Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers

Study Overview
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Brief Summary
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The increasing use of FET emphasizes the importance of preparing and timing the endometrium in FET cycles, however there is no consensus on luteal phase progesterone supplementation in mNC-FET and the optimal day of blastocyst warming and transfer. The aim of this multicenter RCT is to assess the effect of progesterone supplementation in hCG-triggered mNC-FET and the effect of embryo thawing and transfer at hCG+6 or hCG+7 days, respectively. In total 604 patients will be included with n=151 in each of the four study arms. The primary outcome is live birth rate per transfer (LBR) and the goal is to show a 10% increase in LBR after progesterone supplementation and to assess whether blastocyst warming+transfer 6 days after hCG trigger is superior to 7 days after hCG trigger in mNC-FET.

Detailed Description
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Single embryo transfer and freezing of surplus embryos has lowered twin birth rates after in vitro fertilization (IVF) to a level of less than 5% in Denmark. However, several treatments with repeated frozen embryo transfers (FET) before a viable pregnancy is confirmed are burdensome to the patients. New freezing techniques has optimized the quality of the embryo transferred in FET cycles, but optimization of the endometrium in the luteal phase is still lacking behind. In a mNC-FET, which is the routine in many clinics, ovulation is induced with an hCG injection when the leading follicle is ≥17 mm. The hCG trigger is important for controlling the time of ovulation, but triggering an unhealthy follicle at an inappropriate time may cause luteal phase insufficiency and thus suboptimal function of the endometrium. Danish public fertility clinics are not routinely using progesterone supplementation in mNC-FET, but there may be a rationale to do so, and some implantations may be rescued. In this study we will compare live birth rates in mNC-FET with and without progesterone supplementation in the luteal phase, and further we will explore the optimal timing of blastocyst warming and transfer by comparing embryo transfer at hCG trigger +6 days versus +7 days. This is a superiority study with the aim to detect an increase in live birth rates of 10%. Hence, this adequately powered RCT may make a major contribution to knowledge on mNC-FET to the benefits of patients. We will include 604 patients divided 1:1 (302:302) in each arm +/- progesterone and these will further be divided 1:1 in blastocyst warming and transfer +6 and +7 days after hCG injection. The primary endpoint is live birth rate per transfer.

Official Title
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Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers (mNC-FET) - a Randomized Controlled Multicenter Trial

Conditions
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Infertility

Intervention / Treatment
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* Drug: Lutinus + transfer day 6
* Drug: Lutinus + transfer day 7
* Drug: No Lutinus + transfer day 6
* Drug: No Lutinus + transfer day 7


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female age 18-41 years, regular menstrual cycle (23-35 days), vitrified blastocysts derived from 1.-3. IVF/ICSI cycle in a public hospital and undergoing single blastocyst transfer. Exclusion Criteria: - Previous participation in the study, uterine malformations, intrauterine polyps or submucosal myomas, breast feeding, oocyte donation, preimplantation genetic testing, blastocyst conceived with sperm from testicular sperm aspiration, HIV (woman), hepatitis B and C (woman), known luteal phase insufficiency or if patients are not fulfilling the inclusion criteria. Further exclusion criteria are the following contraindications to progesterone; allergy to the study medication, undiagnosed vaginal bleeding, current missed abortion or ectopic pregnancy, hepatic insufficiency or severe hepatic disease, genital or breast cancer, arterial or venous thromboembolism, thrombophlebitis or porphyria. For patients participating in the sub-study, thyroid disease is an exclusion criterion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 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: Randomized, controlled multicenter trial with inclusion of 604 mNC-FET cycles. We will include 604 patients divided 1:1 (302:302) in each arm +/- progesterone supplementation and these will further be divided 1:1 in blastocyst warming and transfer +6 and +7 days after hCG injection. Patients randomised to progesterone supplementation will start administering medicine four days after the ovulation trigger up til the day of the pregnancy test. If the pregnancy test is positive, medication will continue for 30 days more.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vaginal progesterone + transfer 6. day<br>Lutinus + blastocyst warming and transfer 6 days after hCG trigger | Drug: Lutinus + transfer day 6<br>* Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.<br>* Other names: Lutinus;|
| Active Comparator: Vaginal progesterone + transfer 7. day<br>Lutinus + blastocyst warming and transfer 7 days after hCG trigger | Drug: Lutinus + transfer day 7<br>* Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.<br>* Other names: Lutinus;|
| Active Comparator: No progesterone + transfer 6. day<br>No Lutinus + blastocyst warming and transfer 6 days after hCG trigger | Drug: No Lutinus + transfer day 6<br>* Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.<br>|
| Active Comparator: No progesterone + transfer 7. day<br>No Lutinus + blastocyst warming and transfer 7 days after hCG trigger | Drug: No Lutinus + transfer day 7<br>* Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rates per transfer | Comparison of live birth rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Registered at the one-year follow-up after a positive pregnancy test. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chemical pregnancy rates per transfer | Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured 16 days after ovulation trigger (hCG+16). | 
| Clinical pregnancy rates per transfer | Comparison of clinical pregnancy rates (ultrasound) between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or seven after hCG trigger. | Ultrasound performed at 7-8 weeks of gestation. | 
| Abortion rates per transfer | Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Registered at the one-year follow-up after a positive pregnancy test. | 
| ASAT (U/L) | ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone. | Measured at baseline. | 
| ALAT (U/L) | ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone. | Measured at baseline. | 
| AMH (pol/L) | Comparison of AMH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline. | 
| Estradiole (mmol/L) | Comparison of estradiole measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. | 
| FSH (IU/L) | Comparison of FSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. | 
| LH (IU/L) | Comparison of LH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. | 
| Progesterone (nmol/L) | Comparison of progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. | 
| OH-progesterone (nmol/L) | Comparison OH-progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11. | 
| beta-hCG | Comparison of beta-hCG measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at transfer day (hCG+6/7), hCG+11 and hCG+16. | 
| TSH (*10^3 IU/L) | Comparison of TSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7), at hCG+11, at hCG+14 and at hCG+19. | 
| Thyroglobulin antibodies (arb.units/L) | Comparison of thyroglobulin antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline. | 
| Thyroid peroxidase anitbodies (arb.units/L) | Comparison of thyroid peroxidase antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Measured at baseline. | 
| Obstetric complication rates | Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Registered at the one-year follow-up after a positive pregnancy test. | 
| Neonatal complication rates | Comparison of neonatal complication rates for children of patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger. | Registered at the one-year follow-up after a positive pregnancy test. |