Infertility of Uterine OriginERA-niMICNCT03330444
Development of a Microbiome Non-invasive Diagnosis Tool
An observational study of Infertility of Uterine Origin, run by Igenomix at 13 sites in 8 countries.
Trial summary
Although the endometrium tissue has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. In a pilot study conducted by our research team, the microorganisms present in the endometrium were analysed in samples of endometrial fluid (EF) using next… Read more about this study
- Who is it for?
- Ages 18 to 50 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Infertility of Uterine Origin
- What is being tested?
- Endometrial biopsy and endometrial fluid collection
- Type of treatment
- Surgery or procedure
- How many people
- 452 participants
- Where
- 13 sitesin 8 countries
- Study dates
- 4 Aug 2017to 25 Jun 2020
- 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 50 years
- Women only
- Healthy volunteers accepted
- Adult
Study population: ART patients, with indication of diagnosis of endometrial receptivity by ERA that will receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6).
Who may be able to join
- Patients in In Vitro Fertilization (IVF) / IntraCytoplasmic Sperm Injection (ICSI) or OVODON with indication of ERA, with or without Preimplantation genetic screening (PGS) indication, which receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6) on a hormone replacement therapy (HRT) cycle.
- Maternal Age: ≤40 years (IVF/ICSI patients)
- Maternal Age: ≤50 years (OVODONATION patients)
- Body Mass Index (BMI): 18.5 - 30 kg / m2 (both inclusive)
- Negative serological tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Rapid plasma reagin (RPR) for syphilis
- Women with regular menstrual formula (3-4 / 26- 35 days)
- Sperm concentration: > 2 million spermatozoa/ml
Who cannot join
- Patients who are Intra-Uterine Device (IUD) carriers in the last 3 months
- Patients who have taken prescribed antibiotics in the last 3 months before the sample collection. (May be accepted those cases where the patient has received previous prophylactic antibiotics to ovarian puncture in the stimulation cycle, according to the standard clinical practice of the centre. The administration of this antibiotic should be at least 1 month before the sample collection).
- Adnexal or uterine pathologies as uterine malformations that may affect the implantation rate (e.g: Polyps, intramural myoma ≥ 4cm or submucosal, septum, hydrosalpinx, etc). Patients affected (before or after of their inclusion) with any of the previously described pathologies, will be allowed to participate in this study as long as they are surgically treated before any study procedure.
- Existence of bacterial, fungal or viral infections severe or uncontrolled that, in the opinion of the principal investigator, could interfere with the patient's participation in the study or the assessments of the study results.
- Any illness or medical condition that is unstable or can put patient safety at risk and compliance in the study.
Trial locations and contacts
13 sites in 8 countries.
13 sites in 8 countries
United States4 sites
Dominion Fertility
Arlington, Washington, 22203
Missouri Center for Reproductive Medicine (MCRM Fertility)
Chesterfield, Missouri, 63005
IVF Florida
Margate, Florida, 33063
RMA Connecticut
Norwalk, Connecticut, 06861
Argentina2 sites
Pregna Medicina Reproductiva
Buenos Aires, C1425DGQ
Gestanza Medicina Reproductiva
Rosario, Santa Fe Province
Canada1 site
Pacific Center for Reproductive Medicine
Burnaby, British Columbia, V5G 4X7
About this study
Official title: Development of a Non-invasive Diagnosis Tool for the Analysis of the Microbiota to Improve Reproductive Outcomes in Infertile Patients.
Although the endometrium tissue has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. In a pilot study conducted by our research team, the microorganisms present in the endometrium were analysed in samples of endometrial fluid (EF) using next generation sequencing (NGS).Consistent with previously published studies, in normal conditions the endometrium is mainly composed of different species of the genus Lactobacillus. It was further noted that the presence of other pathogenic bacteria such as Streptococcus, and/or Gardnerella may alter the endometrial microbiome and can disrupt the uterine environment, affecting implantation rates and pregnancy success.
