Luteal Phase Ovarian Stimulation With Follitropin Delta and Dydrogesterone

NCT05521828 | Recruiting DMC

• 1 other identifier: CS-10459
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The last decade has shown a progressive scientific interest for new strategies to improve the outcomes of controlled ovarian stimulation (COS). Given the fact that interovulatory period has been described to have multiple waves of follicular recruitment, luteal phase ovarian stimulation (LPOS) has been proposed as new protocol for COS, with satisfactory ovarian response and pregnancy outcomes. On the other hand progestin-primed ovarian stimulation (PPOS) is today considered an innovative protocol aiming to achieve multi-follicle recruitment and block the luteinizing hormone (LH) surge through progesterone administration in place of the traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist. This protocol has been shown to be equally effective as LH suppression with GnRH antagonist reporting equivalent oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes. Due to the feasibility and patients-friendly characteristics of PPOS in oocytes donors, the current study aims to investigate the impact on the number of cumulus-oocyte complexes (COCs) when a PPOS protocol is associated to both conventional follicular phase stimulation and LPOS for vitrification of oocytes in oocyte donors. Moreover, it aims to determine whether LPOS using PPOS protocol has comparable outcomes to conventional follicular phase stimulation with PPOS protocol, in oocyte donor patients.

Conditions

Oocyte Donors; Oocyte Donation

Keywords

cumulus-oocyte complexes; progestin primed ovarian stimulation; controlled ovarian stimulation; luteal phase ovarian stimulation; follicular phase ovarian stimulation; follitropin delta; dydrogesterone

Outcome Measures

Primary Outcomes (1)

• number of retrieved COCs in both treatment groups

  number of retrieved cumulus-oocyte complexes

  10-20 minutes after oocyte retrieval

Secondary Outcomes (5)

• Endocrine profile in both treatment groups

  through study completion, an average of 1 year

• Consumption of gonadotrophins in both treatment groups

  through study completion, an average of 1 year

• Duration of ovarian stimulation in both treatment groups

  through study completion, an average of 1 year

• Days of progestin use in both treatment groups

  through study completion, an average of 1 year

• Total number of MII oocytes in both treatment groups

  1-2 hours after oocyte retrieval

Study Arms (2)

Follitropin delta and dydrogesterone (treatment A followed by treatment B)

OTHER

Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH \> 10 IU/L until day of trigger. For both treatment (A and B) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles \>20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated.

Drug: Follitropin delta (Rekovelle); Drug: Duphaston; Drug: GnRH agonist (Gonapeptyl)

Follitropin delta and dydrogesterone (treatment B followed by treatment A)

OTHER

Treatment B: From day 20 of the menstrual cycle onwards, daily subcutaneous injections of Follitropin delta (Rekovelle) 12 mcg/daily will be administered. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 or when serum LH \> 10 IU/L until day of trigger. Treatment A: Ovarian stimulation is started with daily subcutaneous injections of Follitropin delta12 mcg/daily (Rekovelle) from day 2 of the follicular phase onwards. Dydrogesterone (Duphaston) 20mg/day will be initiated on stimulation day 7 until the criteria for oocyte trigger are achieved. For both treatment (B and A) oocyte maturation trigger will be planned when transvaginal ultrasound shows at least 3 follicles \>20mm in diameter with a single subcutaneous injection of GnRH agonist (Gonapeptyl 0.2 mg). Oocyte retrieval will be performed 36 hours after trigger. The retrieved cumulus oocyte complexes will be counted, denuded and the number of mature oocytes evaluated.

