Infertile Patient Undergoing ICSI Procedure
Conditions
Brief summary
This prospective randomized clinical study evaluates a novel physiology-oriented mild ovarian stimulation protocol based on the delayed initiation of corifollitropin alfa. Unlike conventional ovarian stimulation, which begins during the early follicular phase, the proposed protocol postpones exogenous gonadotropin administration until cycle day 4, allowing physiological follicular recruitment to occur before ovarian stimulation. Participants are randomly assigned to one of two strategies for prevention of premature luteinizing hormone (LH) surge: daily GnRH antagonist administration, or progesterone-primed ovarian stimulation (PPOS). The primary objective is to evaluate ovarian response and the feasibility of this simplified stimulation strategy. Secondary objectives include embryological outcomes, pregnancy outcomes, gonadotropin consumption, treatment burden, and the proportion of patients completing stimulation without supplementary gonadotropin administration. The study aims to determine whether a physiology-oriented late-start stimulation protocol can simplify IVF treatment while maintaining satisfactory embryological and clinical outcomes.
Detailed description
Conventional ovarian stimulation protocols initiate exogenous follicle-stimulating hormone (FSH) administration during the early follicular phase to maximize follicular recruitment. Although effective, this approach may expose follicles to supraphysiological gonadotropin concentrations during the earliest stages of follicular development. The present study evaluates a novel concept of ovarian stimulation based on delayed administration of 150 μg corifollitropin alfa on cycle day 4. The underlying hypothesis is that endogenous follicular recruitment and early follicular selection should occur under physiological endocrine regulation before exogenous ovarian stimulation is introduced. Corifollitropin alfa was selected because its prolonged biological activity provides continuous FSH support for approximately seven days following a single administration, making it particularly suitable for this physiology-oriented stimulation concept. Participants are prospectively randomized to receive either daily GnRH antagonist administration or progesterone-based pituitary suppression (PPOS). Apart from the method of LH suppression, all stimulation procedures, monitoring, ovulation triggering, laboratory procedures, and embryo transfer policies are identical between study groups.The study evaluates ovarian response, embryological outcomes, reproductive outcomes, gonadotropin requirements, and treatment feasibility. A predefined feasibility endpoint, the Single-Injection Completion Rate (SICR), is defined as the proportion of ovarian stimulation cycles successfully completed following a single administration of corifollitropin alfa without supplementary gonadotropin administration. The study is designed as a proof-of-concept investigation evaluating whether delayed ovarian stimulation based on physiological follicular recruitment can simplify IVF treatment without compromising embryological competence or reproductive outcomes.
Interventions
A single subcutaneous injection of 150 μg corifollitropin alfa administered on the evening of cycle day 4 as part of a late-start mild ovarian stimulation protocol.
DRUGGnRH antagonist
Daily GnRH antagonist administration for prevention of premature LH surge according to the study protocol.
DRUGProgesterone
Oral micronized progesterone is administered daily as part of progesterone-primed ovarian stimulation for the prevention of a premature LH surge. Treatment is continued until ovulation triggering according to the predefined study protocol.
Additional hMG (150 IU/day) administered only when predefined clinical criteria are met according to the study protocol.
Sponsors
Assisting Nature
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label study. Participants and treating physicians are aware of the assigned intervention because the two study groups use different methods of LH surge suppression. No masking procedures are applied.
Intervention model description
Parallel Assignment
Eligibility
Sex/Gender
FEMALE
Age
28 Years to 43 Years
Healthy volunteers
No
Inclusion criteria
* Female participants aged 28 to 43 years at the time of enrollment. * Clinical diagnosis of infertility requiring IVF or ICSI treatment. * Planned controlled ovarian stimulation according to the study protocol. * Anti-Müllerian hormone concentration of 0.2 ng/mL or greater. * Presence of both ovaries. * Ability to provide written informed consent. * Willingness to comply with all study procedures and follow-up assessments.
Exclusion criteria
* Age younger than 28 years or older than 43 years. * Anti-Müllerian hormone concentration below 0.2 ng/mL. * Untreated endocrine disorders that may interfere with ovarian stimulation, including uncontrolled thyroid disease or hyperprolactinemia. * Contraindication to ovarian stimulation, pregnancy, or transvaginal oocyte retrieval. * Severe systemic disease considered by the investigator to make participation unsafe. * Concurrent participation in another interventional clinical study that could interfere with the study outcomes. * Refusal or inability to provide written informed consent. * Previous enrollment in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Mature (MII) Oocytes Retrieved per Initiated Stimulation Cycle | From initiation of ovarian stimulation through oocyte retrieval, up to 14 days. | The number of mature metaphase II (MII) oocytes obtained following ovarian stimulation, assessed at the time of oocyte retrieval. The outcome will be expressed as the number of MII oocytes per initiated stimulation cycle. Participants whose cycles are cancelled before oocyte retrieval or who have no mature oocytes retrieved will be assigned a value of zero. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Oocytes Retrieved per Initiated Stimulation Cycle | From initiation of ovarian stimulation through oocyte retrieval, up to 14 days. | The total number of oocytes obtained during transvaginal oocyte retrieval. The outcome will be expressed as the number of retrieved oocytes per initiated stimulation cycle. Participants whose cycles are cancelled before oocyte retrieval or who have no oocytes retrieved will be assigned a value of zero. |
| Oocyte maturation rate | At oocyte retrieval, up to 14 days after initiation of ovarian stimulation. | The percentage of retrieved oocytes classified as mature metaphase II (MII) oocytes. The maturation rate will be calculated as the number of MII oocytes divided by the total number of retrieved oocytes, multiplied by 100. The analysis will include participants with at least one retrieved oocyte. |
