Ovarian stimulation with follitropin delta for in vitro fertilization: a multicentre, randomized, assessor-blind comparison with follitropin alfa using conventional dosing regimens (ADAPT-1 trial).

study questionHow do ovarian responses using conventional dosing for follitropin delta 15 µg/day compare with follitropin alfa 225 IU/day in women undergoing ovarian stimulation? SUMMARY ANSWER: The ADAPT-1 trial demonstrates similar ovarian responses with follitropin delta 15 µg/day and follitropin alfa 225 IU/day starting doses in a conventional dosing regimen. WHAT IS KNOWN ALREADY: Follitropin delta, a recombinant FSH (rFSH), is currently approved for ovarian stimulation using an individualized fixed daily dose based on serum anti-Müllerian hormone (AMH) and bodyweight (maximum 12 µg/day for first cycle and 24 µg/day in subsequent cycles). Other rFSHs, such as follitropin alfa, conventionally apply a starting dose of 150-225 IU, fixed for the initial days of stimulation, after which dose adjustments can be made (maximum 450 IU/day). Ovarian stimulation with follitropin delta 10 µg/day provides a similar ovarian response to follitropin alfa 150 IU/day for serum concentration and number of follicles ≥12 mm. STUDY DESIGN, SIZE, DURATION: ADAPT-1 was a randomized, accessor-blinded, multicentre trial comparing efficacy and safety of a starting dose of follitropin delta 15 µg/day with follitropin alfa 225 IU/day in conventional dosing regimens. The primary endpoint was the number of oocytes retrieved; mean difference between treatment groups was estimated using a negative binomial regression model (treatment and serum AMH level as factors). During the follow-up period, clinical pregnancies resulting from the first fresh/frozen transfers within 3 months of the start of stimulation, and ovarian hyperstimulation syndrome (OHSS) rates were assessed. PARTICIPANTS/MATERIALS, SETTING,

methodsParticipants, 18-40 years, undergoing IVF/ICSI could enrol at specialist reproductive clinics in Austria, France, Italy, Spain, and the United Kingdom for ovarian stimulation if they had no contraindications for treatment with a starting gonadotropin dose of 225 IU/day. Patients could enrol if they reported infertility for at least 1 year if ≤37 years and at least 6 months for those >37 years, and regular menstrual cycles (21-35 days). All cycles used a GnRH antagonist protocol. MAIN RESULTS AND THE ROLE OF CHANCE: Between 1 August 2022 and 16 April 2024, 300 of 337 screened patients were randomized to, and received, follitropin delta (n = 200) or follitropin alfa (n = 100). The two treatment groups were comparable in terms of demographics, baseline characteristics, and duration of infertility. The mean duration of treatment was ∼9 days in both groups. The mean total dose of follitropin delta was 143.7 ± 33.6 µg and 154.3 ± 23.1 µg (2105 ± 315 IU) for follitropin alfa. Three-quarters (226/300) used an human Chorionic Gonadotropin trigger for final follicular maturation. A mean of 9.9 oocytes was retrieved for both groups (estimated difference: 0.0 oocytes; 95% CI -1.3, 1.2). The category of 8-14 oocytes retrieved was the most common ovarian response (follitropin delta: 45.5%; follitropin alfa: 50.0%). Clinical pregnancy rates were comparable (31.6% and 31.0%; estimated difference 0.6 (95% CI -10.6, 11.8)). Early OHSS (≤9 days after triggering) occurred in 2.5% and 3.0%, and all cases were Grade 3 (moderate) or lower. No participant had the stimulation cycle cancelled due to excessive ovarian response. LIMITATIONS, REASONS FOR CAUTION: Only pregnancies from the first fresh or cryopreserved transfer within 3 months of oocyte retrieval were recorded. Cumulative pregnancy rates after the first transfer were not followed up. All analyses are of descriptive nature and no formal hypothesis testing or multiplicity adjustment was applied. WIDER IMPLICATIONS OF THE

findingsTreatment groups had similar ovarian responses, supporting equivalence for starting doses follitropin delta 15 µg and follitropin alfa 225 IU, with low rates of early OHSS. Ovarian stimulation cycles with follitropin delta in µg can be planned and adjusted, leveraging the established IU dose equivalence to follitropin alfa. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by Ferring Pharmaceuticals A/S, Kastrup, Denmark. Medical writing support for manuscript development was provided by Celia J. Parkyn, PhD, and was funded by Ferring Pharmaceuticals A/S, Kastrup, Denmark. P.Z. and R.A. have none. A.B. has received grants from Gedeon Richter, IBSA, GP Pharm & Seid, Miguel Hernandez University, Centre for Technological Development and Innovation, Valencian Innovation Agency, Regional Secretary for Industry, Trade and Consumption, and the Government Ministry of Industry and Tourism; payments from University Complutense of Madrid, Ferring Pharmaceuticals, Fentypharm, Miguel Hernandez University, Gedeon Richter, & Vall d'Hebron Hospital; travel support from Ferring Pharmaceuticals, Fentypharm, Gedeon Richter, International ESHRE Congress Organising Committee, Spanish Society of Gynaecology and Obstetrics, CROG Congress Organising Committee, & Vall d'Hebron Hospital; has a patent pending for Sperm plate (U202431456); and is Chair of the Organising Committee of the Infertility and Sterility Section of the Spanish Society of Gynaecologist (non-paid role) and equipment from Obstetrics; & equipment from Cook Medical. J.S. has received consulting fees from Ferring Pharmaceuticals. E.P. has received grants from Merck, Ferring, Theramex, Gedeon Richter, IBSA, and Organon; payments from Merck, Ferring, IBSA, and Organon; travel support from Merck, IBSA, Organon, Theramex, and Ferring; and participated in a Safety Monitoring Board or Advisory Board for Merck. M.G.S. has received patient medication from Ferring; payments from Ferring, Merck for educational events; and travel support from Ferring, Merck, Theramex, and IBSA. R.L. and S.M. are employees of Ferring Pharmaceuticals. I.E.J. was an employee of Ferring Pharmaceuticals at the time of the trial conduct. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT05263388; Eudract 2021-001785-38. TRIAL REGISTRATION DATE: 16 November 2021 (clinicaltrials.gov); 5 August 2021 (Eudract). DATE OF FIRST PATIENT’S ENROLMENT: 1 August 2022.