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AzTrials

Secondary InfertilityniPGT-ANCT04711239

Non-invasive Preimplantation Genetic Testing for Aneuploidies Using Cell-free DNA in Spent Culture Media

An observational study of Secondary Infertility, run by ART Fertility Clinics LLC.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

Analysis of embryonic cell-free DNA (cfDNA) present in the spent culture media (SCM) is a non-invasive alternative for preimplantation genetic testing for aneuploidies (PGT-A) that avoids the technical challenges and limitations of biopsy. Read more about this study

Who is it for?
Ages 18 to 46 years, women onlyHealthy volunteers can take part
Conditions the study is for
Secondary Infertility
What is being tested?
PGT-A / niPGT-A
How many people
0 participants
Where
No sites listed yet
Study dates
15 Oct 2021to 15 Oct 2021
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 46 years
  • Women only
  • Healthy volunteers accepted
  • Adult

Study population: Day 6 blastocysts generated from couples undergoing fertility treatment with PGT-A and meeting the eligibility criteria

Who may be able to join

  • Patients undergoing fertility treatment with PGT-A (Recombinant FSH antagonist protocol with dual trigger)
  • Secondary infertility
  • BMI 18- 35 kg/m2
  • Sperm: fresh ejaculated sperm (abstinence: 2-3 days)
  • At least one blastocyst biopsied on day 6

Who cannot join

  • High progesterone on day of trigger (>1.5ng/ml)
  • Vitrified oocytes
  • Frozen sperm
  • Indications for PGT-SR and PGT-M

About this study

Official title: Non-invasive Preimplantation Genetic Testing for Aneuploidies (niPGT-A) - Evaluation of the Analysis of Cell-free DNA in Spent Culture Medium

Analysis of embryonic cell-free DNA (cfDNA) present in the spent culture media (SCM) is a non-invasive alternative for preimplantation genetic testing for aneuploidies (PGT-A) that avoids the technical challenges and limitations of biopsy. Initial studies investigating this non-invasive PGT-A (niPGT-A) method reported variable concordance between cfDNA in SCM and the trophectoderm sample (~ 30%-86%) and indicated a contribution from both the inner cell mass and trophectoderm to the cfDNA in SCM.

This study aims to evaluate the use of the embryo culture medium as a source of genetic material for PGT-A and validate a niPGT-A protocol using cfDNA in SCM.

Read the detailed description

Multiple studies have demonstrated the ability to detect and amplify cfDNA from SCM, at different stages of embryonic development, with varying rates of amplification success. Differences in analytes, timing of SCM collection and the duration of embryo culture within the collected medium, performance of assisted hatching (AH), whole genome amplification methods, comprehensive chromosome screening methods and next generation sequencing (NGS) platforms, bioinformatic analyses and strategies for identifying maternal contamination all contribute to the ultimate performance of niPGT-A.

This study aims to validate a noninvasive PGT-A (niPGT-A) method utilizing cfDNA released from the human blastocyst into the SCM.

Patients undergoing a fertility treatment with PGT-A due to secondary infertility will be recruited. On day 6 post fertilization, SCM will be collected prior to blastocyst biopsy. The SCM is normally discarded at this stage. Trophectoderm biopsy and sample collection will follow the IVF laboratory's standard practices for clinical PGT-A.

Three aneuploidy screening kits, relying on different whole genome amplification methods followed by NGS on the Ion GeneStudio™ S5 Prime System (ThermoFisher Scientific), will be compared. The concordance between cfDNA and trophectoderm biopsies will be evaluated for approximately 150 blastocysts with the best performing niPGT-A protocol.

Selection of the embryo(s) for transfer will be based solely on the PGT-A result from the biopsied cells. The patient's IVF+PGT-A treatment plan and timeline will not be altered.

Being tested
PGT-A / niPGT-A
Keywords
PGT-A, cell-free DNA, spent culture media, NGS

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PGT-A / niPGT-ADiagnostic test

    PGT-A and niPGT-A will be performed using next generation sequencing (NGS) analysis for chromosome copy number variation (CNV). Embryo transfers will rely solely on the results of PGT-A for trophectoderm biopsies.

Study groups in NCT04711239
Study groupRoleWhat they receive
Two types of samples (TE and SCM) will be collected for all blastocysts included in the studyNot described
Receives: Diagnostic Test: PGT-A / niPGT-A

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. General concordance between results for cfDNA in SCM and trophectoderm biopsies

    General ploidy concordance rate: number of matched (euploid-euploid or aneuploid-aneuploid) result/total number cfDNA samples with a result

    Measured: 4 months

  2. Discordance per chromosome between results for cfDNA in SCM and trophectoderm biopsies

    Discordance per chromosome: number of misidentified chromosomal errors/24*total number of embryos with cfDNA result

    Measured: 4 months

  3. Concordance per chromosome between results for cfDNA in SCM and trophectoderm

    Chromosome error concordance: number of correctly identified chromosomal errors/total number of chromosomal errors detected

    Measured: 4 months

  4. Sensitivity of niPGT-A using cfDNA in SCM

    False negative rate: 1- (true euploid result/total number of samples with a result)

    Measured: 4 months

  5. Specificity of niPGT-A using cfDNA in SCM

    False positive rate: 1- (true aneuploid result/total number of samples with a result)

    Measured: 4 months

Secondary outcomes (6)

  1. Pregnancy outcome for patients having an embryo transfer - Implantation rate

    Implantation rate = number of gestational sacs observed at echographic screening at 6 weeks of pregnancy / number of embryos transferred

    Measured: 12 months

  2. Pregnancy outcome for patients having an embryo transfer - Biochemical pregnancy rate

    Biochemical pregnancy rate = positive βhCG test of > 15IU but no foetal heartbeat / gestational sac on ultrasound examination

