Clinical trial NCT03795220: Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers
Official title: Preparing and Timing of the Endometrium in Modified Natural Cycle Frozen-thawed Embryo Transfers (mNC-FET) - a Randomized Controlled Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infertility
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Copenhagen University Hospital, Hvidovre
name: Regionshospitalet Horsens
name: Copenhagen University Hospital at Herlev
name: Aalborg University Hospital
name: Hillerod Hospital, Denmark
name: Zealand University Hospital
name: Regionshospitalet Viborg, Skive
First posted: 2019-01-07
Enrollment: 679
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Live birth rates per transfer
timeFrame: Registered at the one-year follow-up after a positive pregnancy test.
Secondary outcomes:
measure: Chemical pregnancy rates per transfer
timeFrame: Measured 16 days after ovulation trigger (hCG+16).
measure: Clinical pregnancy rates per transfer
timeFrame: Ultrasound performed at 7-8 weeks of gestation.
measure: Abortion rates per transfer
timeFrame: Registered at the one-year follow-up after a positive pregnancy test.
measure: ASAT (U/L)
timeFrame: Measured at baseline.
measure: ALAT (U/L)
timeFrame: Measured at baseline.
measure: AMH (pol/L)
timeFrame: Measured at baseline.
measure: Estradiole (mmol/L)
timeFrame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
measure: FSH (IU/L)
timeFrame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
measure: LH (IU/L)
timeFrame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
measure: Progesterone (nmol/L)
timeFrame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
measure: OH-progesterone (nmol/L)
timeFrame: Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
measure: beta-hCG
timeFrame: Measured at transfer day (hCG+6/7), hCG+11 and hCG+16.
measure: TSH (*10^3 IU/L)
timeFrame: 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.
measure: Thyroglobulin antibodies (arb.units/L)
timeFrame: Measured at baseline.
measure: Thyroid peroxidase anitbodies (arb.units/L)
timeFrame: Measured at baseline.
measure: Obstetric complication rates
timeFrame: Registered at the one-year follow-up after a positive pregnancy test.
measure: Neonatal complication rates
timeFrame: Registered at the one-year follow-up after a positive pregnancy test.
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Fertility Clinic, Rigshospitalet, Copenhagen University Hospital
Study officials:
affiliation: Fertility Clinic Rigshospitalet
name: Anja B. Pinborg, Prof., DMSC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Saupstad M, Freiesleben NC, Skouby SO, Andersen LF, Knudsen UB, Petersen KB, Husth M, Egeberg A, Petersen MR, Ziebe S, Andersen AN, Lossl K, Pinborg A. Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial. BMJ Open. 2019 Dec 15;9(12):e031811. doi: 10.1136/bmjopen-2019-031811.