Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03773263
Recruitment Status : Not yet recruiting
First Posted : December 12, 2018
Last Update Posted : December 12, 2018
Sponsor:
Collaborators:
Hospital for Reproductive Medicine Affiliated to Shandong University
The First Affiliated Hospital with Nanjing Medical University
First Affiliated Hospital of Wenzhou Medical University
Shanghai 10th People's Hospital
Information provided by (Responsible Party):
Yanhong Deng, Sun Yat-sen University

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.


Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Infertility Drug: sequential IVM system Procedure: intracytoplasmic sperm injection (ICSI) Procedure: Thawed embryo transfer (TET) Drug: traditional IVM system Phase 3

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


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 Name: sage




Primary Outcome Measures :
  1. Clinical pregnancy rate [ Time Frame: 7 weeks gestation ]
    The fetal heart beat in an intrauterine gestational sac under ultrasound will be defined as clinical pregnancy.


Secondary Outcome Measures :
  1. Oocyte maturation rate [ Time Frame: 30 and 46 hours after oocyte retrieval ]
    Oocyte maturation rate (%): number of MII oocytes/ number of oocytes retrieved.

  2. Fertilization rate [ Time Frame: 30 and 46 hours after oocyte retrieval ]
    Fertilization rate (%): number of oocytes fertilized/ number of oocytes retrieved.

  3. Cleavage rate [ Time Frame: 24 hours after ICSI ]
    Cleavage rate (%): number of cleavages/ number of 2PN embryos.

  4. Day 3 embryo rate [ Time Frame: 72 hours after ICSI ]
    Day 3 embryo rate (%): number of Day 3 embryos / number of 2PN embryos.

  5. Good quality embryo rate at cleavage-stage [ Time Frame: 72 hours after ICSI ]
    Good quality embryo rate at cleavage-stage (%): number of good quality embryos at cleavage-stage / number of 2PN embryos.

  6. Number of cycles with available embryo [ Time Frame: 72 hours after ICSI ]
    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.

  7. Blastulation rate [ Time Frame: 144 hours after ICSI ]
    Blastulation rate (%): number of blastocysts / number of 2PN embryos.

  8. Biochemical pregnancy rate [ Time Frame: 4 weeks gestation ]
    A serum β-hCG level above 5 IU/L, which is performed 12 days after embryos transfer, will be defined as biochemical pregnancy.

  9. Implantation rate [ Time Frame: 7 weeks gestation ]
    The implantation rate will be defined as the number of gestational sacs seen on the ultrasound divided by the total number of embryos transferred.

  10. Miscarriage rate (at first trimester) [ Time Frame: 28 weeks gestation in maximum ]
    Miscarriage at first trimester will be defined by any positive pregnancy test that result in a loss of pregnancy before 12 weeks gestation.

  11. Cumulative pregnancy rate [ Time Frame: 1-2year ]
    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.

  12. Preterm birth rate [ Time Frame: 1-2year ]
    Preterm birth means the baby is born before the 37th week of pregnancy in China.

  13. Newborn birth weight [ Time Frame: 1-2year ]
    Newborn birth weight

  14. Neonatal complication rate [ Time Frame: within one month after labor ]
    We will collect complications that occur in the neonate including admission to the neonatal intensive care unit (NICU), hospitalization, etc.

  15. Live birth rate [ Time Frame: 1-2year ]
    Live birth rate(%): number of live birth/ transferred cycle.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 35 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03773263


Contacts
Layout table for location contacts
Contact: Xiao-yan Liang, M.D. & Ph.D 020-38048013 lxyzy@263.net

Locations
Layout table for location information
China, Guangdong
The Sixth Affiliated Hospital, Sun Yat-Sen University
Guangzhou, Guangdong, China, 510610
Contact: Xiao-yan Liang, M.D. & Ph.D.    020-38048013    lxyzy@263.net   
China, Jiangsu
Jiangsu Province Hospital
Nanjing, Jiangsu, China, 210029
China, Shandong
Reproductive medical hospital affiliated to Shandong University
Jinan, Shandong, China, 250001
China, Zhejiang
The First Affiliated Hospital of Wenzhou Medical University
Wenzhou, Zhejiang, China, 325000
China
Tenth People's Hospital of Tongji University
Shanghai, China, 200072
Sponsors and Collaborators
Sun Yat-sen University
Hospital for Reproductive Medicine Affiliated to Shandong University
The First Affiliated Hospital with Nanjing Medical University
First Affiliated Hospital of Wenzhou Medical University
Shanghai 10th People's Hospital
Investigators
Layout table for investigator information
Study Director: Xiao-yan Liang, M.D. & Ph.D The Sixth Affiliated Hospital, Sun Yat-Sen University
Layout table for additonal information
Responsible Party: Yanhong Deng, doctor, Sun Yat-sen University
ClinicalTrials.gov Identifier: NCT03773263    
Other Study ID Numbers: newivf20181206
First Posted: December 12, 2018    Key Record Dates
Last Update Posted: December 12, 2018
Last Verified: December 2018

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yanhong Deng, Sun Yat-sen University:
sequential IVM system
PCOS
infertility
Additional relevant MeSH terms:
Layout table for MeSH terms
Polycystic Ovary Syndrome
Infertility
Syndrome
Disease
Pathologic Processes
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases