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
|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
||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
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|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|
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.
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%.
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
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Estimated Enrollment ICMJE
|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||
|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|
|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|
|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