Trigger Timing in Controlled Ovarian Stimulation for Female Infertility

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Fertility Center of Las Vegas

Disqualifiers: Oocyte banking, Undue risk, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This randomized trial will compare the efficacy of two different times of administration of medications for final oocyte maturation, commonly called a "trigger", in cycles of controlled ovarian stimulation (COS) for cycles in which all embryos will be cryopreserved ("freeze-all cycles").

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the treatment for ovulatory trigger timing in controlled ovarian stimulation for female infertility?

Research suggests that using a combination of triggers, like hCG and GnRH agonist, can improve the number and quality of mature eggs and embryos in women undergoing fertility treatments. This approach, known as a 'dual trigger', has shown promise in improving pregnancy outcomes, especially in women who have a high rate of immature eggs. ^{1 2 3 4 5}

Is the timing of ovulation triggers in controlled ovarian stimulation safe for humans?

The use of human chorionic gonadotropin (hCG) for triggering ovulation can lead to ovarian hyperstimulation syndrome (OHSS), a potential risk. However, using a gonadotropin-releasing hormone agonist (GnRH-a) instead of hCG can reduce this risk, making it a safer option for ovulation triggering. ^{4 6 7 8 9}

How is the ovulatory trigger timing treatment different from other treatments for female infertility?

The ovulatory trigger timing treatment using hCG (human chorionic gonadotropin) is unique because it mimics the natural LH (luteinizing hormone) surge to induce ovulation, but it may not optimally support the early luteal phase compared to natural cycles. This treatment is different from others as it can lead to faster and higher hormone levels than naturally observed, potentially affecting implantation success. ^{1 2 10 11 12}

Eligibility Criteria

This trial is for adult women aged 18-35 with normal ovarian response, who are undergoing IVF and plan to freeze all embryos reaching the blastocyst stage. They must understand English to consent and can have had previous IVF cycles but only one cycle under this study.

Inclusion Criteria

I have had IVF before, but I haven't collected eggs more than once in this study.

Ability to read and understand English sufficiently to obtain informed consent

My tests show I have a normal or better chance of producing eggs.

Exclusion Criteria

Any cycle type that would preclude immediate culture to blastocyst stage (e.g. oocyte banking)

Any condition that, in the opinion of the physician or principal investigator, would place the patient at undue risk under this protocol or would otherwise make the protocol inappropriate for that subject

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo controlled ovarian stimulation with early or delayed trigger timing for final oocyte maturation

Varies based on follicle development

Follow-up

Participants are monitored for the formation of good-quality blastocysts within 7 days of oocyte retrieval

1 week

Treatment Details

Interventions

• Ovulatory trigger timing (Procedure)

Trial Overview The study tests two different timings for administering 'trigger' drugs that help mature eggs in controlled ovarian stimulation during IVF. All participants will have their embryos frozen at the blastocyst stage for future use.

Participant Groups

Group I: Early Trigger Experimental Treatment 1 Intervention

Group II: Delayed trigger Experimental Treatment 1 Intervention

Ovulatory trigger timing is already approved in Canada for the following indications:

Approved in Canada as hCG trigger for:

• Infertility treatment
• Assisted reproductive technology (ART)

Who Is Running the Clinical Trial?

Fertility Center of Las Vegas

Lead Sponsor

Trials

6

Recruited

550+

Findings from Research

This study will evaluate the effectiveness of a dual trigger approach (using both GnRH agonist and hCG) for final oocyte maturation in 90 individuals undergoing controlled ovarian hyperstimulation, aiming to improve the quantity and quality of mature oocytes and pregnancy outcomes.

The primary outcome measured will be the rate of metaphase-II (MII) oocytes, with secondary outcomes including fertilization rates and clinical pregnancy rates, providing a comprehensive assessment of the dual trigger's impact on IVF success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GnRH Agonist and hCG (Dual Trigger) Versus hCG Trigger for Final Oocyte Maturation in Expected Normal Responders With a High Immature Oocyte Rate: Study Protocol for a Randomized, Superiority, Parallel Group, Controlled Trial. Yan, MH., Cao, JX., Hou, JW., et al.[2022]

The combination of GnRH antagonist co-treatment with a GnRH-agonist trigger, along with the addition of a low-dose HCG bolus, has been shown to improve reproductive outcomes in patients at risk for severe ovarian hyperstimulation syndrome (OHSS), although it may not completely eliminate the risk of OHSS.

Using GnRH-agonist triggers alongside standard hCG doses can enhance oocyte and embryo quality, suggesting that this dual or double trigger approach may optimize fertility treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triggering final follicular maturation--hCG, GnRH-agonist or both, when and to whom? Orvieto, R.[2018]

The study aims to evaluate the safety and efficacy of using low dose hCG alongside GnRH agonist for oocyte maturation in 82 women undergoing IVF, focusing on preventing ovarian hyperstimulation syndrome (OHSS) and improving pregnancy rates.

