Progesterone Versus Progesterone Plus Dydrogesterone in FET (MiDRONE)

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

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.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Drug: Micronized Progesterone; Drug: Micronized progesterone plus dydrogesterone

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1364
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Vietnam
  • Tan Binh
    • Ho Chi Minh City, Tan Binh, Vietnam
      • Mỹ Đức Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Micronized progesterone; Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening).	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.; Other Names: Cyclogest 400mg
Active Comparator: 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, Abbott) at the dose of 10mg twice daily (morning and evening).	Drug: 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.; Other Names: Cyclogest 400 mg + Duphaston 10 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The luteal progesterone level	The progesterone level in serum on day four after the progesterone application	On day four of the progesterone application
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
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
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
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
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
Ectopic pregnancy rate	A pregnancy in which implantation takes place outside the uterine cavity	At 12 weeks of gestation
Miscarriage rate	Pregnancy loss at < 12 weeks	At 12 weeks of gestation
Multiple pregnancy rate	Presence of more than one sac at early pregnancy ultrasound (6-8 weeks of gestation)	At 7 weeks' gestation
Gestational diabetes rate	A type of diabetes that develop during pregnancy	At 24 weeks of gestation
Hypertensive disorder of pregnancy rate	Comprising pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia	From 20 weeks of gestation up to at birth
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
Preterm delivery rate	Defined as delivery at <24, <28, <32, <37 completed weeks	At birth
Birth weight (grams) of singletons and twins	Weight of baby born (grams)	At birth
Low birth weight rate	Weight of baby born < 2500 g at birth	At birth
Very low birth weight rate	Weight of baby born < 1500 g at birth	At birth
High birth weight rate	Weight of baby born >4000 gm at birth	At birth
Very high birth weight rate	Weight of baby born > 4500 gm at birth	At birth
Congenital anomaly diagnosed at birth rate	Any congenital anomalies detected in baby born	At birth
Venous thromboembolism (VTE) rate	Including deep venous thrombosis and pulmonary embolism	At 7 weeks of gestation
Gastrointestinal disorders rate	Including nausea, bloating, elevated liver enzymes	At 7 weeks of gestation
Nervous system disorders rate	Including headache, dizziness	At 7 weeks of gestation
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
Vaginal discomfort rate	Including the symptoms of pain, itching, burning and swelling of vagina and vulva	At 7 weeks of gestation
Vulvovaginal pruritus rate	Itchiness of the vulva and vagina	At 7 weeks of gestation

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Investigators: Study Chair: Tuong M Ho, MD, Hope Research Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Labarta E, Mariani G, Holtmann N, Celada P, Remohi 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2019
• Primary Completion (Actual): January 5, 2021
• Study Completion (Actual): January 31, 2021

Study Registration Dates

• First Submitted: June 17, 2019
• First Submitted That Met QC Criteria: June 24, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 22, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Dydrogesterone; FET; Micronized Progesterone
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone; Dydrogesterone
• Other Study ID Numbers: CS/BVMĐ/19/06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No