Intra-ovarian CAPA-IVM vs Standard IVM

This is a prospective, within-patient comparative study in women undergoing fertility treatment. Each participant serves as her own internal control. At the Day 3 baseline visit, the right ovary is assigned to the CAPA-IVM approach and the left ovary is assigned to minimal controlled ovarian stimulation followed by IVF/ICSI. Both approaches are performed within the same menstrual cycle.

For the CAPA-IVM arm, immature oocytes are retrieved from the right ovary beginning on or after menstrual cycle Day 3, before ovarian stimulation is initiated. The right ovary is not stimulated and does not receive an ovulation trigger before oocyte collection. Retrieved cumulus-oocyte complexes are handled separately, and immature oocytes at the germinal vesicle (GV) or metaphase I (MI) stage undergo a biphasic CAPA-IVM process consisting of an initial pre-maturation/capacitation phase followed by transfer to maturation conditions and assessment for development to the metaphase II (MII) stage.

After completion of right-ovary aspiration, minimal controlled ovarian stimulation of the left ovary begins on Day 5. The protocol uses clomiphene citrate for approximately 9 days and follitropin beta for approximately 3 days, with ultrasound and/or hormonal monitoring. Final oocyte maturation is initiated with leuprolide acetate as a GnRH-agonist trigger, followed by routine oocyte retrieval from the left ovary.

Mature oocytes obtained from both approaches may undergo ICSI according to New Hope Fertility Center clinical practice. Oocyte assessment and selection for ICSI, ICSI itself, and standard embryo culture are considered clinical procedures; the research-specific component is the CAPA-IVM maturation approach and the within-patient comparison of outcomes according to ovary of origin. Oocytes and embryos are tracked separately to maintain traceability throughout fertilization, embryo culture, and subsequent clinical outcomes.

The primary endpoint is the proportion of immature CAPA-IVM oocytes that mature to the MII stage. Secondary endpoints include fertilization rate, cleavage, blastocyst formation, high-quality blastocyst formation, implantation, clinical pregnancy, ongoing pregnancy, live birth, neonatal outcomes, and safety outcomes including procedure-related complications and ovarian reserve measures.

• CAPA-IVM (Procedure): Immature cumulus-oocyte complexes are retrieved from the right ovary before ovarian stimulation and undergo a biphasic CAPA-IVM process. The first phase is a pre-maturation/capacitation culture intended to maintain meiotic arrest while supporting developmental competence. Oocytes are then transferred to maturation conditions and assessed for maturation to metaphase II (MII). Mature oocytes may subsequently undergo ICSI and standard embryo culture according to clinical practice.
• In-House CAPA-IVM Pre-Maturation Medium (Device): An investigational in-house reproductive culture medium is used during the pre-maturation/capacitation phase of CAPA-IVM for immature cumulus-oocyte complexes. The proprietary formulation is prepared for use in the CAPA-IVM laboratory procedure. Following the pre-maturation phase, oocytes are transferred to maturation conditions and assessed for MII maturation.
• Minimal-Stimulation OS-IVF (Procedure): After completion of right-ovary CAPA-IVM aspiration, minimal controlled ovarian stimulation of the left ovary begins on menstrual cycle Day 5. The regimen includes clomiphene citrate for approximately 9 days and follitropin beta for approximately 3 days with ultrasound and/or hormonal monitoring. Final oocyte maturation is initiated using leuprolide acetate as a GnRH-agonist trigger. Oocytes are subsequently retrieved from the left ovary and undergo standard IVF/ICSI and embryo culture according to clinical practice.

Primary outcomes

• Maturation Rate to Metaphase II (MII) Following CAPA-IVM [Up to approximately 54 hours after initiation of CAPA-IVM culture]: Proportion of immature oocytes retrieved from the CAPA-IVM ovary that reach the metaphase II (MII) stage after completion of the biphasic CAPA-IVM culture process. Maturation rate will be calculated as the number of oocytes reaching MII divided by the number of immature oocytes undergoing CAPA-IVM.