This project aims to validate the microbiome found in the endometrium of women of reproductive age and try to corroborate the relationship between the endometrial microbiome and the reproductive outcomes in patients undergoing assisted reproduction treatment (ART). The use of Endometrial Receptivity Analysis (ERA) tool, together with the analysis of the endometrial flora before the embryo transfer will allow to evaluate the impact of the presence of endometrial pathogens on implantation in receptive patients.
Therefore, the focus of this project is the development and clinical validation of a non-invasive diagnosis tool to analyse the microbiota, adding the microbiome study to the ERA analysis.
Read the detailed description
Embryonic implantation is a critical process to the survival of the species that is relatively inefficient, especially in humans. Key elements are the embryo, the maternal endometrium, and the cross-communication between them using different scientific perspectives. Endometrial receptivity describes the phenotype that allows embryo adhesion and placentation to occur. Due to the need of an accurate and objective molecular diagnostic test for the receptivity status of endometrium, the Endometrial Receptivity Analysis (ERA) was developed. ERA test is a customized expression microarray that identifies the transcriptomic expression profile signature of the personalized window of implantation (WOI). Its clinical usefulness has been demonstrated in patients with implantation failure in whom 25% of them have a displaced WOI becoming pregnant once the embryo transfer is performed at the proper WOI predicted by ERA. However, this procedure requires an endometrial biopsy (EB), which is the major drawback of this diagnosis test, because embryo transfer has to be delayed to the next cycle, and also the possible discomforts caused to the patients. For this reason, a previous pilot study was conducted in order to confirm whether endometrial receptivity can be predicted through non-invasive methods in endometrial fluid (EF) samples. The gene panel of ERA test was interrogated on epithelial and stromal cells from endometrial biopsies and cells isolated from the EF at the single cell level, demonstrating that the major cells on the EF classifies together with the epithelial population.
On the other hand, to try to better understand the mechanisms that connect endometrial receptivity and/or implantation of the embryo with an altered endometrial microbiome, another pilot study was conducted to determine the composition of the endometrial microbiome after the analysis of the bacterial 16S ribosomal RNA by NGS. Interestingly, in patients with receptive endometrium, diagnosed by Endometrial Receptivity Array (ERA) who had endometrial microbiome with pathogens, or not dominated by bacteria of the genus Lactobacillus (NLD) showed significantly lower implantation (23.1% vs 60.7% p = 0.02), pregnancy (33.3% vs 70.6%, p = 0.03), ongoing pregnancy per embryo transfer (13.3% vs 58.8%, p = 0.03), and live birth (6.7% vs 58.8%, p = 0.002) rates than those with a healthy endometrial microbiome dominated by Lactobacillus (LD). Moreover, this relationship was much more significant when pathogenic species found belonged to the genus Gardnerella and Streptococcus. This is in line with other published studies that analyze the impact of endometrial pathogens in IVF treatments, highlighting the importance of the study of bacterial communities for reproductive health.
Given these preliminary results, the present study aims to validate in a larger sample set, the relationship between the imbalance of endometrial microbiome and the decline in reproductive success in patients undergoing ART. To do this, the experimental design will be improved in the following areas: (i) a higher sample size will be analysed to validate the previous results obtained in the previous pilot study on endometrial microbiome, (ii) paired samples from endometrial fluid and endometrial biopsy will be analysed for the microbial profile to study whether there is bacterial variability associated to the sample type, (iii) the endometrial microbiota will be simultaneously assessed with ERA as a supplementary diagnosis for this tool, and (iv) the analysis of the endometrial microbiota will be performed using the most advanced technology on bacterial metagenome sequencing to widen the information of the microorganisms identified in each sample.
- Conditions
- Infertility of Uterine Origin
- Being tested
- Endometrial biopsy and endometrial fluid collection
- Keywords
- Endometrial microbiota, Bacterial pathogens, Assisted reproductive techniques, Dysbiosis, Endometrial receptivity, Endometrial diagnosis
- Medical subject headings
- Dysbiosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Endometrial biopsy and endometrial fluid collectionProcedure or surgery
On the same day that the EB for ERA is indicated, in day 5 of a HRT cycle with 5 days of progesterone, according to the common clinical practice, a sample of EF will be aspirated immediately prior to EB for ERA. This EF sample will be used for the non-invasive diagnosis of the microbiome, also a small portion of the endometrial tissue obtained for the endometrial receptivity diagnosis by ERA will be used as a control for the study of the endometrial microbiome. Those patients with a receptive endometrium will continue their ART according to the standard clinical protocol. Those patients with non-receptive endometrium will follow the recommendation derived of the ERA test for the election of the day for a second EB sample, in which the collection of EF sample will be repeated. Finally, the receptivity and microbiome results in EF will be correlated with that on the endometrial tissue, and with the reproductive outcomes of these patients after the embryo transfer.
| Study group | Role | What they receive |
|---|---|---|
| LD microbiome receptive to the ERA test | Receptive patients by the ERA test with an endometrial microbiota mainly composed of different species of the genus Lactobacillus, determined by NGS sequencing. Receives: Procedure: Endometrial biopsy and endometrial fluid collection | |
| NLD microbiome receptive to the ERA test | Receptive patients by the ERA test with an endometrial microbiota composed of different pathogenic bacteria such as Streptococcus and Gardnerella, or not dominated by bacteria of the genus Lactobacillus, determined by NGS sequencing. Receives: Procedure: Endometrial biopsy and endometrial fluid collection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Development of a new non-invasive diagnosis test of Endometrial Microbiome (EM) in infertile patients
Bacterial DNA analysis by Next Generation Sequencing (NGS) using endometrial fluid for the EM diagnose. This will be measured by the percentage of each bacterial DNA in EF samples
Measured: 24 months
Secondary outcomes (7)
Live birth rate
Number of babies born per embryo transfer
Measured: 40 weeks
Implantation rate
Number of implanted embryos per total number of embryos transferred
Measured: 12 weeks
Pregnancy rate
Number of pregnancies per embryo transfer
Measured: 20 weeks
Biochemical pregnancies
Number of biochemical pregnancies per total number of pregnancies
Measured: 20 weeks
Ectopic pregnancies
Number of ectopic pregnancies per total number of pregnancies
Measured: 20 weeks
Clinical miscarriages
Number of clinical miscarriages per total number of pregnancies
Measured: 20 weeks
Ongoing pregnacy rate
Number of ongoing pregnancies per embryo transfer
Measured: 40 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2017
- Study start4 Aug 2017
- Primary completion17 May 2019
- Study completion25 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Infertility of Uterine OriginStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 452 participants (actual)
Sponsor and investigators
- Lead sponsor
- Igenomix
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Carlos Simón, MD PhD, Study chair, Igenomix
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03330444
- Sponsor's protocol ID
- IGX1-MIC-CS-17-05
- Acronym
- ERA-niMIC
- Status last verified
- Oct 2020
- First submitted
- 24 Oct 2017
- Last updated
- 9 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Development of a Non-invasive Diagnosis Tool for the Analysis of the Microbiota to Improve Reproductive Outcomes in Infertile Patients.
- ClinicalTrials.gov ID
- NCT03330444
- Acronym / sponsor ID
- ERA-niMIC / IGX1-MIC-CS-17-05
- Conditions
- Infertility of Uterine Origin
- Keywords
- Endometrial microbiota, Bacterial pathogens, Assisted reproductive techniques, Dysbiosis, Endometrial receptivity, Endometrial diagnosis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 452 participants (actual)
- Lead sponsor
- IgenomixIndustry (pharma, biotech, devices)
- Study start
- 4 Aug 2017 (actual)
- Primary completion
- 17 May 2019 (actual)
- Study completion
- 25 Jun 2020 (actual)
- First posted
- 6 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Although the endometrium tissue has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. In a pilot study conducted by our research team, the microorganisms present in the endometrium were analysed in samples of endometrial fluid (EF) using next generation sequencing (NGS).Consistent with previously published studies, in normal conditions the endometrium is mainly composed of different species of the genus Lactobacillus. It was further noted that the presence of other pathogenic bacteria such as Streptococcus, and/or Gardnerella may alter the endometrial microbiome and can disrupt the uterine environment, affecting implantation rates and pregnancy success.
