MIcronized PROgesterone in Frozen Embryo Transfer Cycles

Official title

A Phase III Randomized Controlled Trial Comparing the Efficacy, Safety and Tolerability of Two Formulations of Vaginal Micronized Progesterone

Overview

This randomized trial was designed as non-inferiority trial aiming to compare ongoing pregnancy rates following LPS with 600 mg/day vs 800 mg/day vaginal VMP. All patients will undergo an artificial cycle frozen embryo transfer (AC-FET) with transdermal estradiol 6mg/day Patients undergoing an artificial cycle FET will start estrogen priming with transdermal estradiol 6mg/day (Estrogel®) on cycle D1-D3. Following 10-12 days of estrogen priming, patients will be randomized to luteal phase support with a standard formulation (200mg tid, Utrogestan®) or a new formulation (400mg bid) VMP. All patients will undergo a serum P measurement on the day before embryo transfer (ET). Patients with P\<10 ng/ml will receive a supplement of oral micronized progesterone 300mg, while patients with P≥10ng/ml will maintain the previous luteal phase support (LPS) protocol

Interventions

• Drug Vaginal progesterone 600mg daily
  If endometrial thickness (ETH) ≥7 mm and follicle dominance/ultrasound (US) signs of ovulation P levels are measured: if P ≤1.5 patients start LPS, else cycle is cancelled. If ETH \<7mm and no follicle dominance: estradiol dose is increased to 9mg/day and new US is performed up to 4 days after. If persistent thin endometrium after dose increase, cycle is cancelled. 24-48h pre ET, E2 and P are measured. in the morning, pre VMP dose, or at least 6h after last progesterone dose. If progesterone \<1
• Drug Vaginal progesterone 800mg daily
  If endometrial thickness (ETH) ≥7 mm and follicle dominance/ultrasound (US) signs of ovulation P levels are measured: if P ≤1.5 patients start LPS, else cycle is cancelled. If ETH \<7mm and no follicle dominance: estradiol dose is increased to 9mg/day and new US is performed up to 4 days after. If persistent thin endometrium after dose increase, cycle is cancelled. 24-48h pre ET, E2 and P are measured. in the morning, pre VMP dose, or at least 6h after last progesterone dose. If progesterone \<1

Primary outcome measures

• Ongoing pregnancy rate [Time frame: 7-9 weeks after embryo transfer]

Secondary outcome measures (5)

• Implantation rate [Time frame: 3-4 weeks after embryo transfer]
• Biochemical pregnancy rate [Time frame: 10 to 12 days after embryo transfer]
• Clinical pregnancy rate [Time frame: 3-4 weeks after embryo transfer]
• Miscarriage rate [Time frame: before completion of 12 weeks of gestation]
• Frequency of adverse events [Time frame: Until 15 days after the end of treatment with progesterone]

Eligibility criteria

Inclusion criteria

• Endometrial preparation with hormone replacement therapy
• Age 18-43 years following an autologous IVF cycle (with or without preimplantation genetic testing for aneuploidy)
• Age < 50 years following an egg donation cycle
• BMI > 18 and < 30 kg/m2
• blastocyst embryo transfer
• Willing to participate in the study
• Able to come to the Center to comply with the procedures of the study: blood tests, appointments and drug dispensation.

Exlusion Criteria:

• • Uterine diseases (e.g. submucosal fibroids, polyps, previously diagnosed Müllerian abnormalities)
• Hydrosalpinx
• Recurrent pregnancy loss (≥ 3 previous miscarriages)
• Recurrent implantation failure (≥ 3 previously failed embryo transfers of good-quality blastocysts)
• Allergy to study medication
• Pregnancy or lactation
• Contraindication for hormonal treatment
• Personalized initiation of exogenous progesterone according to a previous endometrial receptivity assay test
• Recent history of severe disease requiring regular treatment (clinically significant concurrent medical condition that could compromise subject safety or interfere with the trial assessment).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 1 center

• Hospital Universitario Quiron Dexeus — Barcelona

Publications

• De Geyter C, Calhaz-Jorge C, Kupka MS, Wyns C, Mocanu E, Motrenko T, Scaravelli G, Smeenk J, Vidakovic S, Goossens V; European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe, 2015: results generated from European registries by ESHRE. Hum Reprod Open. 2020 Feb 24;2020(1):hoz038. doi: 10.1093/hropen/hoz038. eCollection 2020. PMID 32123753
• Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011 Oct;26(10):2593-7. doi: 10.1093/humrep/der251. Epub 2011 Aug 9. PMID 21828116
• Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, Vanderpoel S, Racowsky C. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017 Mar 1;23(2):139-155. doi: 10.1093/humupd/dmw038. PMID 27827818
• Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018 Jan 11;378(2):126-136. doi: 10.1056/NEJMoa1705334. PMID 29320646
• Wei D, Liu JY, Sun Y, Shi Y, Zhang B, Liu JQ, Tan J, Liang X, Cao Y, Wang Z, Qin Y, Zhao H, Zhou Y, Ren H, Hao G, Ling X, Zhao J, Zhang Y, Qi X, Zhang L, Deng X, Chen X, Zhu Y, Wang X, Tian LF, Lv Q, Ma X, Zhang H, Legro RS, Chen ZJ. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019 Mar 30;393(10178):1310-1318. doi: 10.1016/ PMID 30827784
• Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019 Jan 1;25(1):2-14. doi: 10.1093/humupd/dmy033. PMID 30388233
• Groenewoud ER, Cohlen BJ, Al-Oraiby A, Brinkhuis EA, Broekmans FJ, de Bruin JP, van den Dool G, Fleisher K, Friederich J, Goddijn M, Hoek A, Hoozemans DA, Kaaijk EM, Koks CA, Laven JS, van der Linden PJ, Manger AP, Slappendel E, Spinder T, Kollen BJ, Macklon NS. A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer. Hum Reprod. 2 PMID 27179265
• Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017 Jul 5;7(7):CD003414. doi: 10.1002/14651858.CD003414.pub3. PMID 28675921

Identifiers

NCT: NCT05899010 · FSD-MIC-2022-03 · 2022-001045-21

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