Study Comparing Outcomes Between Conventional IVF and a Freeze-all-Strategy in Assisted Reproductive Technology

Study Overview
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Brief Summary
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The purpose of this study is to compare conventional fresh embryo transfer with a freeze all and transfer later strategy in assisted reproductive technology in terms of ongoing pregnancy rates, live birth rates as well as perinatal outcomes.

Detailed Description
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The study is a multicentre randomized controlled double-blinded trial with the purpose to investigate if pregnancy- and live birth rates can be improved by a freeze all and transfer later-strategy with transfer of the best quality, frozen, thawed embryo in a subsequent natural cycle compared with conventional fresh embryo transfer with transfer of the embryo in the stimulated cycle. In total 5 clinics in Denmark and Sweden will be participating in the recruitment of patients for the study. The patients will be screened and randomized computerized on cycle day 2 or 3 and allocated to one of the two study arms: I: hCG (human chorion gonadotrophin) arm with traditional hCG triggering and fresh blastocyst transfer II: GnRH (gonadotropin-releasing hormone)- agonist triggering arm with blastocyst cryopreservation and subsequent transfer in a subsequent natural cycle. The randomization will be done after the decision of gonadotrophin (rFSH/hMG) starting dose, and both doctor and patient will be blinded to the randomization until the day of hCG/agonist trigger. Both groups will be stimulated in a short GnRH antagonist protocol. The ovarian stimulation The gonadotrophin stimulation is performed according to the general standards in each of the clinics and can be altered according to the ovarian response with a maximum of 300 IU. Blood samples are collected at baseline before the first gonadotrophin injection and at day of hCG injection and further blood samples in the luteal phase will be collected for a small subgroup of patients. All blood samples will be kept at the Biobank for the study at Hvidovre Hospital. Women in both arms will furthermore be requested to fill out a physical discomfort and a quality of life questionnaire at two different visits. Additionally the men will be asked to fill out quality of life questionnaires. Comprehensive sonography will be performed at the start of ovulation with details on each ovary. Ultrasound examination is performed on cycle day 2-3, at stimulation day 6 and thereafter every 2-3 days until ovulation is inducted. On the day of oocyte retrieval the randomization is unblinded. The oocytes are fertilized by either IVF or ICSI and cultured individually according to the normal procedures in the clinics. If the patient is allocated to the Fresh embryo transfer-group the best quality blastocyst will be transferred on day five after oocyte pick-up, if a blastocyst is developed. Surplus good quality blastocysts are vitrified on day five or six. For patients in the Freeze all group all embryos of good quality are vitrified at the blastocyst stage day 5 in the stimulated cycle according to the criteria for freezing blastocysts in each clinic. The highest quality embryo is selected and marked and will be the first one to be thawed after at least one mentrual cycle that is considered as a wash out period. Embryo transfer is performed 6-7 days after hCG injection in the blastocyst transfer cycle in this group. A serum beta-hCG test is performed 11 days after blastocyst transfer, and clinical pregnancy is confirmed by transvaginal ultrasound 3 to 4 weeks after a positive serum-hCG test. A follow-up of all pregnancies will be performed within three months after delivery or termination of pregnancy on predefined information sheets. All pregnancies resulting from blastocysts retrieved and thawed according to this study protocol will be followed from study inclusion and one year onwards. All data will be collected in a single database and all participants will be anonymized by way of an identificationcode. The biobank will be closed and all samples destroyed after 5 years of the conclusion of the study at the latest. The study is a superiority study with 424 (212 in each arm) patients required to have an 80 % chance of detecting, as significant at the 5 % level, a decrease in the primary outcome measure from 30 % in the control group to 43 % in the experimental group.

Official Title
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A Multicentre Randomized Controlled Trial of a Freeze All and Transfer Later Versus a Conventional Fresh Embryo Transfer Strategy for Assisted Reproductive Technology (ART) in Women With a Regular Menstrual Cycle

Conditions
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Infertility

Intervention / Treatment
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* Procedure: Freeze all


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: AMH (Anti-Müllerian hormone) > 6.28 pmol/L (Roche Elecsys assay) Female age 18 years to less than 40 years 1, 2 or 3 IVF/ICSI cycle with oocyte aspiration Regular menstrual cycle between 24 and 35 days BMI between 18 and 35 Two ovaries Can and will sign informed consent Exclusion Criteria: Women who do not fulfil the inclusion criteria Endometriosis stage III to IV Ovarian cysts with diameter > 30 mm at day of start of stimulation Submucosal fibroids Women with severe co-morbidity (IDDM, NIDDM, gastrointestinal, cardiovascular, pulmonary, liver or kidney disease) Dysregulation of thyroid disease Not danish or English speaking women Contraindications or allergies to use of Gonadotrophins or GnRH antagonists TESA (testicular sperm aspiration) OD (oocyte donation) Previous inclusion in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Freeze all<br>Transfer of a frozen, thawed blastocyst in a subsequent natural menstrual cycle | Procedure: Freeze all<br>* Freezing of all blastocyst stage embryos with thawing and transfer in a subsequent natural cycle<br>|
| No Intervention: Fresh embryo transfer<br>Standard procedure | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rates | Outcome measured per transfer of the first blastocyst, per oocyte pick-up, per start of ovarian stimulation and per randomized patient. | Two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rates | Outcome measured after the first blastocyst transfer calculated per randomized patient, per started ovarian stimulation, per oocyte pick-up and per transfer | Two years | 
| Cumulative live birth rates | Measured after one stimulated cycle with oocyte retrieval and after use of all frozen blastocysts or after at least 1 year of follow-up | Two years | 
| Number of cycles with no embryo transfer |  | Two years | 
| Time-to-pregnancy | From start of ovarian stimulation to positive hCG | Two years | 
| Time-to-delivery |  | Three years | 
| Preterm birth |  | Three years | 
| Low birth weight |  | Three years | 
| Small-for-gestational age (SGA) |  | Three years | 
| Large-for-gestational age (LGA) |  | Three years | 
| Perinatal mortality |  | Three years | 
| Preeclampsia |  | Three years | 
| Placental rupture |  | Three years | 
| Positive hCG 11 days post embryo transfer |  | Three years | 
| Miscarriages, biochemical pregnancies, ectopic pregnancies |  | Three years | 
| Quality of life for female and partner |  | Two years | 
| Cost-effectiveness |  | Three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Assisted reproduction, In vitro fertilisation, Frozen embryo transfer (FET)