Secondary outcomes

• Fertilization Rate [At fertilization assessment following ICSI]: Proportion of injected MII oocytes showing normal two-pronuclear (2PN) fertilization after ICSI, analyzed by ovary/treatment origin.
• Cleavage Rate [Day 2-3 after fertilization]: Proportion of normally fertilized embryos that undergo cleavage by embryo culture Day 2-3.
• Blastocyst Formation Rate [Day 5-6 after fertilization]: Proportion of embryos developing to the blastocyst stage, analyzed according to CAPA-IVM or minimal-stimulation OS-IVF origin.
• High-Quality Blastocyst Rate [Day 5-6 after fertilization]: Proportion of embryos meeting the center's predefined criteria for high-quality blastocyst morphology.
• Clinical Pregnancy Rate [Approximately 7-8 weeks gestation]: Proportion of embryo transfers resulting in a clinical pregnancy confirmed by ultrasound evidence of fetal cardiac activity.
• Ongoing Pregnancy Rate [Greater than 12 weeks gestation]: Proportion of embryo transfers resulting in an ongoing pregnancy beyond 12 weeks gestation.
• Live Birth Rate [At delivery, up to approximately 10 months after embryo transfer]: Proportion of embryo transfers resulting in a live birth. Outcomes will be analyzed according to embryo origin when traceable.
• Procedure-Related and Treatment-Related Adverse Events [From initiation of study treatment through 6 months after treatment]: Incidence of adverse events including ovarian hyperstimulation syndrome, egg-retrieval complications, sedation/anesthesia complications, and other study-related adverse events.
• Change in Serum Anti-Müllerian Hormone (AMH) [Baseline and 3-6 months after treatment]: Change in serum AMH concentration from baseline to the follow-up ovarian-reserve assessment.
• Gestational Age at Delivery [At delivery]: Gestational age at delivery among live-born infants resulting from embryos included in the study.
• Change in Antral Follicle Count (AFC) [Baseline and 3-6 months after treatment]: Change in antral follicle count from baseline to the follow-up ovarian-reserve assessment.
• Birth Weight [At birth]: Birth weight of live-born infants resulting from embryos included in the study.
• Reported Congenital Anomalies [At birth]: Number and proportion of live-born infants with one or more congenital anomalies documented at birth.

Sex: Female, ages: 18 Years to 38 Years

Inclusion Criteria:

* Female, age 18 to 38 years.
* Undergoing assisted reproductive treatment for infertility.
* Both ovaries present and anatomically suitable for oocyte retrieval, with no prior oophorectomy.
* Adequate ovarian reserve for study participation, including AMH greater than 0.5 ng/mL and antral follicle count greater than 6 per ovary.
* Both ovaries considered suitable for their assigned study procedures: right ovary for CAPA-IVM and left ovary for minimal-stimulation OS-IVF.
* Access to partner or donor sperm for fertilization/ICSI according to clinic protocol.
* Willing and able to provide written informed consent and comply with study procedures and follow-up.

Exclusion Criteria:

* Severe endometriosis, Stage III or IV.
* Known diminished ovarian reserve with AMH less than 0.2 ng/mL, unless specifically permitted under an approved study amendment.
* Active pelvic infection.
* Untreated hydrosalpinx.
* Known chromosomal abnormality in either reproductive partner, unless appropriate genetic testing is planned.
* Contraindication to oocyte retrieval or sedation/anesthesia.
* Any medical or gynecologic condition that, in the investigator's judgment, would interfere with study participation, oocyte retrieval, study procedures, or participant safety.

• Gilchrist RB, Ho TM, De Vos M, Sanchez F, Romero S, Ledger WL, Anckaert E, Vuong LN, Smitz J. A fresh start for IVM: capacitating the oocyte for development using pre-IVM. Hum Reprod Update. 2024 Jan 3;30(1):3-25. doi: 10.1093/humupd/dmad023. PMID 37639630
• Vuong LN, Ho VNA, Ho TM, Dang VQ, Phung TH, Giang NH, Le AH, Pham TD, Wang R, Smitz J, Gilchrist RB, Norman RJ, Mol BW. In-vitro maturation of oocytes versus conventional IVF in women with infertility and a high antral follicle count: a randomized non-inferiority controlled trial. Hum Reprod. 2020 Nov 1;35(11):2537-2547. doi: 10.1093/humrep/deaa240. PMID 32974672
• Vuong LN, Le AH, Ho VNA, Pham TD, Sanchez F, Romero S, De Vos M, Ho TM, Gilchrist RB, Smitz J. Live births after oocyte in vitro maturation with a prematuration step in women with polycystic ovary syndrome. J Assist Reprod Genet. 2020 Feb;37(2):347-357. doi: 10.1007/s10815-019-01677-6. Epub 2020 Jan 4. PMID 31902102
• Sanchez F, Le AH, Ho VNA, Romero S, Van Ranst H, De Vos M, Gilchrist RB, Ho TM, Vuong LN, Smitz J. Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles. J Assist Reprod Genet. 2019 Oct;36(10):2135-2144. doi: 10.1007/s10815-019-01551-5. Epub 2019 Aug 9. PMID 31399916

• Study Protocol and Statistical Analysis Plan (PDF, 2026-07-13)

• John J Zhang, M.D. Ph.D, Principal investigator, New Hope Fertility Center