Drug: Follitropin delta (Rekovelle); Drug: Duphaston; Drug: GnRH agonist (Gonapeptyl)

Interventions

Follitropin delta (Rekovelle) DRUG

12 mcg/day will be used for ovarian stimulation in both arms

Follitropin delta and dydrogesterone (treatment A followed by treatment B); Follitropin delta and dydrogesterone (treatment B followed by treatment A)

Duphaston DRUG

20 mg/day will be used for pituitary suppression in both arms

Follitropin delta and dydrogesterone (treatment A followed by treatment B); Follitropin delta and dydrogesterone (treatment B followed by treatment A)

GnRH agonist (Gonapeptyl) DRUG

(2 ampules:0.2 mg) will be used for ovulation triggering in both arms

Follitropin delta and dydrogesterone (treatment A followed by treatment B); Follitropin delta and dydrogesterone (treatment B followed by treatment A)

Eligibility Criteria

• Age: 18 Years - 36 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Body mass Index (BMI) ≥18 to \< 28
• Signed informed consent
• Regular menstrual cycle length i.e. 24-35 days

You may not qualify if:

• Contraindications to the use of gonadotropins
• Endometriosis grade 3-4
• Patients with Anti-mullerian hormone (AMH) \<1.1 ng/ml and/or antral follicular count (AFC)\<7
• Patients with Follicle Number Per Ovary (FNPO) ≥ 19 and/or AMH \>5ng/ml
• Patients under contraception with hormonal intrauterine device (IUD)
• Any untreated endocrine abnormality

Sponsors & Collaborators

• CRG UZ Brussel: lead

Study Sites (1)

Brussels Ivf

Brussels, 1090, Belgium

RECRUITING

Related Publications (19)

• Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update. 2012 Jan-Feb;18(1):73-91. doi: 10.1093/humupd/dmr039. Epub 2011 Nov 8.

  PMID: 22068695 BACKGROUND

• Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003 Jul;80(1):116-22. doi: 10.1016/s0015-0282(03)00544-2.

  PMID: 12849812 BACKGROUND

• Bosch E, Havelock J, Martin FS, Rasmussen BB, Klein BM, Mannaerts B, Arce JC; ESTHER-2 Study Group. Follitropin delta in repeated ovarian stimulation for IVF: a controlled, assessor-blind Phase 3 safety trial. Reprod Biomed Online. 2019 Feb;38(2):195-205. doi: 10.1016/j.rbmo.2018.10.012. Epub 2018 Dec 14.

  PMID: 30594482 BACKGROUND

• Cakmak H, Tran ND, Zamah AM, Cedars MI, Rosen MP. A novel "delayed start" protocol with gonadotropin-releasing hormone antagonist improves outcomes in poor responders. Fertil Steril. 2014 May;101(5):1308-14. doi: 10.1016/j.fertnstert.2014.01.050. Epub 2014 Mar 14.

  PMID: 24636401 BACKGROUND

• Chian RC, Chung JT, Downey BR, Tan SL. Maturational and developmental competence of immature oocytes retrieved from bovine ovaries at different phases of folliculogenesis. Reprod Biomed Online. 2002 Mar-Apr;4(2):127-32. doi: 10.1016/s1472-6483(10)61929-3.

  PMID: 12470574 BACKGROUND

• Cummins JM, Breen TM, Harrison KL, Shaw JM, Wilson LM, Hennessey JF. A formula for scoring human embryo growth rates in in vitro fertilization: its value in predicting pregnancy and in comparison with visual estimates of embryo quality. J In Vitro Fert Embryo Transf. 1986 Oct;3(5):284-95. doi: 10.1007/BF01133388.

  PMID: 3783014 BACKGROUND

• Demirtas E, Elizur SE, Holzer H, Gidoni Y, Son WY, Chian RC, Tan SL. Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients. Reprod Biomed Online. 2008 Oct;17(4):520-3. doi: 10.1016/s1472-6483(10)60239-8.

  PMID: 18854106 BACKGROUND

• Fernandez-Sanchez M, Visnova H, Yuzpe A, Klein BM, Mannaerts B, Arce JC; ESTHER-1 and ESTHER-2 Study Group. Individualization of the starting dose of follitropin delta reduces the overall OHSS risk and/or the need for additional preventive interventions: cumulative data over three stimulation cycles. Reprod Biomed Online. 2019 Apr;38(4):528-537. doi: 10.1016/j.rbmo.2018.12.032. Epub 2018 Dec 23.

