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Trial record 2 of 4 for:    niPGT-A

RCT Study to Validate niPGT-A Clinical Benefit. (niPGT-A_RCT)

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ClinicalTrials.gov Identifier: NCT04000152
Recruitment Status : Recruiting
First Posted : June 27, 2019
Last Update Posted : December 31, 2020
Sponsor:
Information provided by (Responsible Party):
Igenomix

Brief Summary:

Chromosomal aneuploidies are linked with spontaneous miscarriages and abnormal offspring in human pregnancies. In addition, some types of aneuploidy are reported to prevent implantation. Thus, there is a need to identify the embryos with highest implantation potential on in vitro fertilization (IVF) programs.

Since embryo morphology and kinetics have a weak association with embryo ploidy, trophectoderm biopsy plus Next-Generation Sequencing (NGS) is becoming a very popular approach to determine the embryo chromosomal status. This technique is called Preimplantation Genetic Testing for Aneuploidy (PGT-A). Although shown to be efficient, it is invasive for the embryo, requires specific technical skills and it remains expensive. Therefore, the development of a non-invasive, rapid and cheaper method for assessing embryo ploidy status would represent a progress in the field of IVF.

The non-invasive approach has been explored by some groups that analyzed the Spent Blastocyst Medium (SBM) where the embryo was incubated up to the time of transfer or freezing. In daily routine, this media is discarded after finishing the culture of the embryo. Importantly, though, this media reportedly contains traces of embryonic cell-free DNA (cfDNA) that can represent the genetic load of the embryo.

On the basis of that, the hypothesis of this study is that embryo prioritization according to the analysis of the embryonic cfDNA in the SBM could improve ongoing pregnancy rate in 10 percentual points compared to standard blastocyst transfer based on morphology.


Condition or disease Intervention/treatment Phase
Aneuploidy Chromosome Abnormality Infertility Diagnostic Test: niPGT-A Other: Morphology criteria Not Applicable

Detailed Description:

Current Preimplantation Genetic Testing for Aneuploidy (PGT-A) techniques analyze the full chromosome content of a single or few cells with high sensitivity and specificity using Next-Generation Sequencing (NGS). Although shown to be efficient, the technique suffers from some limitations. It requires an embryo biopsy, specific technical skills and it still remains expensive. Therefore, non-invasive techniques for assessing embryo ploidy status are sought as an alternative. Such non-invasive approaches would have various advantages over current strategies, including the elimination of a costly micromanipulation biopsy procedure and the avoidance of risks associated with cell removal. Furthermore, it would be more advantageous, especially for those patients who undergo in vitro fertilization (IVF) treatment but do not have PGT-A indication or they are not willing to have their embryos tested with invasive techniques.

One of the recent advances in the field is the identification of embryonic cell-free DNA (cfDNA) during embryo culture in the lab. It is released to the culture drop (SBM) and represents the chromosome content of the embryo. In a recent pilot study, we analyzed the concordance rates between trophectoderm (TE) biopsy and SBM. In SBM collected on day 6/7 of development, the results were concordant with TE biopsies in 84% of samples, with a false-positive rate of 8.6% and a false-negative rate of 2.5%. These findings are encouraging and were the base for the design of the current RCT study.

The main objective of this study is to evaluate the potential clinical benefits of a new non-invasive method for PGT-A, based on the analysis of the embryonic cfDNA released into SBM.

Considering a dropout rate of around 30% (treatment or monitoring failures and no day 6/7 blastocysts to transfer), a total of 872 participants will be randomized before the ovum pick-up. They will be allocated on a balanced way (1:1 ratio) in one of the two arms: 1) Single Embryo Transfer (SET) on day 6/7 with deferred blastocyst transfer based on the chromosomal status according to the analysis of the SBM; 2) SET on day 6/7 with deferred blastocyst transfer based on embryo morphology. Reproductive outcomes (defined following The International Glossary on Infertility and Fertility Care, 2017) will be compared between the two groups.

Data exported from the clinical histories and source documents will be duly codified to protect the clinical and personal information of patients in accordance with the current legislation. This information will be exported to an electronic Case Report Form (eCRF). An interim analysis of this data is planned once 30% of the recruitment has been reached. Besides, the study will be overseen by an independent Data Monitoring Committee after 30% of patients´ recruitment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Randomized Controlled Clinical Study to Assess the Benefit of Non-invasive PGT-A, by the Analysis of Spent Blastocyst Media, as a Tool for Embryo Prioritization in Infertile Patients Undergoing Assisted Reproduction.
Actual Study Start Date : June 14, 2019
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : June 2023

Arm Intervention/treatment
Active Comparator: Control group (group 1)
Deferred single blastocyst transfer with blastocyst selection according to morphology.
Other: Morphology criteria
Embryos for transfer will be selected by the only applicable technique, the assessment of morphology according to Gardner´s criteria, which is the most standardized method.

