ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12617000500358

Ethics application status

Approved

Date submitted

7/02/2017

Date registered

6/04/2017

Date last updated

13/12/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

NEST4E: A pilot study into the clinical effectiveness of Non-invasive Preimplantation Genetic Screening (PGS) method for Embryo ploidy status among patients undergoing IVF treatment

Scientific title

NEST4E: A pilot study into the clinical effectiveness of Non-invasive Preimplantation Genetic Screening (PGS) method for determining Embryo ploidy status among patients undergoing IVF treatment

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1192-4733

Trial acronym

NEST4E

Linked study record

none

Health condition

Health condition(s) or problem(s) studied:

Infertility

Embryo genetics

Condition category

Condition code

Reproductive Health and Childbirth

Fertility including in vitro fertilisation

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The purpose of this pilot trial is to test a non-invasive Preimplantation Genetic Screening (PGS) method for human embryos. The investigators have developed a method for amplifying cell-free DNA from human embryo culture medium and using Next Generation Sequencing (NGS) to determine embryo aneuploid vs euploid status of the embryo, This technology eliminates the need for an invasive embryo biopsy to perform preimplantation genetic screening. This trial will be conducted at Repromed on 15 patients undergoing IVF treatment that would benefit from preimplantation genetic screening. Spent media will be collected by the scientists from the embryo culture dish and used to determine if the embryo is aneuploid or euploid. Each embryo undergoes this method once only on a single occasion, with the exception that if the non-invasive screen does not provide a conclusive result, a trophectoderm biopsy will be reformed on the embryo that fails the non-invasive screen to detect aneuploidy/euploidy.

Intervention code [1]

Early detection / Screening

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

The measured primary outcomes of this NEST4E pilot study are:
The number of embryos screened as euploid that are not required to be biopsied. This will be assessed by amplifying the cell-free DNA from the embryos spent culture media, The DNA will be sequenced using next generation sequencing and the data analysed using the Illumina platform to determine the ploidy status of the embryo. If the sequence data shows that the embryo is euploid the embryo will be transferred. The embryo will be confirmed as euploid at the primary time point (ie. following preimplantation and 1st trimester screening)

Timepoint [1]

Following preimplantation and 1st trimester screening.

Primary outcome [2]

For euploid embryos, the percentage of concordance of media sample results to non-invasive NIPT based first trimester screening which can be befriend as early as 10 weeks pregnant.

Timepoint [2]

Following non-invasive NIPT based first trimester screening which can be performed as early as 10 weeks

Primary outcome [3]

For anueploid embryos, the percentage of embryos that show concordance with confirmatory biopsy next generation sequencing screening results.

Timepoint [3]

Next generation sequencing results of biopsied cells can be obtained with 2 weeks post trophectoderm biopsy

Secondary outcome [1]

Measured secondary outcomes are:
Clinical pregnancy rates of embryos screened as euploid using the non-invasive NEST4E technology.

Timepoint [1]

Determination of a positive pregnancy test occurs 12-14 days post embryo transfer via detection of HCG levels from a maternal blood test. Confirmation of a viable pregnancy is performed at 6-8 weeks of pregnancy via ulstrasound to detect fetal heart beat Live birth outcomes will be collected 2-4 weeks post the due date as per standard clinical protocol.,

Secondary outcome [2]

Live birth rates of embryos screened as euploid using the non-invasive NEST4E test

Timepoint [2]

Live birth outcomes will be collected as per standard Repromed patient care. This information is generally collected in writing from the treating obstetrician/doctor, or alternatively directly from the patient with a follow up phone call from the clinic nurses several weeks post due date. It is a regulatory requirement that gestation length, birthweight, sex, method of delivery and details of any maternal or neonatal complications are reported to ANZARD (Australian & New Zealand Assisted Reproduction Database).

Secondary outcome [3]

Percentage of euploid vs aneuploidy embryos as determined by NEST4E non-invasive screening. Any embryos screened as Aneuploid will undergo trophectoderm biopsy and PGS screening to confirm the aneuploidy.

Timepoint [3]

Data collection and analysis will be coordinated by the Principal Investigator and Co Investigators, all who have had extensive previous experience with data analysis and interpretation of pilot studies and clinical trials. These results will be reported directly to the Clinical Genetics Team and the patient’s clinician. A Data Monitoring Committee chaired by Repromed’s Clinical Director will perform an interim analysis after 5 participants embryo’s (approx 16-20 embryos) have been screened using NEST4E to ensure that the results are concordant with the biopsy screening. Final analysis will take place immediately after collection of the final birth outcome.