By comparing two groups—one receiving low dose hCG at the trigger and placebo at retrieval, and the other receiving placebo at trigger and higher hCG at retrieval—the study will assess live birth rates and OHSS incidence, providing insights into optimal IVF protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS. Griffin, D., Benadiva, C., Budinetz, T., et al.[2020]

In a study of 377 IVF patients, cycles with a spontaneous LH surge showed fewer preovulatory oocytes retrieved compared to controls, indicating that timing of oocyte retrieval is crucial for success.

Retrieving oocytes more than 35 hours after hCG administration resulted in a higher number of preovulatory oocytes, while monitoring serum estradiol levels can help optimize retrieval timing and potentially reduce cancellations in IVF cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Timing of oocyte retrieval in cycles with a spontaneous luteinizing hormone surge in a large in vitro fertilization program. Droesch, K., Muasher, SJ., Kreiner, D., et al.[2019]

In a study of 39 patients at risk of ovarian hyper-stimulation syndrome (OHSS) undergoing IVF/ICSI, follicular reduction resulted in a lower median number of punctured follicles compared to coasting, but both methods showed similar rates of OHSS development (10.5% for follicular reduction vs. 30% for coasting).

Pregnancy and cancellation rates were also comparable between the two groups, indicating that neither method significantly improved outcomes in terms of pregnancy success or cycle cancellations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Follicular aspiration versus coasting for ovarian hyper-stimulation syndrome prevention. Bushaqer, NJ., Dayoub, NM., AlHattali, KK., et al.[2018]

In a study of 203 IVF cycles using a low-dose GnRH analogue, elevated LH levels were found in 13% of women at the time of hCG administration, but this did not negatively impact pregnancy success rates.

The presence of elevated LH did not correlate with key reproductive outcomes such as the number of follicles, oocytes, or embryos, indicating that it does not adversely affect the efficacy of the IVF protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated luteinizing hormone on the day of human chorionic gonadotropin administration does not reduce cycle fecundity in a low-dose flare-up in vitro fertilization protocol. Lincoln, SR., Long, CA., Whitworth, NS., et al.[2019]

The traditional use of hCG (human chorionic gonadotropin) as a trigger for oocyte maturation in infertility treatments may not effectively support the hormonal environment needed for optimal luteal phase function, leading to abnormal hormonal patterns compared to natural cycles.

The study suggests that the hCG trigger may induce oocyte maturation less efficiently than the natural surge of luteinizing hormone and follicle-stimulating hormone, potentially impacting implantation success and pregnancy rates, indicating a need for more individualized and physiological approaches in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shortcomings of an unphysiological triggering of oocyte maturation using human chorionic gonadotropin. Andersen, CY., Kelsey, T., Mamsen, LS., et al.[2021]

References

1. Iran pubmed.ncbi.nlm.nih.gov

Controlled Ovarian Hyperstimulation with Intrauterine Insemination Is More Successful After r-hCG Administration Than Spontaneous LH Surge. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Dual trigger for final oocyte maturation in expected normal responders with a high immature oocyte rate: a randomized controlled trial. [2023]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

The effectiveness of earlier oocyte retrieval in the case of a premature luteinizing hormone surge on hCG day in in vitro fertilization-embryo transfer cycles. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

GnRH Agonist and hCG (Dual Trigger) Versus hCG Trigger for Final Oocyte Maturation in Expected Normal Responders With a High Immature Oocyte Rate: Study Protocol for a Randomized, Superiority, Parallel Group, Controlled Trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Does double trigger (GnRH-agonist + hCG) improve outcome in poor responders undergoing IVF-ET cycle? A pilot study. [2019]

6. France pubmed.ncbi.nlm.nih.gov

[Therapeutic induction of ovulation: towards the replacement of hCG with LH]. [2006]

7. England pubmed.ncbi.nlm.nih.gov

Triggering final follicular maturation--hCG, GnRH-agonist or both, when and to whom? [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Timing of oocyte retrieval in cycles with a spontaneous luteinizing hormone surge in a large in vitro fertilization program. [2019]

10. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Follicular aspiration versus coasting for ovarian hyper-stimulation syndrome prevention. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Elevated luteinizing hormone on the day of human chorionic gonadotropin administration does not reduce cycle fecundity in a low-dose flare-up in vitro fertilization protocol. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Shortcomings of an unphysiological triggering of oocyte maturation using human chorionic gonadotropin. [2021]