Fertility
Conditions
Keywords
TiLE, Embryo Assessment, Pregnancy, Implantation
Brief summary
The purpose of the study was to explore the added value of adjunctive use of Early Embryo Viability Assessment (Eeva) with morphological grading in identifying optimal embryos for transfer.
Detailed description
This study is a Phase IV, open label, prospective, randomized, exploratory, multicenter study. Subjects were randomized in 2:1 ratio to two treatment groups: in the experimental group, embryos were assessed for embryo transfer (ET) with Eeva and morphological grading, while in the control group embryos were assessed with morphological grading only.
Interventions
DEVICEEeva
Embryos of subjects randomized in this group were assessed using Eeva System and morphological grading to identify optimal embryos for transfer.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* All infertile subjects treated with In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) * Subject age less than or equal to (\<=) 40 years * Less than or equal to (\<=) 3 failed IVF/ICSI cycles * At least 4 normally fertilized eggs (2 pronuclei \[2PN\]) in current cycle * Normal uterine cavity * Fertilization using only ejaculated sperm (fresh or frozen) * Subject must have read and signed the Informed Consent Form
Exclusion criteria
* Have clinically significant systemic disease * Have abnormal, undiagnosed gynecological bleeding * Have any contraindication to Controlled Ovarian Stimulation (COS) for assisted reproductive technologies (ART) and to gonadotropins to be used in ART * Egg donor cycle * Planned freeze all cycle (oocytes or embryos) * Concurrent participation in another clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Implantation Rate | Gestational Weeks 5 to 8 | Implantation rate was calculated by dividing the number of intrauterine gestational sacs by the number of embryos transferred multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Ongoing Pregnancy Status | Gestational Weeks 10 to 12 | Ongoing pregnancy was defined as having a positive fetal heart beat (FHB) as assessed by ultrasonography at gestational week 10-12. Number of subjects with ongoing pregnancy status has been reported, where Yes indicates participants with positive ongoing pregnancy status and No indicates participants with negative ongoing pregnancy status . |
| Multiple Pregnancy Rate | Gestational Weeks 5 to 8 | Multiple pregnancy rate was defined as a clinical pregnancy with greater than equals to (\>=) 2 fetal sacs as assessed by ultrasonography. Multiple Pregnancies rate was measured by number of multiple pregnancies divided by number of embryo transfer cycles multiplied by 100. |
| Utilization Rate | Day 3 or Day 5/6 of embryo culture | Utilization rate was defined as the sum of number of transferred and frozen embryos divided by number of normally fertilized oocytes multiplied by 100. |
| Clinical Pregnancy Rate | Gestational Weeks 5 to 8 | Clinical pregnancy was confirmed by the presence of a gestational sac with heartbeat as assessed by ultrasonography. Clinical pregnancy rate was measured as the number of clinical pregnancies divided by number of embryo transfer (ET) cycles multiplied by 100. |
| Spontaneous Miscarriage Rate | Gestational Weeks 10 to 12 | Spontaneous miscarriage rate was measured by the number of spontaneous miscarriages as communicated during medical appointment or by telephone contact divided by number of clinical pregnancies multiplied by 100. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 5/6 Embryo Transfer (ET) | Day 5/6 of embryo culture | Eeva Conformity was reported as the number of subjects who were compliant to use Eeva in embryo assessment in the Early Embryo Viability Assessment + morphological grading group. Eeva-compliance subgroup refers to subjects whose embryos were assessed by embryologists following the recommendation of Eeva system and the IFU of Eeva. Subgroup analysis revealed a high incidence of Eeva noncompliance in the experimental group, which compromised the quality of this study. Only Early Embryo Viability Assessment + Morphological Grading reporting arm was applicable for this outcome measure. |
| Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 3 Embryo Transfer (ET) | Day 3 of embryo culture | Eeva Conformity was reported as the number of subjects who were compliant to use Eeva in embryo assessment in the Early Embryo Viability Assessment + morphological grading group. Eeva-compliance subgroup refers to subjects whose embryos were assessed by embryologists following the recommendation of Eeva system and the instructions for use (IFU) of Eeva. Subgroup analysis revealed a high incidence of Eeva noncompliance in the experimental group, which compromised the quality of this study. Only Early Embryo Viability Assessment + Morphological Grading reporting arm was applicable for this outcome measure. |
Countries
Canada, Denmark, France, Germany, Italy, Norway, Spain, Sweden, United Kingdom
Participant flow
Pre-assignment details
A total of 976 subjects were enrolled, out of which 970 subjects were randomized and started the study.
Participants by arm
| Arm | Count |
|---|---|
| Early Embryo Viability Assessment + Morphological Grading Embryos of subjects randomized in this group were assessed using Early Embryo Viability Assessment (Eeva) System and morphological grading to identify optimal embryos for transfer. | 645 |
| Morphological Grading Embryos of subjects randomized in this group were assessed only using morphological grading to identify optimal embryos for transfer. | 325 |
| Total | 970 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Inconclusive due to missing data | 52 | 19 |
Baseline characteristics
| Characteristic | Early Embryo Viability Assessment + Morphological Grading | Morphological Grading | Total |
|---|---|---|---|
| Age, Continuous | 33.6 Years STANDARD_DEVIATION 3.64 | 33.8 Years STANDARD_DEVIATION 3.61 | 33.7 Years STANDARD_DEVIATION 3.63 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 645 Participants | 325 Participants | 970 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
Implantation Rate
Implantation rate was calculated by dividing the number of intrauterine gestational sacs by the number of embryos transferred multiplied by 100.