    Measured: 12 months

  3. Pregnancy outcome for patients having an embryo transfer - Clinical pregnancy rate

    Clinical pregnancy rate (%) defined by positive βhCG test and ultrasound confirmation of gestational sac or heartbeat

    Measured: 12 months

  4. Pregnancy outcome for patients having an embryo transfer - Miscarriage rate

    Miscarriage rate (%) defined by ultrasonographic visualization of one or more gestational sacs, including ectopic pregnancies, with spontaneous pregnancy loss prior to 20 weeks

    Measured: 12 months

  5. Pregnancy outcome for patients having an embryo transfer - Clinical pregnancy rate

    Ongoing pregnancy rate (beyond 20 weeks)

    Measured: 12 months

  6. Pregnancy outcome for patients having an embryo transfer - Implantation failure rate

    Implantation Failure (%)

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jan 2021
  2. Study start15 Oct 2021
  3. Primary completion15 Oct 2021
  4. Study completion15 Oct 2021

Why it stopped: Unavailability of Primary investigator

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04711239
Sponsor's protocol ID
2010-ABU-011-SJ
Acronym
niPGT-A
Status last verified
Mar 2023
First submitted
8 Jan 2021
Last updated
20 Mar 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Shamonki MI, Jin H, Haimowitz Z, Liu L. Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media. Fertil Steril. 2016 Nov;106(6):1312-1318. doi: 10.1016/j.fertnstert.2016.07.1112. Epub 2016 Aug 24.

    PubMed 27565258

  • Xu J, Fang R, Chen L, Chen D, Xiao JP, Yang W, Wang H, Song X, Ma T, Bo S, Shi C, Ren J, Huang L, Cai LY, Yao B, Xie XS, Lu S. Noninvasive chromosome screening of human embryos by genome sequencing of embryo culture medium for in vitro fertilization. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11907-11912. doi: 10.1073/pnas.1613294113. Epub 2016 Sep 29.

    PubMed 27688762

  • Feichtinger M, Vaccari E, Carli L, Wallner E, Madel U, Figl K, Palini S, Feichtinger W. Non-invasive preimplantation genetic screening using array comparative genomic hybridization on spent culture media: a proof-of-concept pilot study. Reprod Biomed Online. 2017 Jun;34(6):583-589. doi: 10.1016/j.rbmo.2017.03.015. Epub 2017 Mar 28.

    PubMed 28416168

  • Rubio C, Navarro-Sanchez L, Garcia-Pascual CM, Ocali O, Cimadomo D, Venier W, Barroso G, Kopcow L, Bahceci M, Kulmann MIR, Lopez L, De la Fuente E, Navarro R, Valbuena D, Sakkas D, Rienzi L, Simon C. Multicenter prospective study of concordance between embryonic cell-free DNA and trophectoderm biopsies from 1301 human blastocysts. Am J Obstet Gynecol. 2020 Nov;223(5):751.e1-751.e13. doi: 10.1016/j.ajog.2020.04.035. Epub 2020 May 26.

    PubMed 32470458

  • Fang R, Yang W, Zhao X, Xiong F, Guo C, Xiao J, Chen L, Song X, Wang H, Chen J, Xiao X, Yao B, Cai LY. Chromosome screening using culture medium of embryos fertilised in vitro: a pilot clinical study. J Transl Med. 2019 Mar 8;17(1):73. doi: 10.1186/s12967-019-1827-1.

    PubMed 30849973

  • Huang L, Bogale B, Tang Y, Lu S, Xie XS, Racowsky C. Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14105-14112. doi: 10.1073/pnas.1907472116. Epub 2019 Jun 24.

    PubMed 31235575

  • Capalbo A, Romanelli V, Patassini C, Poli M, Girardi L, Giancani A, Stoppa M, Cimadomo D, Ubaldi FM, Rienzi L. Diagnostic efficacy of blastocoel fluid and spent media as sources of DNA for preimplantation genetic testing in standard clinical conditions. Fertil Steril. 2018 Oct;110(5):870-879.e5. doi: 10.1016/j.fertnstert.2018.05.031.

    PubMed 30316433

  • Ho JR, Arrach N, Rhodes-Long K, Ahmady A, Ingles S, Chung K, Bendikson KA, Paulson RJ, McGinnis LK. Pushing the limits of detection: investigation of cell-free DNA for aneuploidy screening in embryos. Fertil Steril. 2018 Aug;110(3):467-475.e2. doi: 10.1016/j.fertnstert.2018.03.036. Epub 2018 Jun 28.

    PubMed 29960707

  • Kuznyetsov V, Madjunkova S, Antes R, Abramov R, Motamedi G, Ibarrientos Z, Librach C. Evaluation of a novel non-invasive preimplantation genetic screening approach. PLoS One. 2018 May 10;13(5):e0197262. doi: 10.1371/journal.pone.0197262. eCollection 2018.

    PubMed 29746572

  • Vera-Rodriguez M, Diez-Juan A, Jimenez-Almazan J, Martinez S, Navarro R, Peinado V, Mercader A, Meseguer M, Blesa D, Moreno I, Valbuena D, Rubio C, Simon C. Origin and composition of cell-free DNA in spent medium from human embryo culture during preimplantation development. Hum Reprod. 2018 Apr 1;33(4):745-756. doi: 10.1093/humrep/dey028.

    PubMed 29471395

Questions about this trial

What is this clinical trial studying?

An observational study of Secondary Infertility, run by ART Fertility Clinics LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 20 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

General concordance between results for cfDNA in SCM and trophectoderm biopsies (time frame: 4 months). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04711239, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2023.

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