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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
Sponsor:
Collaborator:
Mỹ Đức Hospital
Information provided by (Responsible Party):
Manh Tuong Ho, Vietnam National University

Tracking Information
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
 (submitted: July 12, 2017)
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
 (submitted: June 12, 2015)
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
 (submitted: July 12, 2017)
  • Clinical pregnancy [ Time Frame: 5 weeks after embryo placement ]
    Clinical pregnancy is explained as the presence of a gestational sac seen by transvaginal sonography.
  • Implantation rate [ Time Frame: 3 weeks after embryo transferred ]
    Implantation rate is explained as as the number of gestational sacs per number of embryos transferred.
  • Multiple pregnancy rate [ Time Frame: 5 weeks after embryo placement ]
    Multiple pregnancy is explained as two or more gestational sacs or positive heart beats by transvaginal sonography.
  • Live birth [ Time Frame: at the time of delivery ]
    Live birth is defined if a live newborn delivered.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2015)
  • Clinical pregnancy rate [ Time Frame: 7 weeks after embryo placement ]
    Clinical pregnancy is explained as the presence of a gestational sac seen by transvaginal sonography 7 weeks after embryo placement.
  • Implantation rate [ Time Frame: 3 weeks after embryo transferred ]
    Implantation rate is explained as as the number of gestational sacs per number of embryos transferred.
  • Multiple pregnancy rate [ Time Frame: 7 weeks after embryo placement ]
    Multiple pregnancy is explained as two or more fetal heart rates by transvaginal sonography 7 weeks after embryo placement
Current Other Pre-specified Outcome Measures
 (submitted: August 22, 2017)
  • Ovarian hyperstimulation syndrome (OHSS) [ Time Frame: at 10 days after hCG injection and 14 days after embryo transfer ]
    Symptoms of OHSS
  • Miscarriage [ Time Frame: at 24 weeks of gestation ]
    complete lost of clinical pregnancy
  • Ectopic pregnancy [ Time Frame: at 12 weeks of gestation ]
    ectopic nidation of a pregnancy confirmed by sonography or laparoscopy
  • Live birth [ Time Frame: at birth ]
    birth of a newborn with any sign of life
  • Gestational age at delivery [ Time Frame: at the time of delivery ]
    gestational age at delivery
  • Birth weight [ Time Frame: at the time of delivery ]
    Weight of newborn
  • congenital malformation [ Time Frame: at the time of delivery ]
    congenital malformation of newborn
  • Macrosomia [ Time Frame: at the time of delivery ]
    Birth weight > 90th percentile
  • small for gestational age [ Time Frame: at the time of delivery ]
    birth weight < 10th percentile
  • NICU admittance [ Time Frame: 7 days after delivery ]
    The admittance of the newborn to NICU
  • Pregnancy-associated hypertension [ Time Frame: at 20 weeks of gestation ]
    systolic blood pressure of ≥140 mmHg or diastolic pressure of ≥90 mmHg on two occasions 2 hours apart, or a severely elevated single blood pressure measurement that led to treatment with an antihypertensive medication.
  • Preeclampsia [ Time Frame: at 20 weeks of gestation ]
    any type of hypertension combined with proteinuria (total protein excretion of 300 mg or other organ involvement [such as renal insufficiency, liver involvement, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction])
  • HELLP syndrome [ Time Frame: at 20 weeks of gestation ]
    elevated liver enzyme levels (aspartate aminotransferase ≥100 U/L), thrombocytopenia (platelet count <100,000/mm3), elevated serum creatinine level (≥1.5 mg/dL [132.6 μmol/L]) and/or hemolysis (hemoglobin <10 g/dL)
  • Prematurity [ Time Frame: at 32 weeks and 37 weeks of gestation ]
    Preterm birth
  • antepartum hemorrhage [ Time Frame: in the second half of pregnancy ]
    bleeding from the genital tract
  • Gestational diabetes mellitus [ Time Frame: at 24 weeks of gestation ]
    using a 75g oral glucose tolerance test
  • Mode of deliver [ Time Frame: at the time of delivery ]
    Normal delivery, vaginal instrument delivery or Cesarean section
  • Permpartum increased blood loss [ Time Frame: 24 hours after delivery ]
    Blood loss more than 1000ml
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
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).
Detailed Description

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.

Study Procedures

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.

METHODS

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).

STUDY ENDPOINTS

Primary endpoint

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).

Secondary endpoints

  • Implantation rate: defined as the number of gestational sacs per number of embryos transferred.
  • Clinical pregnancy: defined as the presence of a gestational sac seen by transvaginal sonography 7 weeks after embryo replacement.
  • Multiple pregnancy rate. defined as a pregnancy with two or more fetal heart beats by transvaginal sonography at 7 weeks of gestation.
  • Vanishing twins: defined as a pregnancy with tow or more gestational sacs or positive heart beats at 7 weeks of gestation, but only one at 12 weeks' gestation.