| Normal fertilization rate (2PN) | At fertilization assessment, 1 day after ICSI. | The percentage of injected mature oocytes demonstrating normal fertilization, defined by the presence of two pronuclei (2PN) following intracytoplasmic sperm injection (ICSI). The fertilization rate will be calculated as the number of normally fertilized (2PN) oocytes divided by the total number of injected MII oocytes, multiplied by 100. |
| Blastocyst formation rate | From fertilization through day 6 of embryo culture. | The percentage of normally fertilized (2PN) embryos developing into blastocysts by day 6 of embryo culture. The blastocyst formation rate will be calculated as the total number of blastocysts formed by day 6 divided by the number of normally fertilized (2PN) oocytes, multiplied by 100. |
| Number of Usable Blastocysts per Oocyte Retrieval | From fertilization through day 6 of embryo culture. | The total number of blastocysts considered suitable for embryo transfer or cryopreservation according to predefined laboratory morphological assessment criteria. Blastocysts will be assessed on days 5 and 6 of embryo culture. |
| Total Supplementary Gonadotropin Consumption | From initiation of ovarian stimulation through ovulation triggering or cycle cancellation, up to 14 days. | The cumulative dose of supplementary human menopausal gonadotropin (hMG) administered during ovarian stimulation, expressed in International Units (IU). Supplementary hMG may be administered at a dose of 150 IU daily from cycle day 8 according to predefined hormonal and ultrasonographic response criteria. Participants who do not require supplementary hMG will be assigned a value of zero. The initial administration of 150 μg corifollitropin alfa will not be included in the calculation of supplementary hMG consumption. |
| Clinical Pregnancy Rate per Embryo Transfer | From oocyte retrieval through clinical pregnancy assessment, up to 9 months. | The percentage of embryo transfer procedures resulting in clinical pregnancy. Clinical pregnancy is defined as ultrasonographic confirmation of at least one intrauterine gestational sac with fetal cardiac activity. All fresh and frozen embryo transfers involving embryos derived from the study stimulation cycle and performed within 6 months after oocyte retrieval will be included. The clinical pregnancy rate will be calculated as the number of embryo transfer procedures resulting in clinical pregnancy divided by the total number of embryo transfer procedures performed within the specified follow-up period, multiplied by 100. |
| Ongoing Pregnancy Rate per Embryo Transfer | From oocyte retrieval through ongoing pregnancy assessment, up to 10 months. | The percentage of embryo transfer procedures resulting in an ongoing pregnancy. Ongoing pregnancy is defined as the presence of a viable intrauterine pregnancy with fetal cardiac activity at 12 completed weeks of gestation. All fresh and frozen embryo transfers involving embryos derived from the study stimulation cycle and performed within 6 months after oocyte retrieval will be included. The ongoing pregnancy rate will be calculated as the number of embryo transfer procedures resulting in ongoing pregnancy divided by the total number of embryo transfer procedures performed within the specified follow-up period, multiplied by 100. |
| Live Birth Rate per Embryo Transfer | From oocyte retrieval through delivery, up to 18 months. | The percentage of embryo transfer procedures resulting in the delivery of at least one live-born infant. Live birth is defined as the complete expulsion or extraction of a fetus from the mother, irrespective of gestational age, showing evidence of life after birth. All fresh and frozen embryo transfers involving embryos derived from the study stimulation cycle and performed within 6 months after oocyte retrieval will be included. Multiple live-born infants resulting from a single embryo transfer procedure will be counted as one live birth event. The live birth rate will be calculated as the number of embryo transfer procedures resulting in at least one live birth divided by the total number of embryo transfer procedures performed within the specified follow-up period, multiplied by 100. |
| Single-Injection Completion Rate (SICR) | From initiation of ovarian stimulation through ovulation triggering or cycle cancellation, up to 14 days. | The percentage of participants completing ovarian stimulation using a single subcutaneous injection of 150 μg corifollitropin alfa without requiring supplementary gonadotropin administration. Successful single-injection completion is defined as reaching ovulation triggering without supplementary hMG or other gonadotropin administration. The rate will be calculated as the number of participants achieving single-injection completion divided by the total number of participants who initiated ovarian stimulation, multiplied by 100. |
| Requirement for Supplementary hMG Administration | From initiation of ovarian stimulation through ovulation triggering or cycle cancellation, up to 14 days. | The percentage of participants requiring supplementary human menopausal gonadotropin (hMG) following the initial administration of 150 μg corifollitropin alfa. Supplementary hMG is administered from cycle day 8 when predefined hormonal and ultrasonographic criteria for continuation without additional gonadotropins are not fulfilled. The rate will be calculated as the number of participants receiving at least one supplementary hMG injection divided by the total number of participants who initiated ovarian stimulation, multiplied by 100. |
| Cumulative Live Birth Rate per Initiated Stimulation Cycle | From initiation of ovarian stimulation through delivery, up to 18 months. | The percentage of initiated ovarian stimulation cycles resulting in at least one live birth following the transfer of embryos derived from the corresponding stimulation cycle. All fresh and frozen embryo transfers performed within 6 months after oocyte retrieval will be included. Each initiated stimulation cycle will be counted only once, regardless of the number of embryo transfers performed or the number of live-born infants. The cumulative live birth rate will be calculated as the number of initiated stimulation cycles resulting in at least one live birth divided by the total number of initiated stimulation cycles, multiplied by 100. |
Countries
Greece
Contacts
STUDY_DIRECTORRobert Najdecki, PhD
Assisting Nature Fertility and Genetics
Outcome results
None listed