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Completed

NCT Number: NCT03795220

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

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.

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Key information

Conditions

Infertility Genital Diseases Urogenital Diseases

Age range

18 year–41 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

Fertility Clinic, Rigshospitalet, Copenhagen University Hospital

Copenhagen, 2100, Denmark

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Lutinus + transfer day 6

Drug

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.

Other names: Lutinus

Lutinus + transfer day 7

Drug

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.

Other names: Lutinus

No Lutinus + transfer day 6

Drug

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.

No Lutinus + transfer day 7

Drug

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.

Primary outcomes

  1. Live birth rates per transfer

    Time frame: Registered at the one-year follow-up after a positive pregnancy test.

    Comparison of live birth rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

Secondary outcomes

  1. Chemical pregnancy rates per transfer

    Time frame: Measured 16 days after ovulation trigger (hCG+16).

    Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  2. Clinical pregnancy rates per transfer

    Time frame: Ultrasound performed at 7-8 weeks of gestation.

    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.

  3. Abortion rates per transfer

    Time frame: Registered at the one-year follow-up after a positive pregnancy test.

    Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  4. ASAT (U/L)

    Time frame: Measured at baseline.

    ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.

  5. ALAT (U/L)

    Time frame: Measured at baseline.

    ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.

  6. AMH (pol/L)

    Time frame: Measured at baseline.

    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.

  7. Estradiole (mmol/L)

    Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.

    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.

  8. FSH (IU/L)

    Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.

    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.

  9. LH (IU/L)

    Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.

    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.

  10. Progesterone (nmol/L)

    Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.

    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.

  11. OH-progesterone (nmol/L)

    Time frame: Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.

    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.

  12. beta-hCG

    Time frame: Measured at transfer day (hCG+6/7), hCG+11 and hCG+16.

    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.

  13. TSH (*10^3 IU/L)

    Time frame: 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.

    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.

  14. Thyroglobulin antibodies (arb.units/L)

    Time frame: Measured at baseline.

    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.

  15. Thyroid peroxidase anitbodies (arb.units/L)

    Time frame: Measured at baseline.

    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.

  16. Obstetric complication rates

    Time frame: Registered at the one-year follow-up after a positive pregnancy test.

    Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.

  17. Neonatal complication rates

    Time frame: Registered at the one-year follow-up after a positive pregnancy test.

    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.

Sponsors and collaborators

Lead sponsor

Anja Bisgaard Pinborg

Other

Collaborators

  • Aalborg University Hospital
  • Copenhagen University Hospital at Herlev
  • Copenhagen University Hospital, Hvidovre
  • Hillerod Hospital, Denmark
  • Regionshospitalet Horsens
  • Regionshospitalet Viborg, Skive
  • Zealand University Hospital

Registry information

Official study title

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

Important dates

Study start
2019
Primary completion
2024
Study completion
2024
First posted
Jan 7, 2019
Registry last updated
May 15, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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