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Time-Lapse Incubation for Embryo Culture - Morphokinetics and Environmental Stability

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ClinicalTrials.gov Identifier: NCT02657811
Recruitment Status : Unknown
Verified February 2017 by Ruthie Ronn, Shaare Zedek Medical Center.
Recruitment status was:  Recruiting
First Posted : January 18, 2016
Last Update Posted : February 23, 2017
Sponsor:
Information provided by (Responsible Party):
Ruthie Ronn, Shaare Zedek Medical Center

Tracking Information
First Submitted Date  ICMJE January 5, 2016
First Posted Date  ICMJE January 18, 2016
Last Update Posted Date February 23, 2017
Actual Study Start Date  ICMJE October 2016
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
Ongoing pregnancy rate [ Time Frame: 12 weeks gestation ]
The number of women with a viable pregnancy (including gestational sac and fetal heart beat) at 12 weeks gestation divided by the number of women having an embryo transfer.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02657811 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2016)
  • Embryo morphology - Number of pronuclei present following fertilization [ Time Frame: Day 1 post-fertilization ]
    Number of pronuclei present in the embryo 1 day following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Number of cells present [ Time Frame: Day 2 and Day 3 post-fertilization ]
    Number of cells present in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - % fragmentation [ Time Frame: Day 2 and Day 3 post-fertilization ]
    Percent fragmentation in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Presence of multi nucleation [ Time Frame: Day 2 post-fertilization ]
    Presence of multi-nucleation in the embryo on day 2 following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Symmetry [ Time Frame: Day 2 and Day 3 post-fertilization ]
    Symmetry in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Stage of development at day 5 [ Time Frame: Day 5 post-fertilization ]
    Stage of development in the embryo 5 days following fertilization. Characterized as: Early blastocyst, Blastocyst, Expanded, Hatched/Hatching, or other. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Inner Cell Mass (ICM) grade [ Time Frame: Day 5 post-fertilization ]
    ICM grade in the embryo 5 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphology - Trophectoderm grade [ Time Frame: Day 5 post-fertilization ]
    Trophectoderm grade in the embryo 5 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
  • Embryo morphokinetics - Abrupt division [ Time Frame: Day 0 to Day 3 post-fertilization ]
    Presence or absence of abrupt division of the embryo from one to three or more cells: a morphokinetic assessment parameter used to grade embryo quality.
  • Embryo morphokinetics - Time of cleavage to five-blastomere embryo [ Time Frame: Day 0 to Day 3 post-fertilization ]
    Presence or absence of optimal time range for cleavage to five-blastomere embryo (48.8-56.6 hours): a morphokinetic assessment parameter used to grade embryo quality.
  • Embryo morphokinetics - Time from two to four-blastomere embryo [ Time Frame: Day 1 to Day 3 post-fertilization ]
    Presence or absence of optimal time duration of division from 2 to 3 cells and subsequent division to 4 cells (0-0.76 hours): a morphokinetic assessment parameter used to grade embryo quality.
  • Embryo morphokinetics - Time from two to three-blastomere embryo [ Time Frame: Day 1 to Day 3 post-fertilization ]
    Presence or absence of optimal time duration of division from two-cell to three-cell embryo (0-11.9 hours): a morphokinetic assessment parameter used to grade embryo quality.
  • Oocyte characteristics - Polar body presence [ Time Frame: Oocyte retrieval until fertilization - less than 1 day ]
    Polar body presence of oocyte on day of oocyte retrieval
  • Biochemical pregnancy rate [ Time Frame: 14 days after embryo transfer ]
    The number of women with a positive β-hCG approximately 14 days after embryo transfer divided by the number of women having an embryo transfer.
  • Cumulative ongoing pregnancy rate [ Time Frame: One year from oocyte pickup ]
    Cumulative number of women with a viable pregnancy at 12 weeks (where pregnancy was obtained with fresh and vitrified embryos from the same ovarian stimulation cycle) divided by the number of women having undergone an oocyte pickup cycle.
  • Live birth rate [ Time Frame: One year and forty weeks ]
    The percentage of all Oocyte Pick Up (OPU) cycles that lead to live birth Approximate time frame will be time of one ovarian stimulation cycle plus term pregnancy
  • Spontaneous abortion rate [ Time Frame: First 20 weeks of gestation ]
    Loss of an embryo or fetus prior to 20 weeks gestation or weighing less than 500 grams.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Time-Lapse Incubation for Embryo Culture - Morphokinetics and Environmental Stability
Official Title  ICMJE Time-Lapse Incubation for Embryo Culture - The Impact of Morphokinetics and Environmental Stability on Reproductive Outcomes
Brief Summary

