Gamete Treatment for Infertility

Overseen By Iman Mohammed, MPH

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Weill Medical College of Cornell University

Disqualifiers: Ivf without icsi, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

1200 Participants Needed

Trial Summary

What is the purpose of this trial?

In this proposed research study, the investigators plan to assess the efficacy of gametes' (egg and sperm) treatment on fertilization as well as pre- and post-implantation embryo development.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the Gamete Treatment for Infertility?

The research on improving outcomes for poor responders in IVF (in vitro fertilization) suggests that strategies like accumulating embryos over multiple cycles and optimizing ovarian stimulation can enhance treatment success. These approaches may indirectly support the effectiveness of Gamete Treatment by improving embryo quality and increasing the chances of successful pregnancy. ^{1 2 3 4 5}

Is Gamete Treatment for Infertility safe for humans?

Assisted reproduction techniques, which include treatments like Gamete Treatment, have some safety concerns. These include risks of multiple pregnancies, potential long-term effects on women and children, and complications like ovarian hyperstimulation syndrome. While some drugs used in these treatments may have side effects, efforts are made to minimize risks, and no treatment is entirely risk-free. ^{6 7 8 9 10}

How is Gamete Treatment different from other infertility treatments?

Gamete Treatment is unique because it involves assisted activation of oocytes (egg cells) and can be used in cases where traditional sperm injection methods fail, such as with globozoospermia (a condition where sperm have round heads and cannot activate the egg). This treatment specifically targets the activation process, which is not addressed by standard treatments. ^{11 12 13 14 15}

Research Team

Gianpiero Palermo, MD, MPH

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

This trial is for individuals who have experienced complete fertilization failure with standard IVF or those who have had one unsuccessful ICSI treatment cycle. It's not open to people who don't meet these specific conditions, or those who have only tried IVF without ICSI.

Inclusion Criteria

I've had unsuccessful standard IVF or one failed ICSI cycle.

Exclusion Criteria

IVF without ICSI

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Gamete Treatment

Spermatozoa are prepared and utilized for injection after exposure to a membrane permeabilizing agent. Oocytes are exposed to activating agents to induce embryo development.

5 days

Culture and Assessment

Successfully fertilized oocytes are kept in culture for up to 5 days, and embryo development is monitored.

5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on fertilization rate and embryo development.

2 months

Treatment Details

Interventions

• Gamete Treatment

Trial Overview The study is examining the effectiveness of a special gamete treatment on egg and sperm. The goal is to see if this can improve fertilization rates and support embryo development before and after implantation in patients facing infertility issues.

Participant Groups

Group I: gamete treatment- oocytes and sperm Experimental Treatment 1 Intervention

The spermatozoa will be prepared in the standard fashion and utilized for injection after exposure to a membrane permeabilizing agent. Patient specimen will be selected through a synthetic, sterile, single-use, culture-tested mesh. The specimen will then be placed in a 37°C environment. After 30 minutes, the selected portion is retrieved from the other side of the mesh. The injected oocytes will be then exposed to the previously mentioned activating agents for the purpose of inducing embryo development. The successfully fertilized oocytes will be further kept in culture for up to 5 days as per standard IVF/ICSI.

Gamete Treatment is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Gamete Treatment for:

• Infertility due to total fertilization failure
• Unexplained infertility

Approved in United States as Gamete Treatment for:

• Infertility due to total fertilization failure
• Recurrent implantation failure

Approved in Canada as Gamete Treatment for:

• Infertility due to total fertilization failure
• Unexplained infertility

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Findings from Research

In a study of 125 women classified as poor responders, undergoing three Natural Modified IVF (ICSI) cycles followed by embryo transfer significantly improved live birth rates (30.6%) compared to a single cycle with fresh embryo transfer (13.3%).

The approach was particularly beneficial for women aged 35-39 and 40-44, with live birth rates of 31% and 26% respectively, and it also resulted in more available embryos and fewer cases of no embryo for transfer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accumulation of embryos over 3 natural modified IVF (ICSI) cycles followed by transfer to improve the outcome of poor responders. Datta, AK., Campbell, S., Felix, N., et al.[2022]

The POSEIDON criteria emphasize the need to shift from viewing poor ovarian response as merely a challenge to understanding it as a poor prognosis, which helps in better identifying and stratifying patients before IVF treatment.

