Evaluation of Luteal Phase Ovarian Stimulation with Follitropin Delta and Dydrogesterone in Oocyte Donors: A Randomized Crossover Pilot Study

The primary objective of this study is to evaluate the effect of **FE 999049** on the number of cumulus-oocyte complexes (COCs) in oocyte donors. This is assessed when a Primed Progestin Ovarian Stimulation (PPOS) protocol is associated with both conventional follicular phase stimulation and Luteal phase Ovarian Stimulation (LPOS) protocol. The clinical relevance of this objective lies in optimizing ovarian stimulation protocols to potentially enhance the yield of COCs, which is crucial for successful oocyte donation and subsequent fertility treatments.

Secondary objectives include determining whether LPOS using the PPOS protocol has comparable outcomes to conventional follicular phase stimulation with the PPOS protocol in oocyte donor patients. This comparison is important for understanding the efficacy and potential benefits of different ovarian stimulation strategies in the context of oocyte donation.

The clinical trial involves a study population of **voluntary women** who wish to donate their oocytes. The participants are exclusively female, with an age range from 18 to 36 years. The trial does not include a vulnerable population. Participants are required to have a **Body Mass Index (BMI)** between 18 and less than 28, and they must have a regular menstrual cycle length of 24 to 35 days. All participants have provided signed informed consent. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the participants are in general good health, with no significant lifestyle considerations such as diet or physical activity explicitly mentioned. The trial population was selected based on specific inclusion criteria, including age, BMI, and menstrual cycle regularity, to evaluate the effect of FE 999049 on the number of cumulus-oocyte complexes in oocyte donors.

The clinical trial is designed to evaluate the effect of **follitropin delta** on the number of cumulus-oocyte complexes (COCs) in oocyte donors using a Primed Progestin Ovarian Stimulation (PPOS) protocol. This study is a randomized, cross-over pilot trial, categorized as low interventional, and involves the administration of **follitropin delta** and **dydrogesterone**. The trial is expected to run from December 2022 to June 2026, with the primary endpoint being the total number of retrieved COCs. Secondary endpoints include the endocrine profile in both treatment groups, consumption of gonadotrophins, duration of ovarian stimulation, days of progestin use, and the total number of MII oocytes.

Participants will be involved in the study for a maximum treatment period of 15 days for **follitropin delta** and 10 days for **dydrogesterone**. The trial includes several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-36 years), BMI (18-28), signed informed consent, and regular menstrual cycle length (24-35 days). Follow-up visits will monitor the administration of the investigational products and assess the primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants may be terminated early from the study if they do not adhere to the protocol, experience adverse effects, or withdraw consent. The trial employs a double-blind, controlled design to ensure unbiased results. The investigational products, **REKOVELLE** and **Duphaston**, are administered via subcutaneous and oral routes, respectively. The study aims to provide valuable insights into the efficacy of the PPOS protocol in enhancing oocyte retrieval outcomes in voluntary oocyte donors.

The clinical trial involves the administration of **REKOVELLE**, a solution for injection containing the active substance **follitropin delta**. This medication is provided in pre-filled pens with varying concentrations: 36 micrograms/1.08 mL, 12 micrograms/0.36 mL, and 72 micrograms/2.16 mL. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous. The maximum daily dose is 12 micrograms, with a total maximum dose of 180 micrograms over a treatment period of up to 15 days. The medication is manufactured by Ferring Pharmaceuticals A/S and is not a paediatric formulation.

Additionally, the trial includes the use of **Duphaston**, which contains the active substance **dydrogesterone**. This medication is available in film-coated tablet form, with each tablet containing 10 mg of dydrogesterone. The tablets are administered orally, with a maximum daily dose of 20 mg and a total maximum dose of 200 mg over a treatment period of up to 10 days. Duphaston is manufactured by Theramex Ireland Limited and is also not a paediatric formulation.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the effect of these medications on the number of cumulus-oocyte complexes in oocyte donors, utilizing both conventional follicular phase stimulation and luteal phase ovarian stimulation protocols.

The efficacy of the clinical trial will be assessed by evaluating the effect of **Follitropin delta** on the number of cumulus-oocyte complexes (COCs) retrieved when a Primed Progestin Ovarian Stimulation (PPOS) protocol is associated with both conventional follicular phase stimulation and Luteal phase Ovarian Stimulation (LPOS) protocol in oocyte donors. The primary endpoint for efficacy assessment is the total number of retrieved COCs. Secondary endpoints include the endocrine profile in both treatment groups, consumption of gonadotrophins measured in micrograms, duration of ovarian stimulation, days of progestin use, and the total number of MII oocytes.