Progesterone Versus Progesterone Plus Dydrogesterone in FET

Infertility Clinical Trial

— MiDRONE  

Official title:

Micronized Progesterone Versus Micronized Progesterone Plus Dydrogesterone for Luteal Phase Support in Frozen - Thawed Transfer: a Prospective Cohort Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03998761
• Other study ID #: CS/BVMÐ/19/06
• Status: Completed
• Phase: N/A
• Start date: June 26, 2019
• Est. completion date: January 31, 2021

Study information

• Verified date: February 2021
• Source: M? Ð?c Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Frozen embryo transfer (FET) has been increasing important in IVF. Progesterone is essential for the endometrial secretory transformation, establishment and maintenance of pregnancy. In FET, as there is neither corpus luteum nor the support of hCG, the role of progesterone is even more important to ensure a sufficient luteal phase support.

Vaginal progesterone has been the most common preparation for luteal support in fresh embryo transfer during IVF because of their ease of use and comparable effectiveness compared to intramuscular progesterone. Recently, there was evidence of the considerable variation in uptake, absorption and metabolism of intra-vaginal micronized progesterone. Dydrogesterone alone has described to have similar effectiveness, safety and tolerability prolfiles for luteal phase support compared to vaginal progesterone in luteal phase support for fresh embryo transfer. This prospective study compares the effectiveness of micronized progesterone versus micronized progesterone plus dydrogesterone for luteal phase support in FET.

Description:

All patients undergoing FET will receive oral estradiol valerate (Valiera®; Laboratories Recalcine) 8 mg/day from the second or third day of menses for 6 days. Endometrial thickness will be monitored from day six onwards. From day 8-9 of menses, the estradiol dose could be adjusted from 8mg/day to 16mg/day according the development of the endometrium. Progesterone will be started when endometrial thickness reached 8 mm or more. In the first four months, all the patients will be treated with micronized progesterone. In five months later, the intervention will be changed to micronized progesterone plus dydrogesterone. In the second group of patients, the duration of study will be extended for one month due to the Lunar New Year holiday.

Group 1: Micronized progesterone Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening).

Group 2: Micronized progesterone plus dydrogesterone Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening) plus dydrogesterone (Duphaston 10mg) at the dose of 10mg twice daily (morning and evening).

In both group, on the day of starting progesterone, the dose of estradiol will be decreased to 8mg/day. A maximum of 2 embryos will be thawed on the day of embryo transfer, which is four days or six days after the start of progesterone depending on day-3 or day-5 embryo transfer. After thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. Estradiol and progesterone will be continued until the day of pregnancy test. If the pregnancy test is positive, the patients will continue to use 800 mg micronized progesterone or 800 mg micronized progesterone plus 20 mg dydrogestetrone, until 7 weeks of gestation.

Blood samples will be obtained at day 4 after the use of progesterone. Serum progesterone will be measured. The blood tests will be taken in the morning, 2-3 h after the dydrogesterone and/or micronized progesterone application.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1364
• Est. completion date: January 31, 2021
• Est. primary completion date: January 5, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Undergoing frozen embryo transfer

• Endometrial prepared by exogenous hormonal regimen

• Permanent resident in Vietnam

Exclusion Criteria:

• Having > 2 embryo transfer attempts

• Having embryo(s) from donors cycles

• Having embryo(s) from IVM

• Having embryo(s) from PGT/PGS

• Having endometrial abnormalities: polyp, sub-mucosal fibroid, cesarean scar defects, endometrial hyperplasia, endometrial fluid accumulation, endometrial adhesion.

• Participating in another IVF study at the same time

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• Micronized Progesterone
Progesterone will be started when endometrial thickness reached 8 mm or more. Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening). A maximum of 2 embryos will be thawed on the day of embryo transfer, which is four days or six days after the start of progesterone depending on day-3 or day-5 embryo transfer. After thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. Estradiol and progesterone will be continued until the day of pregnancy test. If the pregnancy test is positive, the patients will continue to use 800 mg micronized progesterone until 7 weeks of gestation.
• Micronized progesterone plus dydrogesterone
Progesterone will be started when endometrial thickness reached 8 mm or more. Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening) plus dydrogesterone (Duphaston® 10mg, Abbott) at the dose of 10mg twice daily (morning and evening). A maximum of 2 embryos will be thawed on the day of embryo transfer, which is four days or six days after the start of progesterone depending on day-3 or day-5 embryo transfer. After thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. Estradiol and progesterone will be continued until the day of pregnancy test. If the pregnancy test is positive, the patients will continue to use 800 mg micronized progesterone plus 20 mg dydrogestetrone until 7 weeks of gestation.

