Progesterone Versus Progesterone Plus Dydrogesterone in FET

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Micronized Progesterone
* Drug: Micronized progesterone plus dydrogesterone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Micronized progesterone<br>Patients will receive micronized progesterone (Cyclogest® 400mg; Actavis) at the dose of 400mg twice daily (morning and evening). | Drug: Micronized Progesterone<br>* 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.<br>* Other names: Cyclogest 400mg;|
| Active Comparator: Micronized progesterone plus dydrogesterone<br>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<br>* 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.<br>* Other names: Cyclogest 400 mg + Duphaston 10 mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FET, Micronized Progesterone, Dydrogesterone