Randomized Controlled Trial of GnRH Agonist Luteal Phase Support Versus hCG Triggering and Progesterone in IVF/ICSI with Embryo Transfer

The primary objective of this study is to demonstrate an increase in the rate of **live births** after 22 weeks' amenorrhea per cycle with **GnRH agonist** induction and support compared with the reference protocol combining **hCG** induction and luteal support with exogenous vaginal **progesterone**. This is clinically relevant as it aims to improve the success rates of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) protocols, potentially leading to higher live birth outcomes, which is a critical endpoint in reproductive medicine.

Secondary objectives include:

• Demonstrating improved embryo implantation rate with GnRH agonist induction and support versus hCG induction and luteal support with exogenous vaginal progesterone.
• Demonstrating an improvement in the rate of early pregnancy between induction and GnRH agonist support versus induction with hCG and luteal support with vaginal exogenous progesterone.
• Demonstrating improvement in clinical pregnancy rate between induction and GnRH agonist support versus hCG induction and luteal support with exogenous vaginal progesterone.
• Demonstrating a decrease in the rate of miscarriage per incipient pregnancy between induction and GnRH agonist support versus induction with hCG and luteal support with vaginal exogenous progesterone.
• Demonstrating an increase in the rate of progressive pregnancy at 12 weeks' amenorrhea per cycle with GnRH agonist induction and support compared with the reference protocol.
• Comparing the impact on obstetrical data of induction and support with GnRH agonist versus induction with hCG and luteal support with exogenous vaginal progesterone.
• Demonstrating a decrease in the rate of moderate to severe ovarian hyperstimulation syndrome with GnRH agonist induction and support versus hCG induction and luteal support with vaginal exogenous progesterone.
• Comparing the evolution of corpora lutea in the luteal phase between initiation and support by GnRH agonist versus initiation by hCG and luteal support by exogenous vaginal progesterone.
• Evaluating the association of progesterone, estradiol, LH, and hCG levels with pregnancies and miscarriages throughout follow-up between induction and GnRH agonist support, and induction by hCG and luteal support by vaginal exogenous progesterone.
• Evaluating side effects between induction and GnRH agonist support versus induction with hCG and luteal support with vaginal exogenous progesterone.
• Comparing embryonic development between triggering and support by GnRH agonist versus triggering by hCG and luteal support by exogenous vaginal progesterone.

The clinical trial involves a study population of **females** aged 18 to 39 years, who are undergoing **in vitro fertilization (IVF)** or **intracytoplasmic sperm injection (ICSI)** protocols with embryo transfer planned in the same cycle. The trial does not include male participants and does not involve a vulnerable population. Participants are required to have a body mass index (BMI) of less than 35 kg/m² and an anti-Müllerian hormone (AMH) level greater than 1 ng/ml, with an antral follicle count of at least 8. The trial is limited to individuals who are on their first or second attempt at IVF or ICSI, and who are undergoing treatment with daily recombinant follicle-stimulating hormone (FSH) at an initial dose between 75 and 450 IU. The selection criteria also include social security affiliation, excluding AME, and the requirement for signed informed consent. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **GnRH agonist** induction and support compared to the reference protocol involving **hCG** induction and luteal support with exogenous vaginal **progesterone** in the context of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with embryo transfer planned in the same cycle. This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to commence on October 2, 2023, and conclude by May 2, 2027, with the primary objective of demonstrating an increase in the rate of live births after 22 weeks of amenorrhea per cycle.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, BMI, and ovarian reserve markers. The inclusion criteria require participants to be aged 18 to 39, with a BMI less than 35 kg/m², and undergoing their first or second attempt at IVF or ICSI. The trial will involve treatment with daily recombinant **FSH** at doses ranging from 75 to 450 IU. Follow-up visits will be scheduled to monitor the progress of the treatment, including the assessment of hormone levels and the development of embryos. The end-of-study visit will evaluate the primary endpoint of live birth and secondary endpoints such as embryo implantation, early pregnancy, and clinical pregnancy rates.

The expected duration of participant involvement is up to 20 days, depending on the specific treatment protocol assigned. Conditions that may lead to early termination from the study include the occurrence of adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are aware of their rights throughout the study.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Progesterone** is utilized in the form of a vaginal capsule, soft, with a maximum daily dose of 600 mg and a total dose of 9000 mg over a treatment period of 15 days. The route of administration is vaginal use. This hormonal treatment is not a pediatric formulation and is used as an auxiliary product in the trial.

**Follitropin Beta** is administered as a solution for injection, with a maximum daily dose of 450 IU and a total dose of 9000 IU over a 20-day period. The administration route is subcutaneous. This protein-based treatment is used as a comparator in the study.

**Follitropin Alfa** is provided as a powder and solvent for solution for injection, with similar dosing parameters to Follitropin Beta, including a maximum daily dose of 450 IU and a total dose of 9000 IU over 20 days. It is also administered subcutaneously and serves as a comparator in the trial.

**Ganirelix** is delivered as a solution for injection in a pre-filled syringe, with a maximum daily dose of 0.25 mg and a total dose of 3.75 mg over 15 days. The administration is subcutaneous, and it is used as a comparator in the study.

**Nafarelin** is administered as a nasal spray solution, with a maximum daily dose of 400 µg and a total dose of 6000 µg over a 15-day period. This protein-based treatment is used as a test product in the trial.

**Triptorelin** is provided as a solution for injection, with a maximum daily dose of 0.2 mg and a total dose of 0.2 mg over a single day. The administration route is subcutaneous, and it is used as a test product in the study.

**Choriogonadotropin Alfa** is administered as a solution for injection, with a maximum daily dose of 250 µg and a total dose of 250 µg over a single day. The administration is subcutaneous, and it is used as an auxiliary product in the trial.

**Cetrorelix** is delivered as a solution for injection, with a maximum daily dose of 0.25 mg and a total dose of 3.75 mg over 15 days. The administration route is subcutaneous, and it is used as an auxiliary product in the study.

Efficacy in this clinical trial will be assessed primarily through the measurement of live birth rates, defined as the presence of a live birth after 22 weeks of **amenorrhea**. Twin pregnancies will be counted as a single birth. Secondary endpoints include several parameters: embryo implantation, early pregnancy, clinical pregnancy, miscarriage before 12 weeks, ongoing pregnancy, pregnancy-related conditions such as hypertension and gestational diabetes, and ovarian hyperstimulation syndrome. Additionally, hormone levels of progesterone, estradiol, LH, and hCG will be monitored on the day of oocyte retrieval and on day 7 post-retrieval, as well as during follow-up. The number of oocytes collected, mature oocytes, fertilized oocytes, embryos on the second day of development, blastocysts obtained, transferred, and frozen will also be evaluated.

These efficacy parameters will be collected and analyzed at specific timepoints, including the first ultrasound between 5-8 weeks for embryo implantation, and hormone levels will be assessed 14 days after oocyte retrieval to confirm early pregnancy. The trial will utilize validated laboratory tests and ultrasound imaging to ensure accurate and reliable data collection. The study is designed to compare the efficacy of GnRH agonist induction and support with the reference protocol of hCG induction and luteal support with exogenous vaginal **progesterone** in in vitro fertilization (IVF) settings.