MIcronized PROgesterone in Frozen Embryo Transfer Cycles

Study Overview
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Brief Summary
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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

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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Vaginal progesterone 600mg daily
* Drug: Vaginal progesterone 800mg daily


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vaginal progesterone 600mg<br>Vaginal progesterone 600mg daily (200mg tid) will be started and maintained until 10 weeks of pregnancy or either up to menses or up to negative pregnancy test performed 10 days after ET | Drug: Vaginal progesterone 600mg daily<br>* 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.<br>|
| Experimental: Vaginal progesterone 800mg<br>Vaginal progesterone 800mg daily (400mg bid) will be started and maintained until 10 weeks of pregnancy or either up to menses or up to negative pregnancy test performed 10 days after ET. | Drug: Vaginal progesterone 800mg daily<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate | A positive heart beat at ultrasound after 11-13 weeks of gestation | 7-9 weeks after embryo transfer | 

Secondary Outcome Measures

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