Comparison of Controlled Ovarian Stimulation with Corifollitropin Alfa versus Modified Natural Cycles in Subfertility Patients with Poor Ovarian Response

The primary objective of this study is to compare the probability of achieving at least one good quality **blastocyst** following controlled ovarian stimulation with corifollitropin alfa (CFA) versus a first modified natural cycle (MNC) in women with a clinical indication for assisted reproductive technology (ART) and an expected low response to ovarian stimulation. The clinical relevance of this objective lies in optimizing ART outcomes for subfertile women by identifying the most effective stimulation protocol, thereby potentially improving the success rates of achieving a viable pregnancy.

Secondary objectives include: - Comparing the probability of having at least one good quality blastocyst after CFA stimulation versus after a second or third MNC in the same patient population. - Evaluating one cycle of CFA against two or up to three MNCs concerning the relative number of blastocysts after ART, the probability of having at least one good quality blastocyst, the probability of achieving an ongoing pregnancy, and the time to ongoing pregnancy. - Assessing anti-Müllerian hormone (AMH) and antral follicle count (AFC) as treatment selection markers to predict ART treatment effects for individual subjects, aiming to tailor ART approaches to those most likely to benefit based on baseline AMH/AFC levels.

The clinical trial focuses on **subfertility** and involves a study population of women aged 18 to 44 years, with a body mass index (BMI) ranging from 18.5 to 34.9 kg/m². The participants are exclusively female, with no male subjects included, and do not belong to a vulnerable population. The trial targets women with a clinical indication for assisted reproductive technology (ART) who are expected to have a low response to ovarian stimulation, as defined by the POSEIDON classification groups 3 and 4. These groups include women under 35 years with poor ovarian reserve pre-stimulation parameters, such as an antral follicle count (AFC) of less than 5 or an anti-Müllerian hormone (AMH) level of less than 1.2 ng/ml, and women aged 35 years or older with similar parameters. Participants are required to have regular menstrual cycles, two ovaries, and a current desire for pregnancy, with the trial stipulating a single embryo transfer (SET). 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 **corifollitropin alfa** in comparison to modified natural cycles in women with subfertility and an expected low response to ovarian stimulation. This is a randomized, controlled, double-blind trial, ensuring that neither the participants nor the researchers know which treatment is being administered, thereby minimizing bias. The trial is expected to run from June 2022 to May 2026, with participant involvement lasting up to six months, depending on individual response and treatment cycles.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age, body mass index, and ovarian reserve parameters. This visit will also involve obtaining informed consent. Following the inclusion visit, participants will be randomized to receive either corifollitropin alfa or undergo up to three modified natural cycles. Regular follow-up visits will be scheduled to monitor ovarian response, collect data on the number and quality of blastocysts, and assess any adverse events. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted, including the evaluation of primary and secondary endpoints such as the probability of achieving a good quality blastocyst and ongoing pregnancy rates.

Participant involvement may be terminated early if criteria such as adverse reactions, withdrawal of consent, or non-compliance with the study protocol are met. The trial aims to provide valuable insights into the treatment of subfertility, with the primary endpoint being the probability of obtaining at least one good quality blastocyst, defined by the Gardner score, after assisted reproductive technology. Secondary endpoints include the relative number of blastocysts to oocytes and the probability of ongoing pregnancy confirmed by ultrasound.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Ovitrelle** is a solution for injection in a pre-filled syringe, containing **choriogonadotropin alfa** as the active substance. It is administered subcutaneously at a maximum daily dose of 250 micrograms, with a total maximum dose of 1500 micrograms over a treatment period of up to 6 weeks. The product is manufactured by Merck Europe B.V. and is not a paediatric formulation.

**Puregon** is another solution for injection, available in various concentrations, including 900 IU/1.08 mL, 600 IU/0.72 mL, 300 IU/0.36 mL, and 150 IU/0.18 mL. The active substance is **follitropin beta**, and it is administered subcutaneously. The maximum daily dose is 300 IU, with a total maximum dose of 54000 IU over a 6-week treatment period. This product is manufactured by N.V. Organon and is also not a paediatric formulation.

**Orgalutran** is a solution for injection containing **ganirelix** as the active substance. It is administered subcutaneously at a maximum daily dose of 0.25 mg, with a total maximum dose of 37.5 mg over a 6-week treatment period. This product is also manufactured by N.V. Organon and is not intended for paediatric use.

**Elonva** is a solution for injection containing **corifollitropin alfa**. It is administered subcutaneously with a maximum daily dose of 150 micrograms and a total maximum dose of 1800 micrograms over a 6-week treatment period. This product is manufactured by N.V. Organon and is not a paediatric formulation.

All medications in this trial are administered via the subcutaneous route, and participant compliance is monitored throughout the study. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Each medication is authorized for use in the European Union, with marketing authorization numbers provided for reference. The trial aims to evaluate the efficacy of these medications in achieving at least one good quality blastocyst in women with a clinical indication for assisted reproductive technology and an expected low response to ovarian stimulation.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint is the probability of having at least one good quality blastocyst after assisted reproductive technology (ART) on the day of embryo transfer, evaluated as a binary endpoint. Secondary endpoints include the relative number of blastocysts after ART relative to the number of oocytes, the probability of having at least one blastocyst of good quality after ART, and the probability of having an ongoing pregnancy defined as 6 to 8 weeks gestational age, confirmed by ultrasound.

The assessment of good quality blastocysts will be based on the Gardner score, specifically scores 5AA, 5AB, or 5BA. The trial will compare the efficacy of corifollitropin alfa (CFA) stimulation versus modified natural cycles (MNC) in women with a clinical indication for ART and an expected low response to ovarian stimulation. The trial is designed to evaluate these endpoints at specific timepoints, particularly on the day of embryo transfer, to determine the success of the treatment protocols.