InfertilityNCT02657811
Time-Lapse Incubation for Embryo Culture - Morphokinetics and Environmental Stability
A study testing Miri, Benchtop Multi-room incubator and Miri TL, Time-Lapse incubator in people with Infertility and Genetic Diseases, run by Shaare Zedek Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, women only
- Conditions the study is for
- Infertility, Genetic Diseases
- What is being tested?
- Miri, Benchtop Multi-room incubator and Miri TL, Time-Lapse incubator
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 372 participants
- Where
- 1 siteIsrael
- Study dates
- Oct 2016to Aug 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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)
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- 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
Trial locations and contacts
1 site in 1 country.
Israel1 site, 1 recruiting
- Recruiting
Shaare Zedek Medical Center
Jerusalem, 9103102
Ruth Ronn, M.D. C.M., 972-2-655-5111, RuthRonn@szmc.org.il
Talia Eldar-Geva, M.D. PhD., 972-2-655-5111, gevat@szmc.org.il
About this study
Official title: Time-Lapse Incubation for Embryo Culture - The Impact of Morphokinetics and Environmental Stability on Reproductive Outcomes
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.
Read the 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.
- Conditions
- Infertility, Genetic Diseases
- Being tested
- Miri, Benchtop Multi-room incubator, Miri TL, Time-Lapse incubator
- Keywords
- Time-Lapse Imaging, Embryo Culture Techniques, Fertilization in Vitro, Embryology, Assisted Reproductive Techniques, Infertility, Preimplantation diagnosis
- Medical subject headings
- Infertility, Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Miri, Benchtop Multi-room incubatorDevice
Bench Incubation - Morphologic Assessment These embryos will undergo multiple evaluations using light microscopy and traditional morphologic assessment.
Miri TL, Time-Lapse incubatorDevice
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.
Miri TL, Time-Lapse incubatorDevice
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 group | Role | What they receive |
|---|---|---|
| Bench Incubation | Active comparator | These embryos will be randomized to the bench incubator. Receives: Device: Miri, Benchtop Multi-room incubator |
| Time Lapse Incubation | Active comparator | These embryos will be randomized to the Time Lapse Incubator. Receives: Device: Miri TL, Time-Lapse incubator |
| Time Lapse Incubation - Modified | Active comparator | These embryos will be randomized to the bench incubator. Receives: Device: Miri TL, Time-Lapse incubator |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ongoing pregnancy rate
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.
Measured: 12 weeks gestation
Secondary outcomes (17)
Embryo morphology - Number of pronuclei present following fertilization
Number of pronuclei present in the embryo 1 day following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 1 post-fertilization
Embryo morphology - Number of cells present
Number of cells present in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 2 and Day 3 post-fertilization
Embryo morphology - % fragmentation
Percent fragmentation in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 2 and Day 3 post-fertilization
Embryo morphology - Presence of multi nucleation
Presence of multi-nucleation in the embryo on day 2 following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 2 post-fertilization
Embryo morphology - Symmetry
Symmetry in the embryo 2 and 3 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 2 and Day 3 post-fertilization
Embryo morphology - Stage of development at day 5
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.
Measured: Day 5 post-fertilization
Embryo morphology - Inner Cell Mass (ICM) grade
ICM grade in the embryo 5 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 5 post-fertilization
Embryo morphology - Trophectoderm grade
Trophectoderm grade in the embryo 5 days following fertilization. Morphologic assessment parameter used to grade embryo quality.
Measured: Day 5 post-fertilization
Embryo morphokinetics - Abrupt division
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.
Measured: Day 0 to Day 3 post-fertilization
Embryo morphokinetics - Time of cleavage to five-blastomere embryo
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.
Measured: Day 0 to Day 3 post-fertilization
Embryo morphokinetics - Time from two to four-blastomere embryo
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.
Measured: Day 1 to Day 3 post-fertilization
Embryo morphokinetics - Time from two to three-blastomere embryo
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.