Locations

Country	Name	City	State
Vietnam	M? Ð?c Hospital	Ho Chi Minh City	Tan Binh

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

Country where clinical trial is conducted

Vietnam, 

References & Publications (9)

Barbosa MW, Silva LR, Navarro PA, Ferriani RA, Nastri CO, Martins WP. Dydrogesterone vs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2016 Aug;48(2):161-70. doi: 10.1002/uog.15814. Epub 2016 Jul 8. Review. — 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

Griesinger G, Blockeel C, Tournaye H. Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Fertil Steril. 2018 May;109(5):756-762. doi: 10.1016/j.fertnstert.2018.03.034. Review. — View Citation

Labarta E, Mariani G, Holtmann N, Celada P, Remohí J, Bosch E. Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2017 Dec 1;32(12):2437-2442. doi: 10.1093/humrep/dex316. Erratum in: Hum Reprod. 2018 Jan 1;33(1):178. — View Citation

Tournaye H, Sukhikh GT, Kahler E, Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017 May 1;32(5):1019-1027. doi: 10.1093/humrep/dex023. Erratum in: Hum Reprod. 2017 Oct 1;32(10):2152. — View Citation

Wang Y, He Y, Zhao X, Ji X, Hong Y, Wang Y, Zhu Q, Xu B, Sun Y. Crinone Gel for Luteal Phase Support in Frozen-Thawed Embryo Transfer Cycles: A Prospective Randomized Clinical Trial in the Chinese Population. PLoS One. 2015 Jul 29;10(7):e0133027. doi: 10.1371/journal.pone.0133027. eCollection 2015. — 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

Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein M. Crinone vaginal gel is equally effective and better tolerated than intramuscular progesterone for luteal phase support in in vitro fertilization-embryo transfer cycles: a prospective randomized study. Fertil Steril. 2010 Dec;94(7):2596-9. doi: 10.1016/j.fertnstert.2010.02.033. Epub 2010 Mar 27. — View Citation

Yovich JL, Conceicao JL, Stanger JD, Hinchliffe PM, Keane KN. Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement. Reprod Biomed Online. 2015 Aug;31(2):180-91. doi: 10.1016/j.rbmo.2015.05.005. Epub 2015 May 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Live birth rate	The birth of at least one newborn after 24 weeks of gestation that exhibits any sign of life such as respiration, heartbeat, umbilical pulsation or movement of voluntary muscles (twin will be a single count).	At least 24 weeks of gestation up to the time of delivery
Secondary	The luteal progesterone level	The progesterone level in serum on day four after the progesterone application	On day four of the progesterone application
Secondary	The length of luteal phase	Starting on the day of progesterone application and ending on the last day prior menses	On day sixteen of progesterone application
Secondary	Positive pregnancy test rate	Serum human chorionic gonadotropin level greater than 5 mIU/mL after the completion of the first transfer	On day sixteen of progesterone application
Secondary	Clinical pregnancy rate	At least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity after the completion of the first transfer	At 7 weeks of gestation
Secondary	Ongoing pregnancy rate	Pregnancy with detectable heart rate at 12 weeks' gestation or beyond after the completion of the first transfer.	At 12 weeks' gestation
Secondary	Implantation rate rate	The number of gestational sacs per number of embryos transferred after the completion of the first transfer.	At 3 weeks after embryo transferred
Secondary	Ectopic pregnancy rate	A pregnancy in which implantation takes place outside the uterine cavity	At 12 weeks of gestation
Secondary	Miscarriage rate	Pregnancy loss at < 12 weeks	At 12 weeks of gestation
Secondary	Multiple pregnancy rate	Presence of more than one sac at early pregnancy ultrasound (6-8 weeks of gestation)	At 7 weeks' gestation
Secondary	Gestational diabetes rate	A type of diabetes that develop during pregnancy	At 24 weeks of gestation
Secondary	Hypertensive disorder of pregnancy rate	Comprising pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia	From 20 weeks of gestation up to at birth
Secondary	Antepartum haemorrhage rate	Defined as bleeding from or in to the genital tract, occurring from 24 weeks of pregnancy and prior to the birth of the baby, including placenta previa, placenta accreta and unexplained	From 24 weeks of gestation up to at birth
Secondary	Preterm delivery rate	Defined as delivery at <24, <28, <32, <37 completed weeks	At birth
Secondary	Birth weight (grams) of singletons and twins	Weight of baby born (grams)	At birth
Secondary	Low birth weight rate	Weight of baby born < 2500 g at birth	At birth
Secondary	Very low birth weight rate	Weight of baby born < 1500 g at birth	At birth
Secondary	High birth weight rate	Weight of baby born >4000 gm at birth	At birth
Secondary	Very high birth weight rate	Weight of baby born > 4500 gm at birth	At birth
Secondary	Congenital anomaly diagnosed at birth rate	Any congenital anomalies detected in baby born	At birth
Secondary	Venous thromboembolism (VTE) rate	Including deep venous thrombosis and pulmonary embolism	At 7 weeks of gestation
Secondary	Gastrointestinal disorders rate	Including nausea, bloating, elevated liver enzymes	At 7 weeks of gestation
Secondary	Nervous system disorders rate	Including headache, dizziness	At 7 weeks of gestation
Secondary	Vaginal discharge rate	A fluid produced by glands in the vaginal wall and cervix that drains from the opening of the vagina	At 7 weeks of gestation
Secondary	Vaginal discomfort rate	Including the symptoms of pain, itching, burning and swelling of vagina and vulva	At 7 weeks of gestation
Secondary	Vulvovaginal pruritus rate	Itchiness of the vulva and vagina	At 7 weeks of gestation