Eligibility

Key inclusion criteria

This study is a pilot study on fifteen couples (approximately 60 transferrable embryos) to assess the ability of this technology to screen embryos for aneuploidy. Participants will be consenting patients undergoing IVF treatment with PGS at Repromed, 180 Fullarton Rd., Dulwich, South Australia. Participation in the study will be offered to those patients whom PGS in general is discussed as a treatment option.

Minimum age

18 Years

Maximum age

53 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Patients involved in the Donor program (oocyte and sperm)
2. Patients with a known infectious disease (HIV, HEP B, HEP C)
3. Patients using Preimplantation Genetic Diagnosis (PGD) for single genes or translocations.

Study design

Purpose of the study

Diagnosis

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation is not concealed

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

non-randomised trial

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

none

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

This study is a pilot study on fifteen couples (approximately 60 transferrable embryos) to assess the ability of this technology to screen embryos for aneuploidy. Data collection and analysis will be coordinated by the Principal Investigator and Co Investigators. These results will be reported directly to the Clinical Genetics Team and the patient’s clinician.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

9/04/2017

Actual

7/04/2017

Date of last participant enrolment

Anticipated

Actual

16/07/2017

Date of last data collection

Anticipated

31/12/2018

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Repromed Day Surgery - Dulwich

Recruitment postcode(s) [1]

5065 - Dulwich

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Repromed

Address [1]

180 Fullarton Road Dulwich SA 5065

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Repromed

Address

180 Fullarton Road Dulwich SA 5065

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

129 Glen Osmond Road Eastwood South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/01/2017

Approval date [1]

09/03/2017

Ethics approval number [1]

2016-12-891

Summary

Brief summary

The primary objective of this pilot study is to evaluate the clinical effectiveness of our NEST4E non-invasive method for screening embryo ploidy by determining the number of embryos that can that be successfully screened for aneuploidy using the NEST4E rather than invasive biopsy.
Aim 1: For euploid embryos the percentage concordance of media sample screening will be confirmed using non-invasive NIPT based first trimester screening as early as 10 week pregnancy. For aneuploid embryos, we will determine the percentage of embryos with concordance by confirmatory trophectoderm biopsy and PGS screening.
Aim 2: To determine clinical pregnancy rates and live birth outcomes of embryos that are transferred once screened as euploid. 
Fifteen patients will be recruited by informed consent to participate in this pilot study to assess the clinical efficacy of our NEST4E non-invasive PGS test to screen their embryos for aneuploidy. Participants will be made aware that their participation in the study is entirely voluntary and that they can withdraw at any point in time. As per standard protocol, patient confidentially will be strictly maintained and their identity will not be revealed in any reviews and reports of this study which may be published. 
Patients treatment will not be altered in any way and will proceed as per standard IVF cycle, including medications, oocyte retrieval, insemination and fertilization and embryo culture. Patient embryos will be cultured as per standard protocols; G1/G2 Plus media (Vitrolife) overlayed with oil (Ovoil, Vitrolife) in 6% CO2, 5% O2, 37 degrees.  A 4 micro litre drop of the spent culture medium will be sampled using PCR grade filtered tips, under laminar flow, and placed into PCR grade 0.6 ml tubes and assessed for aneuploidy as described below.
DNA from the culture media sample will be amplified. If this amplification should fail, the embryo will be removed from the trial and will revert to standard care which involves a biopsy followed by vitrification and sample screening. If the amplification is successful, the embryo will be vitrified and the DNA amplified from the media sample used for screening by NEST4E. If conclusive sequence data is obtained, euploid embryos will be made available for transfer.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Michelle Lane

Address

Repromed - 180 Fullarton Road Dulwich SA 5065

Country

Australia

Phone

+61 8 83338111

Fax

mlane@repromed.com.au

Contact person for public queries

Name

Hamish Hamilton

Address

Repromed - 180 Fullarton Road Dulwich SA 5065

Country

Australia

Phone

+61 8 83338111

Fax

hhamilton@repromed.com.au

Contact person for scientific queries

Name

Hamish Hamilton

Address

Repromed- 180 Fullarton Road Dulwich SA 5065

Country

Australia

Phone

+61 8 83338111

Fax

hhamilton@repromed.com.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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