Measured: Day 1 to Day 3 post-fertilization
Oocyte characteristics - Polar body presence
Polar body presence of oocyte on day of oocyte retrieval
Measured: Oocyte retrieval until fertilization - less than 1 day
Biochemical pregnancy rate
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.
Measured: 14 days after embryo transfer
Cumulative ongoing pregnancy rate
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.
Measured: One year from oocyte pickup
Live birth rate
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
Measured: One year and forty weeks
Spontaneous abortion rate
Loss of an embryo or fetus prior to 20 weeks gestation or weighing less than 500 grams.
Measured: First 20 weeks of gestation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2016 (estimated)
- Study startOct 2016
- Primary completionDec 2017 (estimated)
- Study completionAug 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for InfertilityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 372 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Shaare Zedek Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ruthie Ronn, Shaare Zedek Medical Center
- Investigators
- Ruth Ronn, M.D. C.M., Principal investigator, Shaare Zedek Medical CenterTalia Eldar-Geva, M.D. Ph.D., Principal investigator, Shaare Zedek Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02657811
- Sponsor's protocol ID
- 0169-15-SZMC
- Status last verified
- Feb 2017
- First submitted
- 5 Jan 2016
- Last updated
- 23 Feb 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.
PubMed 21502182Kirkegaard K, Ahlstrom A, Ingerslev HJ, Hardarson T. Choosing the best embryo by time lapse versus standard morphology. Fertil Steril. 2015 Feb;103(2):323-32. doi: 10.1016/j.fertnstert.2014.11.003. Epub 2014 Dec 17.
PubMed 25527231Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril. 2013 Jan;99(1):44-46. doi: 10.1016/j.fertnstert.2012.09.038. Epub 2012 Oct 22.
PubMed 23095140Swain JE. Decisions for the IVF laboratory: comparative analysis of embryo culture incubators. Reprod Biomed Online. 2014 May;28(5):535-47. doi: 10.1016/j.rbmo.2014.01.004. Epub 2014 Jan 27.
PubMed 24656561Fujiwara M, Takahashi K, Izuno M, Duan YR, Kazono M, Kimura F, Noda Y. Effect of micro-environment maintenance on embryo culture after in-vitro fertilization: comparison of top-load mini incubator and conventional front-load incubator. J Assist Reprod Genet. 2007 Jan;24(1):5-9. doi: 10.1007/s10815-006-9088-3. Epub 2006 Dec 13.
PubMed 17160731Zhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010 Apr;20(4):510-5. doi: 10.1016/j.rbmo.2009.12.027. Epub 2009 Dec 28.
PubMed 20129824Armstrong S, Arroll N, Cree LM, Jordan V, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2015 Feb 27;(2):CD011320. doi: 10.1002/14651858.CD011320.pub2.
PubMed 25721906Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011 Oct;26(10):2658-71. doi: 10.1093/humrep/der256. Epub 2011 Aug 9.
PubMed 21828117Lemmen JG, Agerholm I, Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes. Reprod Biomed Online. 2008 Sep;17(3):385-91. doi: 10.1016/s1472-6483(10)60222-2.
PubMed 18765009Meseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 10.1016/j.fertnstert.2012.08.016. Epub 2012 Sep 10.
PubMed 22975113Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Reijo Pera RA. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nat Biotechnol. 2010 Oct;28(10):1115-21. doi: 10.1038/nbt.1686. Epub 2010 Oct 3.
PubMed 20890283Dal Canto M, Coticchio G, Mignini Renzini M, De Ponti E, Novara PV, Brambillasca F, Comi R, Fadini R. Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation. Reprod Biomed Online. 2012 Nov;25(5):474-80. doi: 10.1016/j.rbmo.2012.07.016. Epub 2012 Aug 2.
PubMed 22995750Cruz M, Garrido N, Herrero J, Perez-Cano I, Munoz M, Meseguer M. Timing of cell division in human cleavage-stage embryos is linked with blastocyst formation and quality. Reprod Biomed Online. 2012 Oct;25(4):371-81. doi: 10.1016/j.rbmo.2012.06.017. Epub 2012 Jul 7.
