Infertility
Conditions
Keywords
GERI+, TICON, EEVA, Embryo culture, In Vitro Fertilization, Intracytoplasmic Sperm Injection
Brief summary
The main purpose of the study was to evaluate the overall clinical value of GERI+ as an integrated embryo culture and assessment system, providing an undisturbed culture environment, continuous monitoring of embryo development and automated scoring using a predictive algorithm.
Interventions
DEVICEGERI+ incubator
The embryo culture of consented participants were carried out in GERI+ incubator for both bright-field and dark-field time lapse monitoring until Day 3 of embryo culture. On Day 3, all embryos were reviewed firstly by GERI Assess software, using bright-field imaging. Finally the embryo(s) with the highest EEVA grade are transferred were followed up until the achievement of implantation and confirmation of pregnancy.
DEVICEConventional incubator
The embryo culture of consented participants were carried out in conventional incubator for culture until Day 3 of embryo culture. On Day 3 of embryo culture, all embryos are assessed using a bench-top microscope. The embryo(s) with optimal cell stage and grade were transferred and were followed up until the achievement of implantation and confirmation of pregnancy.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Couples with less than or equal to (\<= ) two failed fresh In Vitro Fertilization/Intracytoplasmic Sperm Injection (IVF/ICSI) embryo transfer cycles * Age greater than or equal to (\>=) 18 and \<= 40 years * Body mass index (BMI): 18-30 kilogram per meter square (kg/m2) * Normal uterine cavity under ultrasound * Participant and her husband/partner must have read and signed the Informed Consent form (ICF) * At least four normally fertilized oocytes (2Pronuclear stage (PN)) in the current cycle
Exclusion criteria
* Male with non-ejaculated sperm * Participants with abnormal, undiagnosed gynecological bleeding or with genitourinary malformations * Participants with any contraindication to Controlled Ovarian Stimulation (COS) for Assisted Reproductive Technologies (ART) or to gonadotropins * Planned freeze all cycle (oocytes or embryos) * Planned preimplantation genetic screening (PGS) or Pre-implantation genetic diagnosis (PGD) cycle * Concurrent participation in another clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Pregnancy Rate With Positive Fetal Heart Beat (FHB) | Gestation Weeks 6 to 8 | Clinical Pregnancy was defined as the pregnancy diagnosed by ultrasonographic or clinical documentation of at least one fetus with heart beat in gestational week 6 to 8. Clinical pregnancy rate with positive FHB was measured as the number of participants with FHB positive clinical pregnancy divided by number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck Global Medical Affairs (GMA) interpretation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Utilizable Embryos Rate | Day 3 of embryo culture | Utilizable embryos rate is defined as the number of transferred and cryopreserved embryos divided by the number embryos stage zygotes per participant multiply by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Good Quality Embryos Rate | Day 3 of embryo culture | Good Quality Embryos is defined embryos with 7 or more blastomeres, less than (\<) 25 % fragmentation, size and symmetry of blastomeres appropriate to the cell number, and no evidence of multinucleation, based on the morphology on Day 3 of embryo culture. Good quality embryos rate was defined as the number of good quality embryos divided by the number of embryos per participant multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Non-viable Embryos Rate | Days 1 to 3 of embryo culture | Non-viable Embryos is defined as the embryos in which development has been arrested for at least 24 hour or in which all the cells have degenerated or lysed. Non-viable embryos rate was defined as the number of non-viable embryos divided by the number of embryos per participant multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Biochemical Pregnancy Rate | From Day 12 of Gestational up to Week 8 | Biochemical Pregnancy defined as a pregnancy diagnosed only by the detection of Human Chorionic Gonadotropin (hCG) in serum or urine and that does not develop into a clinical pregnancy. Biochemical pregnancy rate was defined as the number of participants with biochemical pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Implantation Rate (IR) With Positive Fetal Heart Beat | Gestational Weeks 6 to 8 | A successful implantation is defined as the presence of one gestational sac with fetal heart beat (FHB) under ultrasonography at gestational weeks 6-8. Implantation rate (IR) was defined as the number of intrauterine gestational sacs with positive FHB under ultrasound scans at gestational weeks 6-8 divided by the total number of embryos transferred (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Multiple Pregnancy Rate | Gestational Weeks 10 to 12 | Multiple pregnancy is defined as a pregnancy with more than one fetus. It is identified