Randomized Clinical Trial Comparing Natural Versus Artificial Cycle Endometrial Preparation for Frozen-Thawed Embryo Transfer in Subfertility Using Estradiol Valerate and Micronised Progesterone

The primary objective of this randomized clinical trial is to determine the optimal **endometrial** preparation protocol for the transfer of a frozen-thawed embryo in patients experiencing **subfertility**. This is clinically relevant as it aims to enhance the success rates of embryo implantation and subsequent pregnancy outcomes by comparing natural versus artificial cycle protocols. The study evaluates the efficacy of different hormonal preparations, specifically **estradiol valerate** and **micronised progesterone**, in preparing the endometrium for embryo transfer. The findings could potentially inform clinical guidelines and improve treatment strategies for individuals undergoing assisted reproductive technologies.

The clinical trial focuses on women experiencing **subfertility**, specifically targeting those undergoing frozen-thawed embryo transfer (FET) after their first, second, or third fresh IVF/ICSI cycle. The study population consists exclusively of females aged between 18 and 45 years, all of whom have a natural ovulatory cycle ranging from 24 to 35 days. Participants are required to have a normal uterine cavity, defined as a fundal indentation at the cavity of less than 10mm. The trial does not include a vulnerable population, and only women who have provided written informed consent are eligible. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific criteria, including the type of embryo transfer, with both single embryo transfer (SET) and double embryo transfer (DET) being considered. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to evaluate the optimal endometrial preparation protocol for the transfer of a frozen-thawed embryo in women experiencing **subfertility**. This study is a randomized, controlled, double-blind trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to run from June 26, 2018, to January 1, 2026, with participant involvement lasting up to 12 months, depending on individual treatment protocols.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, ovulatory cycle regularity, and uterine cavity condition. Eligible participants will be women aged 18-45 undergoing frozen embryo transfer (FET) after up to three fresh IVF/ICSI cycles, with either single or double embryo transfer. Following the screening, participants will be randomly assigned to either a natural or artificial cycle for endometrial preparation, using **estradiol valerate** and **progesterone, micronised** as the active substances. The primary endpoint is the clinical pregnancy rate with a fetal heartbeat, while secondary endpoints include biochemical pregnancy rate, miscarriage rate, and other obstetrical outcomes.

Throughout the trial, participants will attend regular follow-up visits to monitor the FET cycle, assess endometrial thickness and pattern, and evaluate any adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or protocol non-compliance. The trial aims to provide comprehensive data on the efficacy and safety of the endometrial preparation protocols, contributing valuable insights into the management of subfertility.

The clinical trial involves the administration of **Progynova 2 mg dragerade tabletter**, which contains the active substance **estradiol valerate**. This medication is provided in the form of a **coated tablet** and is administered orally. The maximum daily dose is 8 mg, with a total maximum dose of 672 mg over a treatment period of up to 12 weeks. The pharmaceutical product is manufactured by Bayer Oy and is classified under the ATC code G03CA03, indicating its role as an estrogen. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Additionally, the trial includes the use of **Utrogestan 200 mg capsule molli vaginali**, which contains **micronised progesterone** as the active ingredient. This medication is formulated as a **soft vaginal capsule** and is administered via vaginal use. The maximum daily dose is 600 mg, with a total maximum dose of 50.4 g over a 12-week treatment period. The product is produced by Besins Healthcare Ireland Limited and is categorized under the ATC code G03DA04, denoting its classification as a progestogen. The administration schedule and participant adherence will be closely monitored to ensure the integrity of the trial data.

Efficacy in this clinical trial will be assessed primarily through the **clinical pregnancy rate with fetal heart beat**. This primary endpoint will provide a direct measure of the trial's main objective, which is to determine the optimal endometrial preparation protocol for the transfer of a frozen-thawed embryo. Secondary endpoints will include a comprehensive range of parameters such as biochemical pregnancy rate, miscarriage rate, ectopic pregnancy rate, live birth rate, multiple pregnancy rate, adverse events, cycle cancellation rate, endometrial thickness, endometrial pattern, number of center visits to monitor the frozen-thawed embryo transfer (FET) cycle, cost analysis per cycle, and patient satisfaction. Additionally, obstetrical outcomes in case of pregnancy will be evaluated, including gestational age, birth weight, and the incidence of pregnancy-induced hypertension, pre-eclampsia, placenta previa, placenta accreta/increta/percreta, abruptio placentae, and postpartum hemorrhage (early, late).