Time frame: Gestational Weeks 5 to 8
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Implantation Rate | 30.1 % of sacs per embryo transferred |
| Morphological Grading | Implantation Rate | 35.3 % of sacs per embryo transferred |
Secondary
Clinical Pregnancy Rate
Clinical pregnancy was confirmed by the presence of a gestational sac with heartbeat as assessed by ultrasonography. Clinical pregnancy rate was measured as the number of clinical pregnancies divided by number of embryo transfer (ET) cycles multiplied by 100.
Time frame: Gestational Weeks 5 to 8
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Clinical Pregnancy Rate | 41.0 Percentage of pregnancy per transfer |
| Morphological Grading | Clinical Pregnancy Rate | 47.6 Percentage of pregnancy per transfer |
Secondary
Multiple Pregnancy Rate
Multiple pregnancy rate was defined as a clinical pregnancy with greater than equals to (\>=) 2 fetal sacs as assessed by ultrasonography. Multiple Pregnancies rate was measured by number of multiple pregnancies divided by number of embryo transfer cycles multiplied by 100.
Time frame: Gestational Weeks 5 to 8
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Multiple Pregnancy Rate | 6.4 Percentage of pregnancy per transfer |
| Morphological Grading | Multiple Pregnancy Rate | 8.4 Percentage of pregnancy per transfer |
Secondary
Number of Subjects With Ongoing Pregnancy Status
Ongoing pregnancy was defined as having a positive fetal heart beat (FHB) as assessed by ultrasonography at gestational week 10-12. Number of subjects with ongoing pregnancy status has been reported, where Yes indicates participants with positive ongoing pregnancy status and No indicates participants with negative ongoing pregnancy status .
Time frame: Gestational Weeks 10 to 12
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | Yes | 30 Subjects |
| Early Embryo Viability Assessment + Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | No | 2 Subjects |
| Early Embryo Viability Assessment + Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | Missing | 613 Subjects |
| Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | Yes | 11 Subjects |
| Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | No | 1 Subjects |
| Morphological Grading | Number of Subjects With Ongoing Pregnancy Status | Missing | 313 Subjects |
Secondary
Spontaneous Miscarriage Rate
Spontaneous miscarriage rate was measured by the number of spontaneous miscarriages as communicated during medical appointment or by telephone contact divided by number of clinical pregnancies multiplied by 100.
Time frame: Gestational Weeks 10 to 12
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Spontaneous Miscarriage Rate | NA Percentage of miscarriages |
| Morphological Grading | Spontaneous Miscarriage Rate | NA Percentage of miscarriages |
Secondary
Utilization Rate
Utilization rate was defined as the sum of number of transferred and frozen embryos divided by number of normally fertilized oocytes multiplied by 100.
Time frame: Day 3 or Day 5/6 of embryo culture
Population: The intention-to-treat population included all randomized subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Utilization Rate | 48.6 Percentage of embryos |
| Morphological Grading | Utilization Rate | 49.6 Percentage of embryos |
Other Pre-specified
Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 3 Embryo Transfer (ET)
Eeva Conformity was reported as the number of subjects who were compliant to use Eeva in embryo assessment in the Early Embryo Viability Assessment + morphological grading group. Eeva-compliance subgroup refers to subjects whose embryos were assessed by embryologists following the recommendation of Eeva system and the instructions for use (IFU) of Eeva. Subgroup analysis revealed a high incidence of Eeva noncompliance in the experimental group, which compromised the quality of this study. Only Early Embryo Viability Assessment + Morphological Grading reporting arm was applicable for this outcome measure.
Time frame: Day 3 of embryo culture
Population: Subgroup Analysis Set included subjects from Early Embryo Viability Assessment + morphology grading group for whom the embryologist has followed the recommendation of the Eeva system. Here, Number of Subjects analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 3 Embryo Transfer (ET) | 163 Subjects |
Other Pre-specified
Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 5/6 Embryo Transfer (ET)
Eeva Conformity was reported as the number of subjects who were compliant to use Eeva in embryo assessment in the Early Embryo Viability Assessment + morphological grading group. Eeva-compliance subgroup refers to subjects whose embryos were assessed by embryologists following the recommendation of Eeva system and the IFU of Eeva. Subgroup analysis revealed a high incidence of Eeva noncompliance in the experimental group, which compromised the quality of this study. Only Early Embryo Viability Assessment + Morphological Grading reporting arm was applicable for this outcome measure.
Time frame: Day 5/6 of embryo culture
Population: Subgroup Analysis Set included subjects from Early Embryo Viability Assessment + morphology grading group for whom the embryologist has followed the recommendation of the Eeva system. Here, Number of Subjects analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Eeva Conformity in Early Embryo Viability Assessment + Morphological Grading Group for Day 5/6 Embryo Transfer (ET) | 87 Subjects |
Post Hoc
Number of Sites With Subjects Reporting Fetal Heart Beat (FHB) Positive Implantation Rate (IR)
Number of sites with subjects reporting fetal heart beat (FHB) positive implantation rate (IR) were reported. Overall combined data for Early Embryo Viability Assessment + Morphological Grading and Morphological Grading arm was planned to be reported.
Time frame: Gestational Weeks 5 to 8
Population: Subgroup analysis set included subjects reporting positive fetal heart beat implantation rate from both Early Embryo Viability Assessment and Morphological grading arm and Morphological grading arm. Here, Number of Subjects analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Early Embryo Viability Assessment + Morphological Grading | Number of Sites With Subjects Reporting Fetal Heart Beat (FHB) Positive Implantation Rate (IR) | Day 3 of embryo transfer | 5 Sites |
| Early Embryo Viability Assessment + Morphological Grading | Number of Sites With Subjects Reporting Fetal Heart Beat (FHB) Positive Implantation Rate (IR) | Day 5/6 of embryo transfer | 7 Sites |