Freeze All Protocol Versus Fresh Embryo Transfer in Women Undergoing In-vitro Fertilization (IVF)
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|ClinicalTrials.gov Identifier: NCT02471573|
Recruitment Status : Completed
First Posted : June 15, 2015
Last Update Posted : September 7, 2017
|First Submitted Date ICMJE||June 11, 2015|
|First Posted Date ICMJE||June 15, 2015|
|Last Update Posted Date||September 7, 2017|
|Actual Study Start Date ICMJE||June 30, 2015|
|Actual Primary Completion Date||April 10, 2016 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Ongoing pregnancy [ Time Frame: 12 weeks of gestation ]
Ongoing pregnancy is defined as a pregnancy with at least one positive heart beat beyond 12 weeks of gestation.
|Original Primary Outcome Measures ICMJE
||Ongoing pregnancy rate (OPR). [ Time Frame: 12 weeks of gestation ]
Ongoing pregnancy is explained as a pregnancy with positive heart beat beyond 12 weeks of gestation.
|Change History||Complete list of historical versions of study NCT02471573 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Freeze All Protocol Versus Fresh Embryo Transfer in Women Undergoing In-vitro Fertilization (IVF)|
|Official Title ICMJE||The Effectiveness of a Freeze All Protocol Versus Fresh Embryo Transfer in Women Undergoing In-vitro Fertilization (IVF) - Intracytoplasmic Sperm Injection (ICSI)|
|Brief Summary||To compare the effectiveness of freeze-all and subsequent frozen embryo transfer (freeze all protocol) with fresh embryo transfer (fresh ET).|
All patients undergoing in-vitro fertilization (IVF) will be treated with GnRH antagonist protocol. Recombinant Follicle-stimulating hormone (FSH) will be given on day 2 or day 3 of menstrual cycle for 5 days. The starting dose is individualized for each patient based on the following criteria: Anti-Mullerian Hormone (AMH) < 0.7 ng/ml, dose 300 IU/day, AMH 0.7 -2.1 ng/ml, dose 225 IU/day, AMH > 2.1 ng/ml, dose 150 IU/day. After that, investigators can titrate the dose based on their clinical judgment. Follicular development will be monitored by ultrasound scanning and measurement of estradiol, progesterone starting on day 5 of stimulation. Scanning and hormonal measurement will be repeated every 2 to 3 days, depending on the size of follicles. Antagonist is routinely used on day 5 until the day of Human chorionic gonadotropin (hCG). Criteria for recombinant hCG (6,500 IU) administration is the presence of at least three leading follicles of 17 mm. Oocyte retrieval is performed 36 hours after recombinant hCG administration.
We will measure progesterone levels during stimulation on the day 5 and day 7, as well as on the day of oocyte triggering.
Insemination will be performed by using intracytoplasmic sperm injection, 3 - 4 hours after oocyte retrieval. Only matured oocytes are inseminated. Fertilization are performed under inverted microscope at period of 16-18 hours after insemination.
On day 3, endometrium thickness will be measured and embryo evaluation will be performed at fixed time point 68±1 hours after fertilization, using Istanbul consensus. After grading embryo, eligible patients will be invited to participate in the study. Written consent will be obtained from each patient for participation into the study. Patients will be randomized into 2 groups fresh embryo transfer and freeze-all. Randomization will be done by third party via telephone, using a computer-generated random list, with block size of 2, 4, 8.
Freeze all group
All grade 1 and grade 2 embryos were cryopreserved using vitrification method. In the next cycle, endometrium will be prepared by using estradiol orally, starting from day 2-3 of menstrual cycle. When endometrium thickness reaches 8mm or more, patients start to use progesterone vaginally. Embryo transfer is performed 3 days after using progesterone. On the day of embryo transfer, maximum two embryos will be thawed. Two hours after thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. Luteal-phase support is done with estradiol 8mg/day and vaginal progesterone 800mg/day until 7th week of gestation.
Fresh ET group
In fresh ET group, maximum 2 embryos will be transferred into the uterus under ultrasound guidance. The remain grade 1 and 2 embryos will be frozen. Luteal phase support is done with estradiol 8mg/day and vaginal progesterone 800mg/day until 7th week of gestation.
