Oral Versus Vaginal Progesterone for Luteal Phase Supplementation in Frozen Embryo Transfer Cycles

Study Overview
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Brief Summary
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To investigate the efficacy of dydrogesterone 30 mg compared to micronized vaginal progesterone 800 mg daily for luteal phase support in hormone replacement therapy frozen embryo transfer cycles, as confirmed by visualization of fetal heart activity by pelvic ultrasound assessment of ongoing pregnancy at 12 weeks of gestation.

Detailed Description
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A randomized controlled trial comparing dydrogesterone 30 mg versus micronized vaginal progesterone 800 mg daily for luteal phase support in hormone replacement therapy frozen embryo transfer cycles. Patients will undergo an embryo transfer in a hormone replacement therapy cycle using Progynova 2 mg three times daily until an endometrium thickness of at least 7 mm is reached. Afterwards two different luteal phase supplementation methods will be compared. The primary outcome of the study is ongoing pregnancy at 12 weeks of gestation. We will also investigate other prenatal and neonatal outcome factors as well as patients satisfaction and safety of dydrogesterone.

Official Title
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Dydrogesterone Versus Micronized Vaginal Progesterone (MVP) for Luteal Phase Support (LPS) in Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) Cycles.

Conditions
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Frozen Embryo Transfer, Hormone Replacement Therapy, Dydrogesterone, Infertility, Female

Intervention / Treatment
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* Drug: Dydrogesterone 10 MG Oral Tablet
* Drug: Micronized progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≤40 years of age at the time of IVF/ICSI treatment BMI ≥18 to ≤30 kg/m2 with a documented history of infertility Have undergone COS as part of an ART treatment and have had an unsuccessful fresh embryo transfer in that cycle, OR, have undergone freeze all strategy Scheduled to undergo FET with a standard exogenous/programmed hormonal replacement therapy (HRT) regimen Have at least 1 blastocyst vitrified on the 5th or 6th day after oocyte retrieval Elective single embryo (blastocyst) transfer (SET) Normal ultrasound examination at enrollment (or if <12 months old) Signed patient authorization for use/disclosure of data. Exclusion Criteria: Women with a history of recurrent miscarriage, defined as >2 consecutive miscarriages (biochemical pregnancy losses are not included) Absence of implantation (serum hCG = negative) after two consecutive cycles of IVF, ICSI or FET where the cumulative number of transferred embryos was >4 cleavage-stage embryos and >2 blastocysts Presence of hydrosalpinx that is not surgically treated Endometrial abnormalities on scanning during ovarian stimulation, such as endometrial polyp(s), sub mucosal fibroid(s), endometrial hyperplasia, endometrial fluid accumulation, or endometrial adhesions Participating in another clinical study at the same time Known allergic reactions to dydrogesterone or other progestogens products Any contraindication or other condition that precludes use of dydrogesterone in a particular patient, in accordance with the precautions listed in the locally approved label Mental disability or any other lack of fitness, in the Investigator's opinion, to preclude subjects in or to complete the study History of prior chemotherapy Contraindication for pregnancy Transfer of >1 embryo

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dydrogesterone<br>Luteal phase support for hormone replacement therapy frozen embryo transfer cycles using dydrogesterone 10 mg 3 times daily | Drug: Dydrogesterone 10 MG Oral Tablet<br>* 10 mg three times daily<br>|
| Active Comparator: Micronized progesterone<br>Luteal phase support for hormone replacement therapy frozen embryo transfer cycles using micronized progesterone 2x200 mg twice daily vaginally | Drug: Micronized progesterone<br>* 2x 200 mg vaginal tablets two times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy | visualisation of a fetal heart activity via pelvic (vaginal/abdominal) ultrasound examination at 12 weeks of gestation. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rate | as the birth of a live newborn after 22 weeks of gestation | 22-42 weeks | 
| Time of delivery | time of delivery (gestational week) will be confirmed (by calculation from date of embryo transfer) | follow-up time of 30 days after delivery | 
| Incidence of Treatment-Emergent Adverse Events | Tolerability and safety will be asses during the whole study period. Adverse events will be considered as unexpected if the nature, seriousness, severity or outcome of the reaction(s) is not consistent with the reference information. The expectedness of adverse events for the medications used in this study is detailed in the reference safety information in the current summary of product characteristics (SmPCs) issued in the participating countries. All serieus suspected unexpected serious adverse drug reactions (SUSARs) will be subject to expedited reporting. The investigator is responsible for submitting reports of SUSARs to the appropriate national regulatory authorities within the required reporting period. The investigator is responsible for notifying the IECs/IRBs in writing of the SUSARs within the required reporting timelines. Copies of the notification will be maintained by the investigator in the study documentation files. | follow-up time of 30 days after delivery | 
| Patient reported outcome | Questionnaire (using the Treatment Satisfaction Questionnaire of Medication (TSQM)) and recording information on treatment tolerability and convenience | day 12-18 of luteal phase supplementation (pregnancy test) and at 12 weeks gestation | 
| Incidence of newborn adverse events | Newborn wellbeing and safety including congenital malformations will be evaluated after delivery via a telephonic contact with the patient | follow-up time of 30 days after delivery | 
| Biochemical pregnancy rate | serum hCG test (> 25 mIU/ml), without ultrasound evaluation of a pregnancy | day 12-18 of luteal phase supplementation (pregnancy test) | 
| Clinical pregnancy rate | assessed by transvaginal ultrasound and defined as the presence of ≥1 gestational sac on examination | Day 33-39 of LPS (Verification of pregnancy) | 
| Miscarriage rate | defined as spontaneous loss of a clinical pregnancy before 22 weeks of gestation (where embryo(s) or fetus(es) is/are nonviable and is/are not spontaneously absorbed or expelled from the uterus) | 22 weeks | 
| Rate of preterm birth | Delivery before 37 weeks of gestation | follow-up time of 30 days after delivery | 
| Rate of pre-eclampsia | Incidence of pre-eclampsia as defined by the defined as the development of hypertension after 20 weeks of gestation together with one or more new-onset conditions: proteinuria, maternal or uteroplacental dysfunctions. Univariate and multivariable regression analysis were performed to control for known or potential PE risk factors, more specifically: body mass index (BMI), African ethnicity, previous history of hypertensive disorders of pregnancy, mean arterial pressure (MAP) at the first prenatal consultation, polycystic ovary syndrome (PCOS) and ovulation disorders, endometrial thickness and oocyte recipients. | follow-up time of 30 days after delivery | 
| Occurence of antenatal bleeding, ultrasonographic abnormalities, gestational diabetes, cholestasis | Occurence of antenatal bleeding, ultrasonographic abnormalities, gestational diabetes, cholestasis | follow-up time of 30 days after delivery | 
| Implantation rate | assessed by ultrasound and defined as the number of gestational sacs per number of embryos transferred | Day 33-39 of LPS (Verification of pregnancy) | 
| Blastocyst development score | using the system developed by Gardner | at the time of embryo transfer (visit 2: day 6 of luteal phase supplementation) | 
| Number of cryopreserved embryos | Number of cryopreserved embryos | day of screening and enrollment | 
| Summary characteristics of the preceding controlled ovarian stimulation cycle | information on used stimulation medication, total dose of stimulation medication used, duration of stimulation medication, trigger medication | day of screening and enrollment |