Progesterone as Luteal Support in Frozen IVF Natural Cycles

Study Overview
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Brief Summary
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The ProFET study aims to investigate if luteal phase support by vaginal progesterone, is superior to no luteal phase support, in terms of live birth rate per woman after a frozen embryo transfer (FET), in a natural cycle (NC) after in-vitro fertilization (IVF), and if 7 weeks of treatment is superior to 3 weeks duration.

Detailed Description
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Vaginal progesterone supplementation is routine treatment after IVF with fresh embryo transfer, but it is uncertain whether vaginal progesterone after frozen embryo transfer in natural cycles is efficacious in terms of increasing the chance of a live birth. The ProFET study is a multicenter, open randomized, controlled trial planning to include 1800 women, intended to undergo a FET in a natural cycle. Primary objectives are to investigate if luteal phase support by vaginal progesterone, is superior to no luteal phase support, in terms of live birth rate per woman after a frozen embryo transfer, in a natural cycle and if 7 weeks of treatment is superior to 3 weeks duration. Secondary objectives are to compare groups regarding pregnancy outcomes including biochemical pregnancy, clinical, ongoing and term pregnancy rates, as well as rates of miscarriage, termination of pregnancy, and ectopic pregnancy. Secondary objectives are also perinatal and obstetrics outcomes, self-reported side effects, adverse events and cost effectiveness. The investigators will also analyze the effect of S-Progesterone level before FET on the chance of achieving live birth and secondary pregnancy outcomes.

Official Title
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Vaginal Progesterone as Luteal Support for Improvement of Live Birth in Frozen/Thawed In-vitro Fertilization Natural Cycles; a Multicenter, Open, Randomized Trial

Conditions
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Infertility, Embryo Transfer