Experimental: Intervention group (group 2)
Deferred single blastocyst transfer with blastocyst selection according to the analysis of the spent culture media (niPGT-A).
Diagnostic Test: niPGT-A

Two scenarios should be considered according to the results in the SBM analysis:

  1. The couple decides to transfer the blastocyst selected according to the SBM result (blastocyst prioritization system).
  2. The couple decides to biopsy the blastocysts (if SBM results show low euploidy score). This PGT-A analysis will be offered for free but the outcome of these transfers will be excluded for the analysis per completed protocol. However, all transfers will be included in the intention-to-treat analysis.




Primary Outcome Measures :
  1. Non-invasive analysis of the chromosomal status of the embryo [ Time Frame: 7 days ]
    Number and structure of the embryo chromosomes

  2. Ongoing pregnancy rate [ Time Frame: Over 12 weeks ]
    Number of ongoing pregnancies per single embryo transfer


Secondary Outcome Measures :
  1. NGS results of the SBM [ Time Frame: 7 days at least ]
    Informativity rates and prioritization category of the SBM analysis results with embryo development, culture conditions and collection time

  2. Non-Invasive Prenatal Testing (NIPT) [ Time Frame: Up to 12 weeks ]
    Incidence of chromosomal abnormalities in NIPT within ongoing pregnancy cases

  3. Clinical miscarriage rate [ Time Frame: Up to 6 months after the ovum pick-up ]
    Number of clinical miscarriages per total number of ongoing pregnancies

  4. Analysis of the Products of Conception (POC) [ Time Frame: Up to 20 weeks ]
    Incidence of chromosomal abnormalities in POC within miscarriage cases

  5. Cumulative ongoing pregnancy rate [ Time Frame: Over 6 months after the ovum pick-up ]
    Cumulative ongoing pregnancy rate per patient in the 6 months after the pick-up

  6. Time to get an ongoing pregnancy [ Time Frame: Up to 6 months after the ovum pick-up ]
    Time to get an ongoing pregnancy within the 6 months after the pick-up

  7. Live birth rate [ Time Frame: Over 40 weeks ]
    Number of babies born per embryo transfer

  8. Cumulative live birth rate [ Time Frame: Over 6 months after the ovum pick-up ]
    Cumulative live birth rate per patient in the 6 months after the pick-up

  9. Obstetrical outcomes comparison [ Time Frame: Over 40 weeks ]
    To compare birth weight, gestational age, APGAR, type of delivery, pregnancy complications, etc.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   IVF patients between 20 and 40 years of age undergoing fertility treatment with their own oocytes, with no intention or medical indication for PGT-A.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients whose written informed consent approved by the Ethics Committee (EC) has been obtained, after having been duly informed of the nature of the study and voluntarily accepted to participate after being fully aware of the potential risks, benefits and any discomfort involved.
  • IVF patients intending to undergo deferred day 6/7 blastocyst SET for any medical indication.
  • All the oocytes/embryos from the cycle should follow the laboratory protocol described in the study (embryo culture and vitrification on day 6/7).
  • ICSI, IVF or ICSI/IVF performed in fresh own oocytes from couples not undergoing PGT-A. Note: Donor sperm is allowed.
  • Female age: 20-40 years, both included.

Exclusion Criteria:

  • A known abnormal karyotype if the couple provides it at consultation. If not, karyotype is not compulsory.
  • Couples planning to undergo PGT-M or PGT-SR cases will be excluded.
  • Surrogate pregnancy (in those countries where it is allowed).
  • ERA test and embryo transfer according to ERA result.
  • Time-lapse culture systems are not allowed after day 4 of culture.
  • Presence of pathologies or malformations that affect the uterine cavity such as polyps, intramural myomas ≥ 4cm or submucosal, septum or hydrosalpinx during the patient's participation in the study. Patients suffering these pathologies before or after their inclusion in the study can participate if the pathology is corrected before performing any study procedure.
  • Any illness or medical condition that is unstable or which, according to medical criteria, may put at risk the patient's safety and her compliance in the study.