PubMed 22877944Hlinka D, Kalatova B, Uhrinova I, Dolinska S, Rutarova J, Rezacova J, Lazarovska S, Dudas M. Time-lapse cleavage rating predicts human embryo viability. Physiol Res. 2012;61(5):513-25. doi: 10.33549/physiolres.932287. Epub 2012 Aug 8.
PubMed 22881225Rubio I, Kuhlmann R, Agerholm I, Kirk J, Herrero J, Escriba MJ, Bellver J, Meseguer M. Limited implantation success of direct-cleaved human zygotes: a time-lapse study. Fertil Steril. 2012 Dec;98(6):1458-63. doi: 10.1016/j.fertnstert.2012.07.1135. Epub 2012 Aug 25.
PubMed 22925687
Study at a glance
From the registry record, last updated by the sponsor on 23 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Time-Lapse Incubation for Embryo Culture - The Impact of Morphokinetics and Environmental Stability on Reproductive Outcomes
- ClinicalTrials.gov ID
- NCT02657811
- Acronym / sponsor ID
- 0169-15-SZMC
- Conditions
- Infertility, Genetic Diseases
- Keywords
- Time-Lapse Imaging, Embryo Culture Techniques, Fertilization in Vitro, Embryology, Assisted Reproductive Techniques, Infertility, Preimplantation diagnosis
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 372 participants (estimated)
- Lead sponsor
- Shaare Zedek Medical CenterUniversity, hospital or other
- Study start
- Oct 2016 (actual)
- Primary completion
- Dec 2017 (estimated)
- Study completion
- Aug 2018 (estimated)
- First posted
- 18 Jan 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Bench Incubation | Active comparator | Device: Miri, Benchtop Multi-room incubatorThese embryos will be randomized to the bench incubator. |
| Time Lapse Incubation | Active comparator | Device: Miri TL, Time-Lapse incubatorThese embryos will be randomized to the Time Lapse Incubator. |
| Time Lapse Incubation - Modified | Active comparator | Device: Miri TL, Time-Lapse incubatorThese embryos will be randomized to the bench incubator. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Patients requiring assisted reproductive technologies for one or more of the following reasons:
- 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.
Key exclusion criteria (12 listed)
- An infertility diagnosis that includes the following:
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Miri, Benchtop Multi-room incubatorBench Incubation - Morphologic Assessment These embryos will undergo multiple evaluations using light microscopy and traditional morphologic assessment. | Device | Bench Incubation |
| Miri TL, Time-Lapse incubatorTime 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 | Time Lapse Incubation |
| Miri TL, Time-Lapse incubatorTime 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. | Device | Time Lapse Incubation - Modified |
Primary outcome
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.
17 secondary outcomes
Embryo morphology - Number of pronuclei present following fertilization
Time frame: Day 1 post-fertilization
Embryo morphology - Number of cells present
Time frame: Day 2 and Day 3 post-fertilization
Embryo morphology - % fragmentation
Time frame: Day 2 and Day 3 post-fertilization
Embryo morphology - Presence of multi nucleation
Time frame: Day 2 post-fertilization
Embryo morphology - Symmetry
Time frame: Day 2 and Day 3 post-fertilization
Embryo morphology - Stage of development at day 5
Time frame: Day 5 post-fertilization
Embryo morphology - Inner Cell Mass (ICM) grade
Time frame: Day 5 post-fertilization
Embryo morphology - Trophectoderm grade
Time frame: Day 5 post-fertilization
Embryo morphokinetics - Abrupt division
Time frame: Day 0 to Day 3 post-fertilization
Embryo morphokinetics - Time of cleavage to five-blastomere embryo
Time frame: Day 0 to Day 3 post-fertilization
Embryo morphokinetics - Time from two to four-blastomere embryo
Time frame: Day 1 to Day 3 post-fertilization
Embryo morphokinetics - Time from two to three-blastomere embryo
Time frame: Day 1 to Day 3 post-fertilization
Oocyte characteristics - Polar body presence
Time frame: Oocyte retrieval until fertilization - less than 1 day
Biochemical pregnancy rate
Time frame: 14 days after embryo transfer
Cumulative ongoing pregnancy rate
Time frame: One year from oocyte pickup
Live birth rate
Time frame: One year and forty weeks
Spontaneous abortion rate
Time frame: First 20 weeks of gestation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Feb 2017.