Intervention / Treatment
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* Drug: Progesterone vaginal tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Planned for a FET-NC with a blastocyst BMI >18.5 <35 Regular menstrual cycles 24-35 days Given informed consent Understand written and spoken Swedish, English or Arabic Exclusion Criteria: Oocyte donor cycles, preimplantation genetic testing (PGT) cycles. Uterine malformation, submucous myoma and endometrial polyps. Hypersensitivity against study medication. Other contraindications according to www.fass.se Development of serious disease contraindicating ART or pregnancy. Participation or recent participation in a clinical study with an investigational product (past 30 days). Previous participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 43 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: Two main arms, of which the experimental arm is split in two arms with different duration of treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No progesterone<br>Patients will have FET in natural cycles with no extra intervention. | |
| Experimental: Progesterone for 3 weeks<br>At day LH+3 patients will start treatment with vaginal progesterone tablet at 100mg three times daily for three weeks. | Drug: Progesterone vaginal tablet<br>* The study drug is progesterone 100 mg administrated as a vaginal tablet three times daily.<br>* Other names: Lutinus, manufactured by Ferring GmbH. ATC code G03DA04;|
| Experimental: Progesterone for 7 weeks<br>At day LH+3 patients will start treatment with vaginal progesterone tablet at 100mg three times daily for seven weeks. | Drug: Progesterone vaginal tablet<br>* The study drug is progesterone 100 mg administrated as a vaginal tablet three times daily.<br>* Other names: Lutinus, manufactured by Ferring GmbH. ATC code G03DA04;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with live birth | A child born alive. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix. | Up to 41 weeks after embryo transfer. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with biochemical pregnancy | A pregnancy diagnosed only by the detection of beta hCG in serum or urine. | 2-3 weeks after embryo transfer. | 
| Number of participants with clinical pregnancy | A pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs. | 4-8 weeks after embryo transfer. | 
| Number of participants with ongoing pregnancy | An intrauterine pregnancy with one or more fetuses with heartbeats measured in gestational week 7+5 to 9+0 with vaginal ultrasound. | 5-7 weeks after embryo transfer. | 
| Number of participants with miscarriage | The spontaneous loss of an intra-uterine pregnancy prior to 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix. | Up to 20 weeks after embryo transfer. | 
| Number of participants with ectopic pregnancy | A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization, or histopathology. | Up to 20 weeks after embryo transfer. | 
| Number of participants with termination of pregnancy | Defined as the termination of a clinical pregnancy, by deliberate interference that takes place before 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix. | Up to 20 weeks after embryo transfer. | 
| Birth weight | Defined as weight in grams at birth. | Up to 41 weeks after embryo transfer. | 
| Gestational age at delivery | The gestational age at FET is calculated by adding the number of culture days to ovulation (ovulation=day 14). Gestational age at delivery is then calculated by adding the number of days since FET. | Up to 41 weeks after embryo transfer. | 
| Preterm birth | Defined as a child born alive before 37 completed weeks of pregnancy. | Up to 35 weeks after embryo transfer. | 
| Very preterm birth | Defined as a child born alive before 32 completed weeks of pregnancy. | Up to 30 weeks after embryo transfer. | 
| Low birth weight | Birth weight less than 2500 g. | Up to 41 weeks after embryo transfer. | 
| Very low birth weight | Birth weight less than 1500 g. | Up to 41 weeks after embryo transfer. | 
| Stillbirth | The death of a fetus prior to the complete expulsion or extraction from its mother, after and including 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix. | Up to 41 weeks after embryo transfer. | 
| Perinatal death | Fetal or neonatal death occurring during late pregnancy (at 22 completed weeks of gestational age and later), during childbirth, or up to seven days after birth. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix. | Up to 41 weeks after embryo transfer and 7 days after birth. | 
| Number of children with birth defects | Congenital birth defects were defined according the International Statistical Classification of Diseases and Related Health Problems (ICD-10). And further defined according to the EUROCAT classification system. | Up to 41 weeks after embryo transfer. | 
| Number of children admitted to Neonatal Intensive Care Unit (NICU) | Defined as children that were admitted to NICU after birth. | Up to 41 weeks after embryo transfer and 7 days after birth. | 
| Number of participants with hypertensive disorders of pregnancy | Hypertensive disorders of pregnancy defined as high blood pressure disorders including preeclampsia, gestational hypertension and chronic hypertension. | Up to 41 weeks after embryo transfer including the postpartum period before discharge of mother. | 
| Number of participants with placenta previa | Defined as a placenta covering the internal os of the cervix, at time of delivery. | Up to 41 weeks after embryo transfer. | 
| Number of participants with placenta abruption | Defined as the premature separation of a normally located placenta from the uterine wall that occurs before delivery of the fetus. | Up to 41 weeks after embryo transfer. | 
| Number of participants with postpartum hemorrhage | Defined as a cumulative blood loss of greater than 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process. | Up to 41 weeks after embryo transfer. | 
| Number of participants with Cesarean section | Defined as a surgical procedure used to deliver a baby through incisions in the abdomen and uterus. | Up to 41 weeks after embryo transfer. | 
| Number of participants with thromboembolic events | Defined as formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. | Up to 41 weeks after embryo transfer including the postpartum period before discharge of mother. | 
| Maternal mortality | Defined as female deaths from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes) during pregnancy and childbirth. | Up to 41 weeks after embryo transfer including the postpartum period before discharge of mother. | 
| Number of participants with treatment related side effects | Side effects reported according to study specific questionnaire. Questions are answered with yes or no. If yes, symptoms are described, but not by using a scale. | Up to 8 weeks after embryo transfer. | 
| Number of participants with adverse events | Any untoward medical occurrence in symptom or disease temporally associated with the use of the medicinal (investigational) product, whether or not related to the medicinal product. | Up to 8 weeks after embryo transfer. | 
| Cost effectiveness | Comparison between groups regarding the total costs for the intervention divided by treatment efficacy (live birth). | After study completion, an average of 1 year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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progesterone, luteal phase support, frozen embryo transfer, natural cycles, live birth