Embryo culture and selection has been a continuous challenge in evolution since the birth of In Vitro Fertilization (IVF). Traditionally, embryo quality and its presumed suitability for transfer were assessed based on morphologic features. However, the consensus as to the optimal time points for embryo assessment and as to 'preferable' characteristics have been challenging. Alongside this has been the challenge of achieving balance between multiple points of assessment, yet stabilizing the embryo environment for growth. In standard incubation, each new morphological assessment of embryos in culture theoretically creates an additional disruption to culture.

Most recently, time-lapse incubators (TLI) have been introduced as a novel embryo culture system attempting to limit culture disturbances. These incubators have been integrated with digital imaging, allowing for a substantial limitation in embryo handling and environmental disturbances. They have also introduced new morphokinetic parameters to embryo assessment and to optimizing selection of embryos. Thus far, a limited number of studies have examined the clinical outcomes and value of time lapse monitoring systems versus the more ubiquitous incubators (e.g. multichamber) for reproductive outcomes. In particular, the isolated value of morphokinetics in embryo assessment and of this new stable culture environment in TLI are still in question.

The objectives of this study are to prospectively assess and compare fertility outcomes when embryos are cultured in the TLI system versus more traditional bench incubators (BI). We will specifically assess the added value of the closed and isolated TLI compared to BI on reproductive outcomes, as well as the value of morphokinetic grading in IVF.

Detailed Description

Research Objectives:

We are now reaching a new age with an opportunity to advance to theoretically better culture environments and improvements on measures of embryo assessment.

The objectives of this research study will be to evaluate and compare the reproductive outcomes in isolating one of two new interventions introduced by the Time-Lapse Incubator (TLI) system. The first will be an assessment of the TLI environment compared to the standard Bench Incubator (BI) environment. The second will be an assessment of the added morphokinetic grading of embryos compared to the traditional morphologic grading alone.

Although the primary objective of this study will focus on clinical pregnancy rates and fresh embryo transfers, further research using embryos frozen from this study will be conducted to also evaluate cumulative pregnancy rates per oocyte pick-up (OPU) cycle in the future.

Methods The current study will be a prospective randomized and double-blinded study using three patient arms. The first arm will include patients randomized to embryo culture in a tri-gas bench incubator (Miri, Benchtop Multi-room incubator). These embryos will undergo multiple evaluations using light microscopy and traditional morphologic assessment according to accepted criteria. The second arm will include patients randomized to embryo culture in a time-lapse incubator (Miri TL, Time-Lapse Incubator). These embryos will remain in the TLI and undergo both morphologic and morphokinetic evaluation and grading according to a multivariable scoring model. They will not be removed from incubation for the duration of culture. The third arm will include patients also randomized to embryo culture in a time-lapse incubator (Miri TL, Time-Lapse Incubator). These embryos will remain in the TLI and undergo only traditional morphologic assessment according to accepted criteria with no additional imaging. They will also not be removed from incubation for the duration of culture. The time points and evaluated parameters will be identical to those in arm 1 of the study.