Treatment complications

  • Ovarian hyperstimulation syndrome (OHSS): classified as moderate or severe by RCOG guidelines [Green-top Guideline No. 5, 2006].
  • Miscarriage: defined as the complete loss of a clinical pregnancy prior to 24 weeks' gestation.
  • Ectopic pregnancy: defined as the ectopic nidation of a pregnancy, confirmed by sonography or laparoscopy.

Obstetric outcomes

  • Live birth rate, defined as the birth of a newborn, irrespective of the duration of gestation, that exhibits any sign of life, such as respiration, heart-beat, umbilical pulsation or movement of voluntary muscles.
  • Gestational age at delivery.
  • Birth weight.
  • Congenital malformations.
  • Macrosomia (birth weight >90th percentile)
  • Small for gestational age (birth weight <10th percentile)
  • NICU admittance
  • Perinatal mortality: defined as the death of a fetus or infant from 24 weeks of gestation to the end of the neonatal period of 4 weeks after birth.

Pregnancy complications

  • Pregnancy-associated hypertension: defined as a diagnosis of pregnancy-induced hypertension made after the 20th week of gestation, excluding intraoperative blood pressures and intrapartum systolic pressures, with systolic blood pressure of ≥140 mmHg or diastolic pressure of ≥90 mmHg on two occasions 2 hours apart, or a severely elevated single blood pressure measurement that led to treatment with an antihypertensive medication.
  • Preeclampsia: defined as any type of hypertension combined with proteinuria (total protein excretion of 300 mg or other organ involvement [such as renal insufficiency, liver involvement, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction]) according to the International Society of Studies in Hypertension in Pregnancy.
  • HELLP syndrome: defined as elevated liver enzyme levels (aspartate aminotransferase ≥100 U/L), thrombocytopenia (platelet count <100,000/mm3), elevated serum creatinine level (≥1.5 mg/dL [132.6 μmol/L]) and/or hemolysis (hemoglobin <10 g/dL).
  • Prematurity: defined as iatrogenic preterm birth at <32 weeks' gestation, spontaneous preterm birth at <32 weeks' gestation; iatrogenic preterm birth at <37 weeks gestation; spontaneous preterm birth at <37 weeks' gestation
  • Antepartum hemorrhage: defined as bleeding from the genital tract in the second half of pregnancy.
  • Gestational diabetes mellitus: diagnosed using a 75g oral glucose tolerance test (Fasting: 92 mg/dL [5.1 mmol/L]; 2 h: 153 mg/dL [8.5 mmol/L]) [American Diabetes Association 2013].

Labor

Induction of labor

  • Cesarean section

    • Elective
    • Suspected fetal distress
    • Non-progressive labor
  • Vaginal instrumental delivery

    • Suspected fetal distress
    • Non-progressive labor
  • Peripartum increased blood loss (≥1000 mL)

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.

STATISTICAL EVALUATION

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

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.

SAFETY REPORTING

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;

  • is life threatening (at the time of the event);
  • requires hospitalisation or prolongation of existing inpatients' hospitalisation;
  • results in persistent or significant disability or incapacity;
  • is a congenital anomaly or birth defect;
  • is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction.

ETHICAL CONSIDERATIONS

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
Condition  ICMJE Infertility
Intervention  ICMJE
  • Procedure: Freeze-all protocol
    Embryos are selected for cryopreservation using vitrification technique. Two vitrified embryos will be warmed and transferred in subsequent cycle.
  • Procedure: Fresh transfer protocol
    Two embryos are selected and transferred fresh in the same cycle.
Study Arms  ICMJE
  • Active Comparator: Freeze-all protocol
    Embryos are selected for cryopreservation using vitrification technique. Two vitrified embryos will be warmed and transferred in subsequent cycle.
    Intervention: Procedure: Freeze-all protocol
  • Active Comparator: Fresh transfer protocol
    Two embryos are selected and transferred fresh in the same cycle.
    Intervention: Procedure: Fresh transfer protocol
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 Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 23, 2017)
782
Original Estimated Enrollment  ICMJE
 (submitted: June 12, 2015)
780
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

Inclusion Criteria:

  • Undergoing In-vitro fertilization (IVF) treatment
  • Number of previous failed embryo transfers ≤ 2
  • Permanent living in Viet Nam
  • Ovarian hyperstimulation with Gonadotropin releasing hormone (GnRH) antagonist protocol
  • Eligible for embryo transfer (ET) on day 3
  • Having at least one top-quality embryo on day 3.
  • Number of embryos transferred ≤ 2
  • Willing to participate in the study
  • Not to participate in another IVF study at the same time

Exclusion Criteria:

  • women with polycystic ovary syndrome
  • In vitro maturation (IVM) cycles
  • Oocyte donation cycles
  • Using GnRH agonist for triggering
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
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  
 
Administrative Information
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
Plan to Share IPD: Undecided
Responsible Party Manh Tuong Ho, Vietnam National University
Study Sponsor  ICMJE Vietnam National University
Collaborators  ICMJE Mỹ Đức Hospital
Investigators  ICMJE
Study Chair: Tuong M Ho, MD Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University HCMC
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