Clinical trial for the treatment of infertility due to poor oocyte quality

Plain English Summary

Background and study aims
There is a significant number of IVF patients who continue to suffer from infertility. Such patients go through numerous cycles of traditional IVF and after failing in the end are offered egg donor programs to be able to have a family or healthy child. Furthermore, according to reports from the Centers for Disease Control and Prevention (CDC), by 2016 women aged 30 or older exhibited a higher birth rate than women aged 25–29. Maternal age is a critical factor in women’s fertility - as many as half of oocytes (eggs) from IVF patients over the age of 38 years contain errors in chromosome numbers. The emerging trend of delaying having children combined with the fertility problems associated with advanced maternal age calls for clinical trials of new IVF techniques to include investigating age-related infertility. The aims of this study are: 1) to assess whether undergoing meiosis (cell division) in a young healthy cytoplasm can reduce the rate of aneuploidy (abnormal number of chromosomes) for “old” oocytes and 2) to assess whether removal of defective oocyte cytoplasm followed by complete replacement with healthy, young donor cytoplasm alleviates preimplantation embryonic developmental arrest and increases the rate of healthy embryos. As a preliminary step, patient oocytes are reconstructed via nuclear transfer. Reconstructed oocytes contain the nucleus (carrying all of the chromosomes, which provide the genetic instructions for the body) from the patient and the ooplasm (non-nuclear cellular material) from the donor egg. The reconstructed oocyte is fertilized at the MII stage with the partner or donor’s sperm to create an embryo, which is then screened for chromosomal abnormalities before transferring to the mother.

Who can participate?
Infertile women with a regular menstrual cycle who have had at least three previous failed IVF attempts

What does the study involve?
In order not to lyse (break) the oocyte during removal of the nucleus, Cytochalasin membrane relaxants are used. Germinal vesicles (GV) transfer into fresh, enucleated donor GV oocyte (under 32 years old) is the first step for the age-related infertility participants (over 41 years of age), followed by in vitro maturation (IVM). Nuclear transfer at the immature GV stage allows the patient nucleus to undergo meiosis (to mature) in a young healthy cytoplasm. When the reconstituted GV matures in vitro to the MII stage, the second nuclear transfer step is conducted (spindle nuclear transfer) into an in-vivo (grown in the mother) MII donor oocyte. This is because numerous model studies have shown that the manipulated oocytes grown in vitro (not in the mother) do not produce live offspring successfully. In addition, if the matured MII oocyte displays a viable polar body, it may also undergo Polar Body 1 Genome transfer (PBGT). The PBGT technique involves the transfer of the first polar body (PB) of the unfertilized MII oocyte to another enucleated donor oocyte and may create an additional embryo which increases opportunities for every patient affected by infertility. The procedure is similar to the Spindle Nuclear Transfer, with the notable difference that the polar body is transferred instead of the oocyte’s spindle. If the MII oocyte from the patient does not display a visible spindle, it is fertilized at the MII phase, and pronuclear transfer is performed next-day at the zygote stage, when the egg is fertilized. After fusion of the donor ooplast with the patient nucleus, one of the partner/donor’s sperm is injected into each reconstituted eggs. All other IVF processes are applied in a routine manner. For patients under 41 years of age with non-age-related infertility, the treatment starts with Spindle Nuclear Transfer, or if no spindle is visible, with fertilization and next-day pronuclear transfer. Resulting pregnancies from euploid balstocysts are followed up until delivery and newborns are followed regularly by pediatricians until the age of 18.

What are the possible benefits and risks of participating?
Treatment with novel IVF techniques may be able to overcome infertility which was not successfully treated with traditional IVF methods and could be a reasonable alternative to egg donation. This may give the opportunity of participants to have children who are genetically related to them. Currently there are 10 babies born from nuclear transfer, to the researchers' knowledge, the oldest of whom is a 3-year-old girl. As per her last medical screenings at Nadiya Clinic, she is in full health. Although long-term follow up is undoubtedly necessary, regulatory bodies such as the HFEA in the UK has concluded that there is no reason to believe that the cytoplasmic replacement technique is an unsafe procedure.
Although nucleus to ooplasm fusion procedures with Cell Fusion Reagents have been applied to eggs and embryos of several animal models and in a limited number of human live births, their application and long-term consequences in the human are unknown. The long-term consequences of Cytochalasin during human oocyte micromanipulations are largely unknown. The long-term consequences of mitochondrial heteroplasmy in the human blastocyst are largely unknown. The long-term epigenetic effects from cytoplasmic replacement is largely unknown. Patients in the trial are informed that there is no guarantee for a pregnancy. Due to the recent move from basic research into clinical trials, patients are informed of the uncertainty whether individuals resulting from nuclear transfer may develop unknown symptoms or disease because of the novel procedures. At the time of enrollment, patients considering to participate in the trial are informed of the latest status of clinical trial progress.

Where is the study run from?
Darwin Life-Nadiya LLC (Ukraine)

When is the study starting and how long is it expected to run for?
October 2017 to January 2022

Who is funding the study?
Darwin Life-Nadiya LLC (Ukraine)

Who is the main contact?
1. Dr John Zhang
info@darwinlife.com
2. Dr Valery Zukin
info@ivf.com.ua

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• Ukraine

Study participating centre

Sponsor information

Funders

Funder type

Research organisation

Results and Publications

Study outputs

Additional files

ISRCTN13358803_PROTOCOL_1_23Aug2019.pdf

Uploaded 19/09/2019

ISRCTN13358803_PROTOCOL_2_23Aug2019.pdf

Uploaded 19/09/2019

Editorial Notes

19/09/2019: Uploaded protocols 23 August 2019 (not peer reviewed).
18/09/2019: Trial's existence confirmed by ethics committee.