Patients will be assessed for suitability, inclusion and exclusion criteria by the physician and nursing team prior to initiation of an IVF/ICSI cycle at our centre. Once the patient is deemed eligible, a member of the care team will discuss details of the study with the patient.

Approved study subjects will undergo standard controlled ovarian hyperstimulation (COH). Protocols and their corresponding medications will be decided upon at the discretion of the treating physician. These may include long gonadotropin-releasing hormone (GnRH) agonist protocol and GnRH antagonist protocol. Follicular aspiration will be performed in the IVF unit via transvaginal needle aspiration. Endometrial preparation and luteal phase support will be recommended as per our departmental protocol. The number of embryos for transfer will be defined prior to cycle initiation, according to The Israel Society of Obstetrics & Gynecology.

Patient randomization will occur after Human Chorionic Gonadotropin (hCG) administration has already been ensured, prior to Intracytoplasmic Sperm Injection (ICSI). The randomization procedure will be accomplished using computer-generated randomization.

After follicular aspiration and transfer to the laboratory, the follicular fluid will be examined for presence of oocytes. Oocytes will then be scored for maturity and any morphologically abnormal features. ICSI will then be performed using fresh sperm from the corresponding partner.

Embryos will then be placed in culture media. The embryos within culture media will then be placed in either the Miri Benchtop or Miri Timelapse incubator according to their corresponding group of randomization. Note that the environment of the Miri benchtop and Miri TL incubators will be considered identical. oxygen concentration and carbon dioxide concentrations set at 5% and 5.5% respectively.

Embryos in arm 1 of the study (Miri Benchtop incubator) will be morphologically assessed by light microscopy at pre-defined time points and according to accepted criteria by one of the trained laboratory embryologists. The time points for evaluation will be at 16 - 20 hours post-ICSI (for normal fertilization), at 44 - 48 hours (day 2) post-ICSI, and then at 64 - 72 hours (day 3) post-ICSI. Evaluated parameters will include cell number, cell size, cell symmetry, and percent fragmentation. Any gross abnormalities will be noted. Embryos will then be graded on day 3 according to these evaluated parameters and transferred according to preferential grading. If embryo transfer has been predetermined for day 5, additional assessment will take place at approximately 116 hours.

Embryos in arm 2 of the study (Miri TL incubator) will be morphologically and morphokinetically assessed by the same laboratory embryologists using digital images generated by the incubator's integrated time-lapse imaging system. Assessment and scoring will be performed as per our scoring classification system. Morphological screening of embryos will initially be performed in order to discard or exclude those clearly not viable for transfer. Morphokinetic parameters will then be used in order to rank remaining embryos score categories from a maximum of 4.0 to a minimum of -2.0, in order of hypothesized decreasing implantation potential.

Embryos in arm 3 of the study (Miri TL incubator) will be morphologically assessed by the embryologists using digital images generated by the incubator's integrated time-lapse imaging system. As noted above, the time points and evaluated parameters will be identical to those in arm 1 of the study. Decisions on embryos for transfer will also be identical.

For each patient, embryos will be selected for transfer based on their morphologic scoring alone (Arm 1 and 3) or by the morphokinetic decision tree scoring (Arm 2). The number of embryos for transfer will have been pre-determined (as noted above).

Those embryos not selected and deemed appropriate for future transfer will undergo cryopreservation by vitrification.

Blinding of the current study will be ensured at multiple points. The gynecologists performing oocyte retrieval and embryo transfer will be blinded to the predefined and randomized patient group. Patients will be unaware of their group of randomization. Statisticians will also be blinded to the group of randomization in calculating pregnancy outcomes. It will unfortunately not be possible to ensure blinding of those embryologists performing the morphologic and morphokinetic assessments.

Sample Size calculation:

The pregnancy rate in our IVF Unit in the sub-group of patients with demographic and clinical characteristics similar to those included in the study, is about 40%. Assuming that in the TLI group pregnancy rate will increase by 10%, the sample size required per group is 124 patients per arm, with an alpha risk of 5% and a power of 80%.

Statistics:

The statistical analysis will be done by intention to treat.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Infertility
  • Genetic Diseases
Intervention  ICMJE
  • Device: Miri, Benchtop Multi-room incubator
    Bench Incubation - Morphologic Assessment These embryos will undergo multiple evaluations using light microscopy and traditional morphologic assessment.
  • Device: Miri TL, Time-Lapse incubator
    Time Lapse Incubation - Morphologic/Morphokinetic Assessment These embryos will remain in the TLI and undergo both morphologic and morphokinetic evaluation and grading according to a hierarchical multivariable model. They will not be removed from incubation for the duration of culture.
  • Device: Miri TL, Time-Lapse incubator
    Time Lapse Incubation - Morphologic Assessment These embryos will remain in the TLI and undergo only traditional morphologic assessment according to accepted criteria with no additional imaging. They will also not be removed from incubation for the duration of culture. The time points and evaluated parameters will be identical to those in arm 1 of the study.
Study Arms  ICMJE
  • Active Comparator: Bench Incubation
    These embryos will be randomized to the bench incubator.
    Intervention: Device: Miri, Benchtop Multi-room incubator
  • Active Comparator: Time Lapse Incubation
    These embryos will be randomized to the Time Lapse Incubator.
    Intervention: Device: Miri TL, Time-Lapse incubator
  • Active Comparator: Time Lapse Incubation - Modified
    These embryos will be randomized to the bench incubator.
    Intervention: Device: Miri TL, Time-Lapse incubator
Publications *

*   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 Unknown status
Estimated Enrollment  ICMJE
 (submitted: January 13, 2016)
372
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2018
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients requiring assisted reproductive technologies for one or more of the following reasons:

    • Male factor infertility
    • Unexplained infertility
    • Mechanical factor infertility
    • Ovulatory infertility
  • Patients undergoing fertility treatment at Shaare Zedek Medical Centre alone.
  • Patients attempting pregnancy with autologous gametes.
  • Patients receiving embryo transfers according to the Israel Society of Obstetrics and Gynecology guideline on number of embryos for transfer during in vitro fertilization.
  • Patients undergoing their first or second ICSI cycle (cumulative to all other institutions involved in prior treatment) since their previous pregnancy.
  • BMI criteria: >18 and <30 kg/m2

Exclusion Criteria:

  • An infertility diagnosis that includes the following:

    • Severe male factor infertility requiring testicular aspiration, testicular biopsy for sperm retrieval, or less than 1000 sperm per ejaculate.
    • Untreated hydrosalpinx
    • Persistently thin endometrial lining or endometrial factor
    • Severe Endometriosis
    • Low ovarian reserve (≤8 antral follicle count (AFC) follicles measuring 2 to 10 mm in diameter on day 2-4 of menstrual cycle, or day 3 follicle stimulating hormone (FSH) ≥10 milli-International unit (mIU) /mL)
    • High risk for Ovarian Hyperstimulation Syndrome (Estradiol level >13 000 pmol/L or >20 follicles ≥16 mm diameter during controlled ovarian hyper stimulation, ≥20 oocytes collected).
  • Patients obtaining GnRH agonist for final follicular maturation
  • Patients requiring preimplantation genetic diagnosis (PGD)
  • Patients who require freezing of all oocytes or embryos
  • More than 2 previous cycles of IVF since previous pregnancy
  • Current smokers
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02657811
Other Study ID Numbers  ICMJE 0169-15-SZMC
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ruthie Ronn, Shaare Zedek Medical Center
Study Sponsor  ICMJE Shaare Zedek Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ruth Ronn, M.D. C.M. Shaare Zedek Medical Center
Principal Investigator: Talia Eldar-Geva, M.D. Ph.D. Shaare Zedek Medical Center
PRS Account Shaare Zedek Medical Center
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP