Clinical trial NCT04774432: Effect of GM-CSF on CAPA-IVM System Success Rates in PCOS
Official title: Effect of Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) on Human in Vitro Oocyte Maturation (CAPA-IVM System) Success Rates in PCOS
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: IVF
PCOS
IVM
Keywords: GM-CSF
CAPA-IVM
Lead sponsor: Mỹ Đức Hospital
Sponsor class: OTHER
First posted: 2021-03-01
Enrollment: 100
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 36
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In-vitro maturation (IVM) of human oocytes obtained from minimally stimulated or unstimulated ovaries offers a more "patient friendly" treatment option than the conventional Assisted Reproductive Technology (ART) treatment with controlled ovarian hyperstimulation (COH). However, maturation rate and the total blastocyst yield in oocytes undergoing in vitro maturation are still limited.

This pilot study aims to evaluate the addition of an important growth factor known as Granulocyte macrophage colony stimulating factor (GM-CSF). The investigators hypothesize that the addition of GM-CSF to human IVM culture media will increase pregnancy rates to comparable levels to that of IVF, making it a viable clinical option for couples undergoing assisted reproductive treatment.

Detailed description: In-vitro maturation (IVM) of human oocytes obtained from minimally stimulated or unstimulated ovaries offers a more "patient friendly" treatment option than the conventional Assisted Reproductive Technology (ART) treatment with controlled ovarian hyperstimulation (COH).

Typically, IVM will be offered to women with polycystic ovaries (PCO/PCOS), or to patients with an excellent ovarian reserve, i.e. a high antral follicle count. IVM treatment is characterized by minimal administration of FSH or HMG and NO HCG ovulation trigger.

The IVM approach is less disruptive to patients' daily life through the reduced need for hormonal and ultrasound monitoring, avoids a range of minor and major complications, such as ovarian hyperstimulation syndrome, and aims to reduce the total cost of infertility treatment for the patient and for the health care budget.

Human oocytes retrieved from small antral follicles are able to resume meiosis by undergoing germinal vesicle breakdown and extrusion of the first polar body, if they have reached meiotic competence. These oocytes can be fertilized although only a proportion (less than 50%) of them can develop further into viable embryos. It has been hypothesized that failure of embryonic development may, at least in part, be due to an immature oocyte cytoplasm.

The investigators have developed a novel human in vitro maturation (IVM) culture system (named CAPACITATION-IVM , hereafter named "CAPA") using 1°) natural compounds known to influence cGMP and cAMP levels within the cumulus-oocyte-complex and 2°) compounds that are crucial for the oocyte-cumulus cross-talk. Keeping cyclic AMP high after retrieval in the GV oocyte prevents occurrence of nuclear maturation, enabling increased communication between the oocyte and the cumulus cells. This allows for the improvement in the synchronization of nuclear and cytoplasmic maturation processes in the oocyte, to the benefit of embryo quality.

The clinical outcomes of using CAPA-IVM in PCOS instead of fully stimulated GnRH-antagonist HP-HMG stimulated IVF-ICSI treatments showed equivalent live-birth rates after a first embryo transfer cycle done in artificial endometrial preparation in the two arms. Nevertheless, the CAPA-IVM cumulative live birth at 12 months was 44%, while in IVF it was 62,6. (Vuong et al., 2020). Hence the attrition rate of embryos in CAPA-IVM is larger than in conventional ART. In order to correct for this difference in good embryo number there is a need to refine the culture conditions.

This pilot study aims to evaluate the addition of an important growth factor known as Granulocyte macrophage colony stimulating factor (GM-CSF). In a recent breakthrough it has been shown that adding GM-CSF to IVM media can improve preimplantation embryo development in pigs, cattle and mice (unpublished results from Prof Mark Nottle, Adelaide University, Australia). Moreover, in mice, these improvements lead to an increased in implantation rate (+62%) and tended to increase birth rate (+25%) following the transfer of vitrified/warmed blastocysts compared with standard IVM. Based on these findings, this pilot study aims to determine the beneficial effect of using GM-CSF during the biphasic CAPA-IVM. The investigators hypothesize that the addition of GM-CSF to human IVM culture media will increase pregnancy rates to comparable levels to that of IVF, making it a viable clinical option for couples undergoing assisted reproductive treatment.

GM-CSF (Leukine in EmbryoGene medium, Medicult) has previously been used as an additive in embryo culture in order to increase the implantation rate of exposed embryos. This study in more than 1000 patients showed no advantage of adding GMCSF routinely. However in a subset of patients, those with poor implantation, the addition of this factor improved clinical results (Ziebe et al., 2013). In this study no safety issues were mentioned by exposing human oocytes during fertilization and early embryo formation.