by ultrasonography at gestational weeks 10-12. Multiple pregnancy rate was defined as the number of participants with multiple pregnancy divided by the number of participants with ongoing pregnancy multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Ectopic Pregnancy Rate | Gestational Weeks 6 to 8 | Ectopic pregnancy is defined as a pregnancy in which implantation takes place outside the uterine cavity. It is identified by ultrasonography at weeks 6-8. Ectopic Pregnancy Rate was defined as the number of participants with ectopic pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Spontaneous Miscarriage Rate | Gestational Weeks 10 to 12 | Spontaneous miscarriage (SM) is the spontaneous loss of a clinical pregnancy before 20 completed weeks of gestational age (18 weeks after fertilization). In this study, the spontaneous miscarriage was tracked up to 10-12 weeks of gestational age. Spontaneous miscarriage rate was defined as the number of participants with spontaneous miscarriage divided by the number of participants with clinical pregnancy multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
| Ongoing Pregnancy Rate | Gestational Weeks 10 to 12 | Ongoing pregnancy is defined as the presence of viable fetuses identified by ultrasonography at gestational weeks 10-12. Ongoing pregnancy rate is defined as the number of participants with ongoing pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation. |
Countries
Canada, Denmark, France, Italy, Norway, Portugal, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GERI+ Incubator The embryo culture of consented participants carried out in Genea Embryo Review Instrument Plus (GERI+) incubator for both bright-field and dark-field time lapse monitoring until Day 3 of embryo culture. On Day 3, all embryos were reviewed firstly by GERI Assess software, using bright-field imaging. Finally the embryo(s) with the highest EEVA grade were transferred and were followed up until the achievement of implantation and confirmation of pregnancy. | 200 |
| Conventional Incubator The embryo culture of consented participants were carried out in conventional incubator for culture until Day 3 of embryo culture. On Day 3 of embryo culture, all embryos were assessed using a bench-top microscope. The embryo(s) with optimal cell stage and grade were transferred and were followed up until the achievement of implantation and confirmation of pregnancy. | 208 |
| Total | 408 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cancellation of Fresh Embryo Transfer | 12 | 14 |
| Overall Study | Imaging discontinued prior completion | 8 | 0 |
| Overall Study | Other | 8 | 2 |
| Overall Study | Participant was non-compliant | 1 | 0 |
Baseline characteristics
| Characteristic | GERI+ Incubator | Conventional Incubator | Total |
|---|---|---|---|
| Age, Continuous | 33.27 Years STANDARD_DEVIATION 4.076 | 33.23 Years STANDARD_DEVIATION 3.996 | 33.25 Years STANDARD_DEVIATION 4.03 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 200 Participants | 208 Participants | 408 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Clinical Pregnancy Rate With Positive Fetal Heart Beat (FHB)
Clinical Pregnancy was defined as the pregnancy diagnosed by ultrasonographic or clinical documentation of at least one fetus with heart beat in gestational week 6 to 8. Clinical pregnancy rate with positive FHB was measured as the number of participants with FHB positive clinical pregnancy divided by number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck Global Medical Affairs (GMA) interpretation.
Time frame: Gestation Weeks 6 to 8
Population: Full analysis (FA) dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Clinical Pregnancy Rate With Positive Fetal Heart Beat (FHB) | 39.4 Percentage of pregnancy per ET |
| Conventional Incubator | Clinical Pregnancy Rate With Positive Fetal Heart Beat (FHB) | 38.9 Percentage of pregnancy per ET |
Secondary
Biochemical Pregnancy Rate
Biochemical Pregnancy defined as a pregnancy diagnosed only by the detection of Human Chorionic Gonadotropin (hCG) in serum or urine and that does not develop into a clinical pregnancy. Biochemical pregnancy rate was defined as the number of participants with biochemical pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: From Day 12 of Gestational up to Week 8
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Biochemical Pregnancy Rate | 7.2 Percentage of Pregnancy per ET |
| Conventional Incubator | Biochemical Pregnancy Rate | 4.7 Percentage of Pregnancy per ET |
Secondary
Ectopic Pregnancy Rate
Ectopic pregnancy is defined as a pregnancy in which implantation takes place outside the uterine cavity. It is identified by ultrasonography at weeks 6-8. Ectopic Pregnancy Rate was defined as the number of participants with ectopic pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Gestational Weeks 6 to 8
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Ectopic Pregnancy Rate | 1.1 Percentage of Pregnancy per ET |
| Conventional Incubator | Ectopic Pregnancy Rate | 0.5 Percentage of Pregnancy per ET |
