are included as secondary endpoints.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial. The trial is designed as a multicenter, open, randomized study, ensuring a robust evaluation of the efficacy of **progesterone** as luteal support. The trial is expected to conclude by January 31, 2026, with recruitment having started on April 21, 2021. The study will utilize validated scales and laboratory tests to measure the specified endpoints, ensuring the reliability and accuracy of the efficacy assessments.