In both of groups, serum hCG was measured 2 weeks after embryo transferred, and if positive, an ultrasound scan of the uterus was performed at gestational weeks 7 and 12.
SAMPLE SIZE CALCULATION
At IVFMD, the current ongoing pregnancy rate (with 2 embryos transferred) is 30%. To show an improvement in the freeze-all group of 10% (from 30% to 40%), it was calculated that 712 couples (356 in each group) would be needed (power 0.80, alpha-error 5%, two-sided test). To account for an estimated loss to follow-up rate of 10%, the number of patients needed was defined as 780 (390 patients per group).
Ongoing pregnancy (OP). Ongoing pregnancy is explained as a pregnancy with positive heart beat beyond 12 weeks of gestation (twins is count as a single pregnancy).
Induction of labor
SUBJECT INFORMED CONSENT A review of patient information should be done prior to enrolment to determine preliminary eligibility according to patient inclusion and exclusion criteria. When a patient signs an informed consent she is considered to be enrolled in the study.
WITHDRAWAL OF INDIVIDUAL PATIENTS Patients can leave the study at any time for any reason if they wish to do so without any consequences for their treatment. The investigator can decide to withdraw a subject from the study or urgent medical reasons.
Event rates will be calculated for dichotomous endpoints. These will be compared by calculating relative risk and 95% confidence interval values. Between-group differences in non-continuous variables will be assessed using the Fisher exact test. Continuous variables will be reported as mean values ± standard deviation (SD) or as percentages. Between-group differences in continuous variables will be assessed with the Student's t-test.
In a secondary analysis we will assess whether the biomarkers progesterone at triggering day and endometrial thickness on day 3 after oocyte pick up can be used to identify patients in whom the freeze all strategy is particularly effective. To do so, we will look for interaction between progesterone or endometrial thickness and treatment effect.
A p-value <0.05 is defined as indicating a statistically significant difference. The analysis will be done with R statistical package (R version 3.3.1).
Interim analysis will be performed after recruitment of the first 400 patients. An independent Data Safety Monitoring Committee (DSMC) will evaluate the data. A specific stopping rule will not be formulated, but continuation of the study will depend on the advice of the DSMC.
The investigator will inform the subjects and the reviewing accredited medical research ethics committee; if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The investigator will take care that all subjects are kept informed.
ADVERSE AND SERIOUS ADVERSE EVENTS All observed or volunteered adverse events, regardless of treatment group or suspected causal relationship to intervention, will be recorded. Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, whether or not considered related to the intervention. All adverse events reported spontaneously by the subject or observed by the investigator or his staffs will be recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose results in death;
RECRUITMENT AND CONSENT The subject should be given the time to read and understand the statement herself before signing her consent and dating the document. The subject should receive a copy of the written statement once signed.
PRIVACY ASPECTS Participating subjects will be registered by a 5-digit number. This personal code will be on all forms retrieved from participants.
BENEFITS AND RISKS ASSESSMENT, GROUP RELATEDNESS There is insufficient evidence for a rational policy in between the 2 strategies, freeze all or fresh ET. The potential benefits of freeze all are higher pregnancy rate, with a lower incidence of ovarian hyperstimulation syndrome (OHSS) and/or ectopic pregnancy. The potential harm would be time-consuming.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Vuong LN, Dang VQ, Ho TM, Huynh BG, Ha DT, Pham TD, Nguyen LK, Norman RJ, Mol BW. IVF Transfer of Fresh or Frozen Embryos in Women without Polycystic Ovaries. N Engl J Med. 2018 Jan 11;378(2):137-147. doi: 10.1056/NEJMoa1703768.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||February 1, 2017|
|Actual Primary Completion Date||April 10, 2016 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 42 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Vietnam|
|Removed Location Countries|
|NCT Number ICMJE||NCT02471573|
|Other Study ID Numbers ICMJE||NCKH/CGRH_ 03_2015|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||Manh Tuong Ho, Vietnam National University|
|Study Sponsor ICMJE||Vietnam National University|
|Collaborators ICMJE||Mỹ Đức Hospital|
|PRS Account||Vietnam National University|
|Verification Date||September 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP