Clinical trial NCT03773263: New Application of Sequential in Vitro Muturation System for Infertility Patients With Polycystic Ovary Syndrome
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome
Infertility
Keywords: sequential IVM system
PCOS
infertility
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
Collaborators: name: Hospital for Reproductive Medicine Affiliated to Shandong University
name: The First Affiliated Hospital with Nanjing Medical University
name: First Affiliated Hospital of Wenzhou Medical University
name: Shanghai 10th People's Hospital
First posted: 2018-12-12
Enrollment: 300
Sex: FEMALE
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Clinical pregnancy rate
timeFrame: 7 weeks gestation
Secondary outcomes:
measure: Oocyte maturation rate
timeFrame: 30 and 46 hours after oocyte retrieval
measure: Fertilization rate
timeFrame: 30 and 46 hours after oocyte retrieval
measure: Cleavage rate
timeFrame: 24 hours after ICSI
measure: Day 3 embryo rate
timeFrame: 72 hours after ICSI
measure: Good quality embryo rate at cleavage-stage
timeFrame: 72 hours after ICSI
measure: Number of cycles with available embryo
timeFrame: 72 hours after ICSI
measure: Blastulation rate
timeFrame: 144 hours after ICSI
measure: Biochemical pregnancy rate
timeFrame: 4 weeks gestation
measure: Implantation rate
timeFrame: 7 weeks gestation
measure: Miscarriage rate (at first trimester)
timeFrame: 28 weeks gestation in maximum
measure: Cumulative pregnancy rate
timeFrame: 1-2year
measure: Preterm birth rate
timeFrame: 1-2year
measure: Newborn birth weight
timeFrame: 1-2year
measure: Neonatal complication rate
timeFrame: within one month after labor
measure: Live birth rate
timeFrame: 1-2year
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The Sixth Affiliated Hospital, Sun Yat-Sen University
state: Guangdong
city: Nanjing
country: China
facility: Jiangsu Province Hospital
state: Jiangsu
city: Jinan
country: China
facility: Reproductive medical hospital affiliated to Shandong University
state: Shandong
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
city: Shanghai
country: China
facility: Tenth People's Hospital of Tongji University
Study officials:
affiliation: The Sixth Affiliated Hospital, Sun Yat-sen University
name: Xiao-yan Liang, M.D. & Ph.D
role: STUDY_DIRECTOR
References: