New Application of Sequential in Vitro Muturation System for Infertility Patients With Polycystic Ovary Syndrome

New Application of Oocyte Sequential Culture and in Vitro Muturation System for Infertility Patients With Polycystic Ovary Syndrome: a Multi-center Prospective Randomized Clinical Trial

Oocyte in vitro maturation (IVM) is an artificial reproductive technologies (ART) in which cumulus-oocyte complex (COC) are collected at the immature germinal vesicle (GV) stage from unstimulated or FSH-primed ovaries and matured in vitro before fertilization. IVM has been proposed as a more patient-friendly ART alternative to conventional IVF. Contrary to IVF, IVM is the only ART method with no cases of OHSS reported. Hence, patients with PCOS represent the major target population for IVM treatment.

In clinical practice of standard IVM, COCs are aspirated from unstimulated or mildly stimulated ovaries and rapidly removed from the meiotic-inhibiting influence of the follicle and the follicular fluid. Regardless of in vitro gonadotrophin treatment, oocytes mature spontaneously in vitro, hence undergoing meiotic resumption in the absence of the usual elaborate cascade of endocrine and paracrine molecular signals that induce maturation in vivo. As such, the maturation of oocytes by standard IVM techniques is an artefact that compromises subsequent oocyte developmental competence. Numbers of studies have been proposed to improve the efficiency of IVM system. Synchronization of meiotic and cytoplasmic maturation in antral oocytes arrested at the immature GV-stage remains a major challenge and is of fundamental importance for successful fertilization. High intra-oocyte levels of cyclic adenosine monophosphate (cAMP), is crucial to maintain the nearly fully-grown oocytes under meiotic arrest and to induce oocyte maturation. Research in animal models has indicated that a non-physiological drop of cAMP levels in the oocyte results in asynchronous nuclear and cytoplasmic maturation.

Investigators have reported the development of a novel in vitro simulated sequential oocyte maturation system. Critical to success of the approach is a pre-IVM phase that generates a rapid increase in COC cAMP levels. Secondly, the system utilizes an extended IVM phase containing sufficient FSH to drive meiotic induction in the presence of a type-3 PDE inhibitor. The high levels of cAMP in the oocyte and the induced nature of oocyte maturation mimics some of the key, newly characterized molecular signals that occur during oocyte maturation in vivo. Technical and conceptual elements were first developed using mouse, bovine and human COCs. Investigators propose a randomized clinical trial to compare a novel sequential culture system with the traditional standard oocyte IVM system for PCOS patients.

Study Overview

• Status: Unknown
• Conditions: Polycystic Ovary Syndrome; Infertility
• Intervention / Treatment: Drug: sequential IVM system; Procedure: intracytoplasmic sperm injection (ICSI); Procedure: Thawed embryo transfer (TET); Drug: traditional IVM system

Detailed Description

A multi-center, prospective, randomized clinical trial will be conducted, of comparing sequential oocyte IVM system with traditional oocyte IVM system for high OHSS risk PCOS patients (AMH>5.6ng/ml). The inclusion criteria will be infertile patients diagnosed by the Chinese PCOS criteria, aged below 35 years, and without other known factors interfere reproductive or metabolic functions. 300 PCOS patients will be included and randomized into either of two groups: group A will administrate sequential oocyte IVM system and group B will administrate traditional standard oocyte IVM system. The comparison will be made between groups, and both groups are conducted with the HMG administration and embryo vitrification freezing. The primary outcome of the study is live birth rate. The embryo development and pregnancy outcomes will be followed up and compared between groups.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 200072
    • Tenth People's Hospital Of Tongji University
  • Guangdong
    • Guangzhou, Guangdong, China, 510610
      • The Sixth Affiliated Hospital, Sun Yat-sen University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province Hospital
  • Shandong
    • Jinan, Shandong, China, 250001
      • Reproductive medical hospital affiliated to Shandong University
  • Zhejiang
    • Wenzhou, Zhejiang, China, 325000
      • The First Affiliated Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 35 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Women age ≤35 years;
2. AMH level ≥5.6ng/ml;
3. Women diagnosed as PCOS according to Chinese PCOS diagnosis criteria;
4. Written informed consent.

Exclusion Criteria:

• Women who diagnosed as uterus abnormality, adenomyosis, submucous myoma, intrauterine adhesion;
• Women who diagnosed as untreated hydrosalpinx;
• Women who had underwent unilateral ovariectomy;
• Women with medical condition that represent contraindication to assisted reproductive technology or pregnancy;
• Women or their partner with abnormal chromosome karyotype;
• Male partner with oligoasthenozoospermia or obstructive azoospermia;
• Male partner whose sperm is collected by surgery;
• Subjects are found breach the inclusion criteria, or in accordance with exclusion criteria during the test, excluded;
• Patients request withdrawal and exit the trial because adverse events occur during the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sequential oocyte IVM group; From day 7~9 of the menstrual cycle, 225 IU HMG (Menotrophins for Injection) per day will be administrated for 3 days. COCs were removed from aspirated follicular fluid and transferred into HEPES-buffered collection medium. The immature oocytes will be cultured in sequential IVM medium 1 for 6 hours (37℃, 5% CO2), and removed into sequential IVM medium 2 for further cultivation. After 24 and 40 hours cultivation, the mature oocytes will be fertilized by intracytoplasmic sperm injection (ICSI). Two of the D3 embryos (if available) which graded as top-quality embryo will be vitrified and the rest of embryos will be cultivated extendedly. Thawed embryo transfer (TET) will give preference to D3 embryos and carried out with a hormone replacement cycle.	Drug: sequential IVM system; The immature oocytes will be cultured in sequential oocyte IVM medium 1 for 6 hours (37℃, 5% CO2). After flushed 3 times, COCs were removed into sequential oocyte IVM medium 2 for further cultivation.; Procedure: intracytoplasmic sperm injection (ICSI); intracytoplasmic sperm injection (ICSI); Procedure: Thawed embryo transfer (TET); Patients administrates oestrogen (Progynova) 3mg twice a day for 10 to 12 days. From the day when endometrium reach a thickness of 8 mm and above, luteal phase support will be given with 10 mg progesterone (Dydrogesterone Tablets,) triple per day and utrogestan (Laboratories Besins International, Paris, France) 0.2g triple per day, until 14 days after embryo transfer.
Active Comparator: traditional oocyte IVM group; From day 7~9 of the menstrual cycle, 225 IU HMG (Menotrophins for Injection) per day will be administrated for 3 days. On the day of ovulation, COCs were aspirated and the immature oocytes will be cultured in traditional standard oocyte IVM system (Sage). 30 and 44 hours after cultivation, the maturity of oocytes will be assessed and the mature oocytes will be fertilized by intracytoplasmic sperm injection (ICSI). Two of the D3 embryos (if available) which graded as top-quality embryo will be vitrified and the rest of embryos will be cultivated extendedly. Thawed embryo transfer (TET) will give preference to D3 embryos and carried out with a hormone replacement cycle. If biochemical pregnancy is not achieved, thawed blastocysts transfer will be performed.	Procedure: intracytoplasmic sperm injection (ICSI); intracytoplasmic sperm injection (ICSI); Procedure: Thawed embryo transfer (TET); Patients administrates oestrogen (Progynova) 3mg twice a day for 10 to 12 days. From the day when endometrium reach a thickness of 8 mm and above, luteal phase support will be given with 10 mg progesterone (Dydrogesterone Tablets,) triple per day and utrogestan (Laboratories Besins International, Paris, France) 0.2g triple per day, until 14 days after embryo transfer.; Drug: traditional IVM system; COCs were aspirated and the immature oocytes will be cultured in traditional standard oocyte IVM system (Sage). 30 and 44 hours after cultivation, the maturity of oocytes will be assessed.; Other Names: sage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy rate	The fetal heart beat in an intrauterine gestational sac under ultrasound will be defined as clinical pregnancy.	7 weeks gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oocyte maturation rate	Oocyte maturation rate (%): number of MII oocytes/ number of oocytes retrieved.	30 and 46 hours after oocyte retrieval
Fertilization rate	Fertilization rate (%): number of oocytes fertilized/ number of oocytes retrieved.	30 and 46 hours after oocyte retrieval
Cleavage rate	Cleavage rate (%): number of cleavages/ number of 2PN embryos.	24 hours after ICSI
Day 3 embryo rate	Day 3 embryo rate (%): number of Day 3 embryos / number of 2PN embryos.	72 hours after ICSI
Good quality embryo rate at cleavage-stage	Good quality embryo rate at cleavage-stage (%): number of good quality embryos at cleavage-stage / number of 2PN embryos.	72 hours after ICSI
Number of cycles with available embryo	Available embryos will be defined as three days after oocyte retrieval with containing more than 4 cells and grade 1 to 2 or containing 4 cells with a grade of 1.	72 hours after ICSI
Blastulation rate	Blastulation rate (%): number of blastocysts / number of 2PN embryos.	144 hours after ICSI
Biochemical pregnancy rate	A serum β-hCG level above 5 IU/L, which is performed 12 days after embryos transfer, will be defined as biochemical pregnancy.	4 weeks gestation
Implantation rate	The implantation rate will be defined as the number of gestational sacs seen on the ultrasound divided by the total number of embryos transferred.	7 weeks gestation
Miscarriage rate (at first trimester)	Miscarriage at first trimester will be defined by any positive pregnancy test that result in a loss of pregnancy before 12 weeks gestation.	28 weeks gestation in maximum
Cumulative pregnancy rate	Cumulative pregnancy rate will be defined as clinical pregnancies with intrauterine fetal heart beat detected divided by the number of retrieval cycles whose embryos are all transferred.	1-2year
Preterm birth rate	Preterm birth means the baby is born before the 37th week of pregnancy in China.	1-2year
Newborn birth weight	Newborn birth weight	1-2year
Neonatal complication rate	We will collect complications that occur in the neonate including admission to the neonatal intensive care unit (NICU), hospitalization, etc.	within one month after labor
Live birth rate	Live birth rate(%): number of live birth/ transferred cycle.	1-2year

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; Shanghai 10th People's Hospital; First Affiliated Hospital of Wenzhou Medical University; Hospital for Reproductive Medicine Affiliated to Shandong University
• Investigators: Study Director: Xiao-yan Liang, M.D. & Ph.D, The Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2018
• Primary Completion (Anticipated): July 1, 2019
• Study Completion (Anticipated): March 1, 2020

Study Registration Dates

• First Submitted: December 8, 2018
• First Submitted That Met QC Criteria: December 10, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): December 12, 2018
• Last Update Submitted That Met QC Criteria: December 10, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: PCOS; infertility; sequential IVM system
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Infertility
• Other Study ID Numbers: newivf20181206

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No