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): NCT04000152


Contacts
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Contact: Carlos Gómez, BSc MSc +34 963905310 carlos.gomez@igenomix.com
Contact: Carmen Rubio, PhD +34 963905310 carmen.rubio@igenomix.com

Locations
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United States, California
Fertility Associates of California (FSAC) Recruiting
Thousand Oaks, California, United States, 91361
Contact: Mousa Shamonki, MD    805-719-7531    mshamonki@gmail.com   
Principal Investigator: Mousa Shamonki, MD         
United States, Florida
South Florida Institute for Reproductive Medicine (IVFMD) Active, not recruiting
Florida City, Florida, United States, 33458
United States, Massachusetts
Boston IVF Fertility Clinic Active, not recruiting
Boston, Massachusetts, United States, 02109
Argentina
Crecer: Centro de Reproducción y Genética Humana Recruiting
Mar Del Plata, Buenos Aires, Argentina
Contact: Alicia Pené, BSc       aliciapene@hotmail.com   
Contact: Débora Petrona, MD       debopet@hotmail.com   
Principal Investigator: Alicia Pené, BSc         
Saresa - Reproducción Humana Asistida Recruiting
Salta, Argentina, 4400
Contact: María Florencia Giménez Marcuzzi, BSc    +54 387-422-2272    f.gimenez@saresa.com.ar   
Contact: Juan José Aguilera, MD    +54 387-422-2272    jaguilera@saresa.com.ar   
Principal Investigator: María Florencia Giménez Marcuzzi, BSc         
Brazil
Nilo Frantz - Centro de Reprodução Humana Not yet recruiting
Boa Vista, Porto Alegre, Brazil, 91330-002
Contact: Adriana Bos-Mikich, MD    + 55 51 3328 4680    adriana.bosmikich@gmail.com   
Contact: Nilo Frantz, MD    +55 51 3328 4680    nilo@nilofrantz.com.br   
Principal Investigator: Nilo Frantz, MD         
Vida - Centro de Fertilidade Not yet recruiting
Rio De Janeiro, Brazil, 22793-080
Contact: María Cecilia de Almeida Cardoso, MD    +55 21 2493 0758    mceciliacardoso@vidafertil.com.br   
Principal Investigator: María Cecilia de Almeida Cardoso, MD         
France
Hôpital Foch Not yet recruiting
Suresnes, France, 92150
Contact: Marine Poulain, PhD    +33 (0)1.46.25.35.21    marine.poulain@hopital-foch.com   
Principal Investigator: Marine Poulain, PhD         
Principal Investigator: Jean-Marc Ayoubi, MD         
Italy
Società Italiana Studi di Medicina della Riproduzione (S.I.S.M.e.R.) Not yet recruiting
Bologna, Italy, 40138
Contact: Luca Gianaroli, MD    051 307307    pazienti@sismer.it   
Principal Investigator: Luca Gianaroli, MD         
Centro Procreazione Assistita DEMETRA Not yet recruiting
Firenze, Italy, 50141
Contact: Francesca Benini, MSc PhD    (+39) 055 488709    benini@centrodemetra.com   
Contact: Claudia Livi, MD    (+39) 055 488709    livi@centrodemetra.com   
Principal Investigator: Francesca Benini, MSc PhD         
Promea S.p.A Not yet recruiting
Torino, Italy, 10126
Contact: Antonio Monaco, MD    +39 011-664-0800    amonaco@promea.net   
Principal Investigator: Antonio Monaco, MD         
Spain
Hospital Ruber Internacional Recruiting
Madrid, Spain, 28035
Contact: Josu Franco Iriarte, PhD    (+34) 913875017    josufranco@hotmail.es   
Contact: Amelia Villa, MD    (+34) 91387504    amelia.villa@ruberinternacional.es   
Principal Investigator: Elena Carrillo de Albornoz Riaza, MD PhD         
Turkey
Bahçeci Health Group Not yet recruiting
Istanbul, Turkey, 34394
Contact: Meral Gultomruk, BSc    (+90) 2123103100    mgultomruk@bahceci.com   
Contact: Mustafa Bahçeci, MD PhD    (+90) 2123103166    mbahceci@bahceci.com   
Principal Investigator: Mustafa Bahçeci, MD PhD         
Sponsors and Collaborators
Igenomix
Investigators
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Principal Investigator: Carmen Rubio, PhD Igenomix S.L.
Study Chair: Carlos Simón, MD PhD Igenomix S.L.
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Responsible Party: Igenomix
ClinicalTrials.gov Identifier: NCT04000152    
Other Study ID Numbers: IGX1-NIP-CS-18-05
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: December 31, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Igenomix:
Blastocyst
Non-invasive
PGT-A
Aneuploidy
Spent culture medium
Trophectoderm biopsy
Sustained implantation
Miscarriage
Livebirth
Additional relevant MeSH terms:
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Infertility
Chromosome Disorders
Aneuploidy
Chromosome Aberrations
Congenital Abnormalities
Pathologic Processes
Genetic Diseases, Inborn