A key goal in ovarian stimulation is to retrieve enough oocytes to produce at least one euploid blastocyst for transfer, serving as a useful marker for clinicians to optimize strategies aimed at achieving live births efficiently.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The POSEIDON stratification - moving from poor ovarian response to low prognosis. Roque, M., Haahr, T., Esteves, SC., et al.[2023]

The win ratio is a new method for measuring treatment effects in medical studies that involve multiple outcomes, allowing researchers to prioritize and combine these outcomes effectively.

Using the win ratio can enhance the clarity and interpretability of results in clinical trials, making it easier to assess the overall impact of a treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Win Ratio -An Intuitive and Easy-To-Interpret Composite Outcome in Medical Studies. Wang, H., Peng, J., Zheng, JZ., et al.[2020]

The sequential step-up/step-down protocol for IVF in women with PCOS resulted in the highest pregnancy rates and the lowest miscarriage rates compared to conventional low dose step-up and step-down regimens, based on a study of 225 women.

Patients using the sequential regimen also showed better ovarian response, including more uniform follicular growth and higher egg retrieval rates, indicating its efficacy in improving IVF outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison study of a novel stimulation protocol and the conventional low dose step-up and step-down regimens in patients with polycystic ovary syndrome undergoing in vitro fertilization. Koundouros, SN.[2008]

Increasing the dose of hMG from three to five or more ampules daily in women who initially showed a poor response resulted in higher peak serum E2 levels and more mature preovulatory follicles, indicating a better hormonal response.

However, despite these improvements in hormone levels and follicle count, there was no significant increase in the overall chance of conception (cycle fecundity) for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of increasing the dose of human menopausal gonadotropins in women who initially demonstrate a poor response. Manzi, DL., Thornton, KL., Scott, LB., et al.[2019]

Assisted reproduction techniques (ART) are effective for treating subfertile couples, but there is a need for more attention to the safety aspects, including potential adverse events and complications.

A consensus meeting highlighted key concerns regarding ART, such as the risks of multiple pregnancies, long-term effects on women, impacts on offspring, and the importance of morbidity and mortality registries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and complications in assisted reproduction techniques: Report of an ESHRE consensus meeting. Land, JA., Evers, JL.[2019]

Assisted reproduction techniques (ART) have significantly improved the chances of conception for infertile couples, but the use of pharmacological agents in ART can lead to various adverse effects, including ovarian hyperstimulation syndrome and potential congenital malformations.

While gonadotropins are effective in stimulating ovarian function, they may be associated with risks such as luteal phase deficiency and concerns about long-term cancer risks, although these have not been conclusively proven.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of drugs used in assisted reproduction techniques. Al-Shawaf, T., Zosmer, A., Dirnfeld, M., et al.[2018]

Intracytoplasmic sperm injection (ICSI) and similar infertility treatments carry potential risks not only for the parents undergoing the procedure but also for the children conceived through these methods, highlighting the need for thorough risk assessment.

Participants in clinical trials for reproductive techniques should be well-informed about the potential hazards, as understanding these risks is crucial for making informed decisions about their participation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracytoplasmic sperm injection (ICSI): risks reconsidered. Elliston, S.[2019]

In a case study involving a patient with multiple morphological abnormalities of the sperm flagella (MMAF) due to a DNAH1 mutation, artificial oocyte activation (AOA) using ionomycin did not improve clinical outcomes compared to non-AOA methods during intracytoplasmic sperm injection (ICSI).

Transcriptome analysis of embryos that failed to develop showed that AOA may introduce risks of chromosome structure defects, transcriptional regulation defects, and epigenetic defects, highlighting potential safety concerns with this approach in MMAF cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella. Liu, Z., Guo, Y., Chen, X., et al.[2023]

Intracytoplasmic sperm injection (ICSI) is highly effective for male factor infertility, but fertilization failure still occurs in 1-3% of cases, prompting the exploration of assisted oocyte activation (AOA) to improve outcomes.

AOA aims to enhance fertilization and pregnancy rates after ICSI failures, though there are safety concerns due to the artificial nature of the activation agents used, which do not fully replicate natural oocyte activation processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assisted oocyte activation following ICSI fertilization failure. Vanden Meerschaut, F., Nikiforaki, D., Heindryckx, B., et al.[2022]

The study identified a deficiency in oocyte activation capacity in sperm from a patient with globozoospermia, confirmed through a mouse oocyte activation test and lack of activation in human oocytes after standard sperm injection.

Assisted oocyte activation using calcium chloride and ionophore treatment successfully activated human oocytes, leading to an ongoing pregnancy after embryo transfer, demonstrating its efficacy in treating infertility linked to globozoospermia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fertilization and pregnancy after assisted oocyte activation and intracytoplasmic sperm injection in a case of round-headed sperm associated with deficient oocyte activation capacity. Rybouchkin, AV., Van der Straeten, F., Quatacker, J., et al.[2022]

Human cumulus cell conditioned medium (hCCCM) significantly improved the maturation rates of immature mouse oocytes compared to a standard control medium, with maturation rates of 24.16% versus 0%.

hCCCM not only enhanced oocyte maturation but also positively affected the morphology of the oocytes, indicating its potential as a beneficial medium for in vitro maturation in assisted reproductive technologies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of the human cumulus cells-conditioned medium on in vitro maturation of mouse oocyte: An experimental study. Adib, M., Seifati, SM., Ashkezari, MD., et al.[2023]

In a study of 114 couples experiencing fertilization failure with ICSI, a tailored superovulation protocol significantly improved fertilization rates from 2.1% to 59.0% and clinical pregnancy rates from 0% to 28.6% for those with oocyte-related activation deficiencies.

For couples with sperm-related activation deficiencies, the assisted gamete treatment (AGT) led to a fertilization rate of 42.1% and a clinical pregnancy rate of 36%, with the revised AGT protocol showing even better outcomes, resulting in healthy births for all couples who achieved clinical pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and treatment of men with phospholipase Cζ-defective spermatozoa. Cheung, S., Xie, P., Parrella, A., et al.[2021]

In a study involving 13 couples with male factor infertility, the injection of round and elongated spermatids into oocytes resulted in the development of zygotes, with single-nucleated zygotes showing a higher development rate than traditional sperm injection methods.

The successful transfer of embryos from single-nucleated zygotes derived from round spermatid injections led to a normal pregnancy and childbirth, indicating that this method can be a viable infertility treatment when sperm is unavailable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnancy and birth after transfer of embryos that developed from single-nucleated zygotes obtained by injection of round spermatids into oocytes. Barak, Y., Kogosowski, A., Goldman, S., et al.[2019]

Only about 25% of men with infertility have specific conditions that lead to sterility or severe infertility, while the remaining 75% experience reduced semen quality without clear treatments to improve fertility.

Assisted reproductive technologies, particularly intracytoplasmic sperm injection, offer promising solutions for couples facing male infertility, especially for those with severe sperm defects or previous IVF failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Male infertility. Baker, HW.[2022]

References

1. Belgium pubmed.ncbi.nlm.nih.gov

Accumulation of embryos over 3 natural modified IVF (ICSI) cycles followed by transfer to improve the outcome of poor responders. [2022]

2. Brazil pubmed.ncbi.nlm.nih.gov

The POSEIDON stratification - moving from poor ovarian response to low prognosis. [2023]

3. China pubmed.ncbi.nlm.nih.gov

Win Ratio -An Intuitive and Easy-To-Interpret Composite Outcome in Medical Studies. [2020]

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

A comparison study of a novel stimulation protocol and the conventional low dose step-up and step-down regimens in patients with polycystic ovary syndrome undergoing in vitro fertilization. [2008]

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

The value of increasing the dose of human menopausal gonadotropins in women who initially demonstrate a poor response. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Risks and complications in assisted reproduction techniques: Report of an ESHRE consensus meeting. [2019]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Safety of drugs used in assisted reproduction techniques. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Intracytoplasmic sperm injection (ICSI): risks reconsidered. [2019]

9. England pubmed.ncbi.nlm.nih.gov

The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Assisted oocyte activation following ICSI fertilization failure. [2022]

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

Fertilization and pregnancy after assisted oocyte activation and intracytoplasmic sperm injection in a case of round-headed sperm associated with deficient oocyte activation capacity. [2022]

12. Iran pubmed.ncbi.nlm.nih.gov

The effect of the human cumulus cells-conditioned medium on in vitro maturation of mouse oocyte: An experimental study. [2023]

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

Identification and treatment of men with phospholipase Cζ-defective spermatozoa. [2021]

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

Pregnancy and birth after transfer of embryos that developed from single-nucleated zygotes obtained by injection of round spermatids into oocytes. [2019]

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

Male infertility. [2022]