Diminished Ovarian Reserve, Infertility, In Vitro Fertilization
Conditions
Keywords
DOR, Infertility, IVF, ART, GnRHa, GnRH Antagonist Protocol, Ganirelix
Brief summary
In couples with infertility secondary to Diminished Ovarian Reserve, the investigators hypothesize that a delayed start (7 day) to ovarian stimulation with an GnRH antagonist (Ganirelix) will improve oocyte maturation and quality, and improve pregnancy outcomes.
Detailed description
Over the past two decades, the success rate of assisted reproductive technology (ART) has dramatically increased. This increase is attributed to improvements in embryo culture, laboratory conditions, and optimization of ovarian stimulation protocols. Over the past years, there has been more interest in altering the ovarian stimulation protocol to improve outcomes. For example, recently our group found that a modification of ovulation trigger toward a more physiologic process improves oocyte quality and pregnancy outcomes. Others have suggested minimal stimulation improves in vitro fertilization (IVF) outcomes. The investigators propose to further investigate modifying the ovarian stimulation for women who have decreased ovarian reserve. The investigators propose that a delayed start to ovarian stimulation will improve oocyte maturation and quality and pregnancy outcomes. No published studies to date have evaluated if a delayed start to ovarian stimulation improves pregnancy outcomes. However, the investigators hypothesize that the use an antagonist for a delayed start of stimulation will work by one of two mechanisms: I. The partial suppression of FSH will allow for further recruitment of early antral follicles. II. The partial suppression of FSH will allow for further FSH responsiveness in existing follicles to synchronize the primary cohort, thereby increasing the total number of follicles.
Interventions
Subjects will receive 7 days of pre-treatment with the GnRH antagonist
Sponsors
Merck Sharp & Dohme LLC
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Antral Follicle Count (AFC) less than or equal to 4 as measured by transvaginal ultrasound (TVUS), or * Cancellation of a prior IVF cycle due to poor ovarian response. * Patients will receive an antagonist stimulation protocol for IVF, or IVF with Intracytoplasmic Sperm Injection (ICSI).
Exclusion criteria
* Severe male factor infertility requiring surgical intervention to obtain sperm * Major uterine abnormality, * Preimplantation genetic diagnostic (PGD) testing, * Planned cycles without embryo transfer (for example, freeze-all, donor, or surrogate cycles).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fertilization Proportions | 8 to 24 hours after in vitro fertilization, oocytes will be checked for fertilization | Developmental competence (fertilization of oocytes) through standard in vitro fertilization (estimated time frame to be between 8-24 hours following IVF). This percentage will be calculated as the number of fertilized eggs ( 2PN stage) per total number of eggs collected from the egg retrieval. |
| Number of Oocytes Retrieved | up to 1 hour after oocytes retrieved | The egg retrieval procedure will be performed 36 hours after the ovulation trigger. The procedure is estimated to take up to 1 hour at study visit as part of routine care. The number of retrieved eggs will be counted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stages of Oocyte Nuclear Maturation | average of 1 to 2 hours on the Day of Retrieval | Quality of oocytes will be assessed for developmental stages (Germinal Vesicles, Meiosis I, or Meiosis II) |
| Embryo Quality | One hour on day 2 or 3 (following IVF procedure) | Embryo quality will be assessed by the embryologist on days 2 or 3 (Cleavage stage) following IVF using standard embryo grading criteria. Embryos grading is based on three criteria: the number of blastomere cells present in the embryo, the degree of observed cell fragmentation and the degree of observed symmetry of the cells. |
| Oocyte Recovery Rate | up to 1 hours after oocyte retrieval | The number of oocytes recovered at the time of oocyte retrieval following ovarian stimulation. |
| Number of Mature Follicles | up to 1 hour (during the Transvaginal Ultrasound before Retrieval of Oocytes) | Maturation of follicles will be assessed by measuring the size of follicles (mature \> 13mm) prior to (or at the time of) oocytes retrieval. |
| Pregnancy Rates | 2 to 3 weeks following embryo transfer | Beta HCG levels will be assessed at 2 weeks and 3 weeks after embryo transfer. A positive pregnancy is defined as two positive beta HCG levels (a value \> 5 mIU/ml ) observed over the time frame. |
Countries
United States
Participant flow
Recruitment details
With a goal of enrolling a total of 114 subjects, 330 potential candidates were screened for eligibility. 300 candidates were either not eligible or declined participation. 30 subjects were found eligible to participate and enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Delayed Start Study subjects will receive 7 days of pre-treatment with a GnRH antagonist (Delayed Start) before standard ovarian stimulation with FSH/LH.
Ganirelix acetate: Subjects will receive 7 days of pre-treatment with the GnRH antagonist | 15 |
| Conventional Start Ovarian stimulation with standard antagonist protocols (no delay).
Ganirelix acetate: Subjects will receive 7 days of pre-treatment with the GnRH antagonist | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 6 | 5 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Study terminated early by sponsor and was unable to collect data | 8 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Delayed Start | Conventional Start | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 15 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 13 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 30 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 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Fertilization Proportions
Developmental competence (fertilization of oocytes) through standard in vitro fertilization (estimated time frame to be between 8-24 hours following IVF). This percentage will be calculated as the number of fertilized eggs ( 2PN stage) per total number of eggs collected from the egg retrieval.
Time frame: 8 to 24 hours after in vitro fertilization, oocytes will be checked for fertilization
Population: The study was terminated early and no data were collected for this outcome measure
Primary
Number of Oocytes Retrieved
The egg retrieval procedure will be performed 36 hours after the ovulation trigger. The procedure is estimated to take up to 1 hour at study visit as part of routine care. The number of retrieved eggs will be counted
Time frame: up to 1 hour after oocytes retrieved
Population: The study was terminated early and no data were collected for this outcome measure
Secondary
Embryo Quality
Embryo quality will be assessed by the embryologist on days 2 or 3 (Cleavage stage) following IVF using standard embryo grading criteria. Embryos grading is based on three criteria: the number of blastomere cells present in the embryo, the degree of observed cell fragmentation and the degree of observed symmetry of the cells.
Time frame: One hour on day 2 or 3 (following IVF procedure)
Population: The study was terminated early and no data were collected for this outcome measure
Secondary
Number of Mature Follicles
Maturation of follicles will be assessed by measuring the size of follicles (mature \> 13mm) prior to (or at the time of) oocytes retrieval.
Time frame: up to 1 hour (during the Transvaginal Ultrasound before Retrieval of Oocytes)
Population: The study was terminated early and no data were collected for this outcome measure
Secondary
Oocyte Recovery Rate
The number of oocytes recovered at the time of oocyte retrieval following ovarian stimulation.
Time frame: up to 1 hours after oocyte retrieval
Population: The study was terminated early and no data were collected for this outcome measure
Secondary
Pregnancy Rates
Beta HCG levels will be assessed at 2 weeks and 3 weeks after embryo transfer. A positive pregnancy is defined as two positive beta HCG levels (a value \> 5 mIU/ml ) observed over the time frame.
Time frame: 2 to 3 weeks following embryo transfer
Population: The study was terminated early and no data were collected for this outcome measure
Secondary
Stages of Oocyte Nuclear Maturation
Quality of oocytes will be assessed for developmental stages (Germinal Vesicles, Meiosis I, or Meiosis II)
Time frame: average of 1 to 2 hours on the Day of Retrieval
Population: The study was terminated early and no data were collected for this outcome measure