In the intended study there will be only exposure of GM-CSF during the oocyte maturation steps, and the embryos will never be in direct contact with the investigational compound.

Eligibility criteria: Inclusion Criteria:

* Diagnosed as PCOS using Rotterdam criteria (AFC=25 or the ovarian volume \>10ml)
* Agree to participate in the study

Exclusion Criteria:

* No major uterine or ovarian abnormalities
* Endometriosis grade 2 or upper
* Severe OAT (concentration \<1 million/ml, motility \<10%), surgical sperm

Primary outcomes:
measure: Blastulation rate
timeFrame: At least seven days after oocyte pick up
Secondary outcomes:
measure: Embryology data (maturation rate, fertilization rate, grade 1 and grade 2 blastocyst rate)
timeFrame: Maturation rate: 2 days after OPU, Fertilization rate: 3 days after OPU, grade 1 and 2 blastocyst: at least 7 days after OPU
measure: Ongoing Pregnancy Rate after the first transfer of the started treatment cycle.
timeFrame: At 12 weeks' gestation
measure: Cumulative ongoing pregnancy rate at 6 months after randomization
timeFrame: At 12 weeks' gestation at 6 months after randomization. After 6 months, most patients doing IVM have finished all their frozen embryos; therefore, we consider this time point for analyzing the cumulative ongoing pregnancy rate.
measure: Adverse events (OHSS rate, miscarriage rate, ectopic rate)
timeFrame: OHSS rate: at 03 days after oocytes pick-up and 14 days after embryo transfer, Miscarriage rate: Before 22 weeks of gestational age, ectopic rate: At 5-7 weeks of gestation
measure: The relative expression ratio ( R ) of human cumulus cell genes
timeFrame: cumulus cells will be collected after at least 30 hours of maturation culture, storaged at -80oC until RNA purification
measure: Infant DNA methylation expression level
timeFrame: At the time of delivery
Other outcomes:
Locations:
city: Ho Chi Minh City
country: Vietnam
facility: My Duc Hospital
Study officials:
affiliation: Hope Research Center
name: Tuong M Ho, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Guzman L, Ortega-Hrepich C, Albuz FK, Verheyen G, Devroey P, Smitz J, De Vos M. Developmental capacity of in vitro-matured human oocytes retrieved from polycystic ovary syndrome ovaries containing no follicles larger than 6 mm. Fertil Steril. 2012 Aug;98(2):503-7.e1-2. doi: 10.1016/j.fertnstert.2012.01.114. Epub 2012 Feb 23.
citation: Guzman L, Adriaenssens T, Ortega-Hrepich C, Albuz FK, Mateizel I, Devroey P, De Vos M, Smitz J. Human antral follicles <6 mm: a comparison between in vivo maturation and in vitro maturation in non-hCG primed cycles using cumulus cell gene expression. Mol Hum Reprod. 2013 Jan;19(1):7-16. doi: 10.1093/molehr/gas038. Epub 2012 Sep 6.
citation: Heijnen EM, Eijkemans MJ, Hughes EG, Laven JS, Macklon NS, Fauser BC. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006 Jan-Feb;12(1):13-21. doi: 10.1093/humupd/dmi036. Epub 2005 Aug 25.
citation: Sanchez F, Lolicato F, Romero S, De Vos M, Van Ranst H, Verheyen G, Anckaert E, Smitz JEJ. An improved IVM method for cumulus-oocyte complexes from small follicles in polycystic ovary syndrome patients enhances oocyte competence and embryo yield. Hum Reprod. 2017 Oct 1;32(10):2056-2068. doi: 10.1093/humrep/dex262.
citation: Ho VNA, Braam SC, Pham TD, Mol BW, Vuong LN. The effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilization in women with a high antral follicle count. Hum Reprod. 2019 Jun 4;34(6):1055-1064. doi: 10.1093/humrep/dez060.
citation: Ziebe S, Loft A, Povlsen BB, Erb K, Agerholm I, Aasted M, Gabrielsen A, Hnida C, Zobel DP, Munding B, Bendz SH, Robertson SA. A randomized clinical trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) in embryo culture medium for in vitro fertilization. Fertil Steril. 2013 May;99(6):1600-9. doi: 10.1016/j.fertnstert.2012.12.043. Epub 2013 Feb 4.