- Background: PubMed 21502182Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.
- Background: PubMed 25527231Kirkegaard K, Ahlstrom A, Ingerslev HJ, Hardarson T. Choosing the best embryo by time lapse versus standard morphology. Fertil Steril. 2015 Feb;103(2):323-32. doi: 10.1016/j.fertnstert.2014.11.003. Epub 2014 Dec 17.
- Background: PubMed 23095140Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril. 2013 Jan;99(1):44-46. doi: 10.1016/j.fertnstert.2012.09.038. Epub 2012 Oct 22.
- Background: PubMed 24656561Swain JE. Decisions for the IVF laboratory: comparative analysis of embryo culture incubators. Reprod Biomed Online. 2014 May;28(5):535-47. doi: 10.1016/j.rbmo.2014.01.004. Epub 2014 Jan 27.
- Background: PubMed 17160731Fujiwara M, Takahashi K, Izuno M, Duan YR, Kazono M, Kimura F, Noda Y. Effect of micro-environment maintenance on embryo culture after in-vitro fertilization: comparison of top-load mini incubator and conventional front-load incubator. J Assist Reprod Genet. 2007 Jan;24(1):5-9. doi: 10.1007/s10815-006-9088-3. Epub 2006 Dec 13.
- Background: PubMed 20129824Zhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010 Apr;20(4):510-5. doi: 10.1016/j.rbmo.2009.12.027. Epub 2009 Dec 28.
- Background: PubMed 25721906Armstrong S, Arroll N, Cree LM, Jordan V, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2015 Feb 27;(2):CD011320. doi: 10.1002/14651858.CD011320.pub2.
- Background: PubMed 21828117Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011 Oct;26(10):2658-71. doi: 10.1093/humrep/der256. Epub 2011 Aug 9.
- Background: PubMed 18765009Lemmen JG, Agerholm I, Ziebe S. Kinetic markers of human embryo quality using time-lapse recordings of IVF/ICSI-fertilized oocytes. Reprod Biomed Online. 2008 Sep;17(3):385-91. doi: 10.1016/s1472-6483(10)60222-2.
- Background: PubMed 22975113Meseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A. Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study. Fertil Steril. 2012 Dec;98(6):1481-9.e10. doi: 10.1016/j.fertnstert.2012.08.016. Epub 2012 Sep 10.
- Background: PubMed 20890283Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Reijo Pera RA. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nat Biotechnol. 2010 Oct;28(10):1115-21. doi: 10.1038/nbt.1686. Epub 2010 Oct 3.
- Background: PubMed 22995750Dal Canto M, Coticchio G, Mignini Renzini M, De Ponti E, Novara PV, Brambillasca F, Comi R, Fadini R. Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation. Reprod Biomed Online. 2012 Nov;25(5):474-80. doi: 10.1016/j.rbmo.2012.07.016. Epub 2012 Aug 2.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ruth Ronn, M.D. C.M. principal investigator
Shaare Zedek Medical Center
Talia Eldar-Geva, M.D. Ph.D. principal investigator
Shaare Zedek Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Miri, Benchtop Multi-room incubator and Miri TL, Time-Lapse incubator in people with Infertility and Genetic Diseases, run by Shaare Zedek Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ruth Ronn, M.D. C.M. (972-2-655-5111, RuthRonn@szmc.org.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ongoing pregnancy rate (time frame: 12 weeks gestation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02657811, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Feb 2017.