  PMID: 30713022 BACKGROUND

• Giles J, Alama P, Gamiz P, Vidal C, Badia P, Pellicer A, Bosch E. Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial. Fertil Steril. 2021 Aug;116(2):404-412. doi: 10.1016/j.fertnstert.2021.02.036. Epub 2021 Apr 2.

  PMID: 33814126 BACKGROUND

• Guan S, Feng Y, Huang Y, Huang J. Progestin-Primed Ovarian Stimulation Protocol for Patients in Assisted Reproductive Technology: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne). 2021 Aug 31;12:702558. doi: 10.3389/fendo.2021.702558. eCollection 2021.

  PMID: 34531825 BACKGROUND

• Ioannidou PG, Bosdou JK, Lainas GT, Lainas TG, Grimbizis GF, Kolibianakis EM. How frequent is severe ovarian hyperstimulation syndrome after GnRH agonist triggering in high-risk women? A systematic review and meta-analysis. Reprod Biomed Online. 2021 Mar;42(3):635-650. doi: 10.1016/j.rbmo.2020.11.008. Epub 2020 Nov 28.

  PMID: 33483281 BACKGROUND

• Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014 Dec;29(6):684-91. doi: 10.1016/j.rbmo.2014.08.009. Epub 2014 Sep 6.

  PMID: 25444501 BACKGROUND

• Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, Shoham Z. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. 2014 Jan;101(1):105-11. doi: 10.1016/j.fertnstert.2013.09.007. Epub 2013 Oct 23.

  PMID: 24161646 BACKGROUND

• Maman E, Meirow D, Brengauz M, Raanani H, Dor J, Hourvitz A. Luteal phase oocyte retrieval and in vitro maturation is an optional procedure for urgent fertility preservation. Fertil Steril. 2011 Jan;95(1):64-7. doi: 10.1016/j.fertnstert.2010.06.064. Epub 2010 Aug 5.

  PMID: 20688325 BACKGROUND

• McNatty KP, Hillier SG, van den Boogaard AM, Trimbos-Kemper TC, Reichert LE Jr, van Hall EV. Follicular development during the luteal phase of the human menstrual cycle. J Clin Endocrinol Metab. 1983 May;56(5):1022-31. doi: 10.1210/jcem-56-5-1022.

  PMID: 6403567 BACKGROUND

• Nyboe Andersen A, Nelson SM, Fauser BC, Garcia-Velasco JA, Klein BM, Arce JC; ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 Feb;107(2):387-396.e4. doi: 10.1016/j.fertnstert.2016.10.033. Epub 2016 Nov 29.

  PMID: 27912901 BACKGROUND

• Qiao J, Zhang Y, Liang X, Ho T, Huang HY, Kim SH, Goethberg M, Mannaerts B, Arce JC. A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients. Hum Reprod. 2021 Aug 18;36(9):2452-2462. doi: 10.1093/humrep/deab155.

  PMID: 34179971 BACKGROUND

• Yildiz S, Turkgeldi E, Angun B, Eraslan A, Urman B, Ata B. Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology. Fertil Steril. 2019 Oct;112(4):677-683. doi: 10.1016/j.fertnstert.2019.06.009. Epub 2019 Jul 29.

  PMID: 31371053 BACKGROUND

• Yu S, Long H, Chang HY, Liu Y, Gao H, Zhu J, Quan X, Lyu Q, Kuang Y, Ai A. New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles. Hum Reprod. 2018 Feb 1;33(2):229-237. doi: 10.1093/humrep/dex367.

  PMID: 29300975 BACKGROUND

MeSH Terms

Interventions

follitropin delta; Dydrogesterone; Gonadotropin-Releasing Hormone

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Christophe Blockeel, Prof, MD

  Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium

  STUDY DIRECTOR

Central Study Contacts

Christophe Blockeel, Prof, MD

CONTACT

+ 32 2 4776699; Christophe.Blockeel@uzbrussel.be

Elsie Nulens

CONTACT

Elsie.Nulens@uzbrussel.be

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: August 25, 2022
• First Posted: August 30, 2022
• Study Start: April 1, 2023
• Primary Completion: September 30, 2024
• Study Completion: December 31, 2024
• Last Updated: February 8, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)