MIcronized PROgesterone in Frozen Embryo Transfer Cycles

Infertility Clinical Trial

— MI-PROF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05899010
• Other study ID #: FSD-MIC-2022-03
• Secondary ID: 2022-001045-21
• Status: Recruiting
• Phase: Phase 3
• Start date: July 5, 2023
• Est. completion date: April 2026

Study information

• Verified date: July 2023
• Source: Institut Universitari Dexeus
• Contact: Nikolaos P Polyzos, MD, PhD
• Phone: 0034932274700
• Email: nikpol[@]dexeus.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1020
• Est. completion date: April 2026
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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).

Related Conditions & MeSH terms

• Infertility

Intervention

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 <10ng/ml, additional 300mg daily oral micronized progesterone is administered on the day of the ET and maintained until 10 weeks pregnancy or up to menses or up to negative pregnancy test 10 days after ET. ET will be performed with available blastocysts 6 days after start of LPS. 3-5 days, after ET, a blood test for P measurement will be performed in the morning, before VMP dose, or at least 6h after last progesterone dose. 10 days after ET, the last P test will be done with pregnancy test.
• 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 <10ng/ml, additional 300mg daily oral micronized progesterone is administered on the day of the ET and maintained until 10 weeks pregnancy or up to menses or up to negative pregnancy test 10 days after ET. ET will be performed with available blastocysts 6 days after start of LPS. 3-5 days, after ET, a blood test for P measurement will be performed in the morning, before VMP dose, or at least 6h after last progesterone dose. 10 days after ET, the last P test will be done with pregnancy test.

Locations

Country	Name	City	State
Spain	Hospital Universitario Quiron Dexeus	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundación Santiago Dexeus Font

Country where clinical trial is conducted

Spain, 

References & Publications (12)

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. Erratum In: Hum Reprod Open. 2020 Sep 22;2020(3):hoaa038. — View Citation

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. — View Citation

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. — View Citation

Griesinger G, Blockeel C, Sukhikh GT, Patki A, Dhorepatil B, Yang DZ, Chen ZJ, Kahler E, Pexman-Fieth C, Tournaye H. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018 Dec 1;33(12):2212-2221. doi: 10.1093/humrep/dey306. — View Citation

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. 2016 Jul;31(7):1483-92. doi: 10.1093/humrep/dew120. Epub 2016 May 13. — View Citation

Groenewoud ER, Cohlen BJ, Macklon NS. Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles. Fertil Steril. 2018 May;109(5):768-774. doi: 10.1016/j.fertnstert.2018.02.135. — View Citation

Nawroth F, Ludwig M. What is the 'ideal' duration of progesterone supplementation before the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement protocols? Hum Reprod. 2005 May;20(5):1127-34. doi: 10.1093/humrep/deh762. Epub 2005 Feb 3. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: N Engl J Med. 2021 Nov 4;385(19):1824. — View Citation

Vaisbuch E, de Ziegler D, Leong M, Weissman A, Shoham Z. Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online. 2014 Mar;28(3):330-5. doi: 10.1016/j.rbmo.2013.10.022. Epub 2013 Nov 14. — View Citation

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/S0140-6736(18)32843-5. Epub 2019 Feb 28. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ongoing pregnancy rate	A positive heart beat at ultrasound after 11-13 weeks of gestation	7-9 weeks after embryo transfer
Secondary	Implantation rate	Number of gestational sacs over total embryo transfered	3-4 weeks after embryo transfer
Secondary	Biochemical pregnancy rate	positive beta-human chorionic gonadotropin (hCG)	10 to 12 days after embryo transfer
Secondary	Clinical pregnancy rate	A positive heart beat at ultrasound	3-4 weeks after embryo transfer
Secondary	Miscarriage rate	any spontaneous abortion that occurred after confirmation of clinical pregnancy	before completion of 12 weeks of gestation
Secondary	Frequency of adverse events		Until 15 days after the end of treatment with progesterone

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