Secondary
Good Quality Embryos Rate
Good Quality Embryos is defined embryos with 7 or more blastomeres, less than (\<) 25 % fragmentation, size and symmetry of blastomeres appropriate to the cell number, and no evidence of multinucleation, based on the morphology on Day 3 of embryo culture. Good quality embryos rate was defined as the number of good quality embryos divided by the number of embryos per participant multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Day 3 of embryo culture
Population: FA dataset included all randomized participants. Here, Number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GERI+ Incubator | Good Quality Embryos Rate | 34.85 Percentage of Good Quality Embryos | Standard Deviation 25.999 |
| Conventional Incubator | Good Quality Embryos Rate | 37.68 Percentage of Good Quality Embryos | Standard Deviation 29.115 |
Secondary
Implantation Rate (IR) With Positive Fetal Heart Beat
A successful implantation is defined as the presence of one gestational sac with fetal heart beat (FHB) under ultrasonography at gestational weeks 6-8. Implantation rate (IR) was defined as the number of intrauterine gestational sacs with positive FHB under ultrasound scans at gestational weeks 6-8 divided by the total number of embryos transferred (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Gestational Weeks 6 to 8
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Implantation Rate (IR) With Positive Fetal Heart Beat | 31.2 Percentage of gestational sacs per ET |
| Conventional Incubator | Implantation Rate (IR) With Positive Fetal Heart Beat | 32.5 Percentage of gestational sacs per ET |
Secondary
Multiple Pregnancy Rate
Multiple pregnancy is defined as a pregnancy with more than one fetus. It is identified by ultrasonography at gestational weeks 10-12. Multiple pregnancy rate was defined as the number of participants with multiple pregnancy divided by the number of participants with ongoing pregnancy multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Gestational Weeks 10 to 12
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Multiple Pregnancy Rate | 1.6 Percentage of Multiple Pregnancy |
| Conventional Incubator | Multiple Pregnancy Rate | 11.4 Percentage of Multiple Pregnancy |
Secondary
Non-viable Embryos Rate
Non-viable Embryos is defined as the embryos in which development has been arrested for at least 24 hour or in which all the cells have degenerated or lysed. Non-viable embryos rate was defined as the number of non-viable embryos divided by the number of embryos per participant multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Days 1 to 3 of embryo culture
Population: FA dataset included all randomized participants. Here, Number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GERI+ Incubator | Non-viable Embryos Rate | 29.64 Percentage of Non-viable Embryos | Standard Deviation 27.932 |
| Conventional Incubator | Non-viable Embryos Rate | 30.67 Percentage of Non-viable Embryos | Standard Deviation 29.001 |
Secondary
Ongoing Pregnancy Rate
Ongoing pregnancy is defined as the presence of viable fetuses identified by ultrasonography at gestational weeks 10-12. Ongoing pregnancy rate is defined as the number of participants with ongoing pregnancy divided by the number of participants with embryo transfer (ET) multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Gestational Weeks 10 to 12
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Ongoing Pregnancy Rate | 35.0 Percentage of Pregnancy per ET |
| Conventional Incubator | Ongoing Pregnancy Rate | 36.3 Percentage of Pregnancy per ET |
Secondary
Spontaneous Miscarriage Rate
Spontaneous miscarriage (SM) is the spontaneous loss of a clinical pregnancy before 20 completed weeks of gestational age (18 weeks after fertilization). In this study, the spontaneous miscarriage was tracked up to 10-12 weeks of gestational age. Spontaneous miscarriage rate was defined as the number of participants with spontaneous miscarriage divided by the number of participants with clinical pregnancy multiplied by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Gestational Weeks 10 to 12
Population: FA dataset included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GERI+ Incubator | Spontaneous Miscarriage Rate | 9.3 Percentage of miscarriages |
| Conventional Incubator | Spontaneous Miscarriage Rate | 10.1 Percentage of miscarriages |
Secondary
Utilizable Embryos Rate
Utilizable embryos rate is defined as the number of transferred and cryopreserved embryos divided by the number embryos stage zygotes per participant multiply by 100. Here, data used for analysis was based on Merck GMA interpretation.
Time frame: Day 3 of embryo culture
Population: FA dataset included all randomized participants. Here, Number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GERI+ Incubator | Utilizable Embryos Rate | 50.72 Percentage of embryos | Standard Deviation 23.379 |
| Conventional Incubator | Utilizable Embryos Rate | 50.11 Percentage of embryos | Standard Deviation 24.183 |