This project aims to validate the microbiome found in the endometrium of women of reproductive age and try to corroborate the relationship between the endometrial microbiome and the reproductive outcomes in patients undergoing assisted reproduction treatment (ART). The use of Endometrial Receptivity Analysis (ERA) tool, together with the analysis of the endometrial flora before the embryo transfer will allow to evaluate the impact of the presence of endometrial pathogens on implantation in receptive patients.
Therefore, the focus of this project is the development and clinical validation of a non-invasive diagnosis tool to analyse the microbiota, adding the microbiome study to the ERA analysis.
Detailed description
Embryonic implantation is a critical process to the survival of the species that is relatively inefficient, especially in humans. Key elements are the embryo, the maternal endometrium, and the cross-communication between them using different scientific perspectives. Endometrial receptivity describes the phenotype that allows embryo adhesion and placentation to occur. Due to the need of an accurate and objective molecular diagnostic test for the receptivity status of endometrium, the Endometrial Receptivity Analysis (ERA) was developed. ERA test is a customized expression microarray that identifies the transcriptomic expression profile signature of the personalized window of implantation (WOI). Its clinical usefulness has been demonstrated in patients with implantation failure in whom 25% of them have a displaced WOI becoming pregnant once the embryo transfer is performed at the proper WOI predicted by ERA. However, this procedure requires an endometrial biopsy (EB), which is the major drawback of this diagnosis test, because embryo transfer has to be delayed to the next cycle, and also the possible discomforts caused to the patients. For this reason, a previous pilot study was conducted in order to confirm whether endometrial receptivity can be predicted through non-invasive methods in endometrial fluid (EF) samples. The gene panel of ERA test was interrogated on epithelial and stromal cells from endometrial biopsies and cells isolated from the EF at the single cell level, demonstrating that the major cells on the EF classifies together with the epithelial population.
On the other hand, to try to better understand the mechanisms that connect endometrial receptivity and/or implantation of the embryo with an altered endometrial microbiome, another pilot study was conducted to determine the composition of the endometrial microbiome after the analysis of the bacterial 16S ribosomal RNA by NGS. Interestingly, in patients with receptive endometrium, diagnosed by Endometrial Receptivity Array (ERA) who had endometrial microbiome with pathogens, or not dominated by bacteria of the genus Lactobacillus (NLD) showed significantly lower implantation (23.1% vs 60.7% p = 0.02), pregnancy (33.3% vs 70.6%, p = 0.03), ongoing pregnancy per embryo transfer (13.3% vs 58.8%, p = 0.03), and live birth (6.7% vs 58.8%, p = 0.002) rates than those with a healthy endometrial microbiome dominated by Lactobacillus (LD). Moreover, this relationship was much more significant when pathogenic species found belonged to the genus Gardnerella and Streptococcus. This is in line with other published studies that analyze the impact of endometrial pathogens in IVF treatments, highlighting the importance of the study of bacterial communities for reproductive health.
Given these preliminary results, the present study aims to validate in a larger sample set, the relationship between the imbalance of endometrial microbiome and the decline in reproductive success in patients undergoing ART. To do this, the experimental design will be improved in the following areas: (i) a higher sample size will be analysed to validate the previous results obtained in the previous pilot study on endometrial microbiome, (ii) paired samples from endometrial fluid and endometrial biopsy will be analysed for the microbial profile to study whether there is bacterial variability associated to the sample type, (iii) the endometrial microbiota will be simultaneously assessed with ERA as a supplementary diagnosis for this tool, and (iv) the analysis of the endometrial microbiota will be performed using the most advanced technology on bacterial metagenome sequencing to widen the information of the microorganisms identified in each sample.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LD microbiome receptive to the ERA test | – | Procedure: Endometrial biopsy and endometrial fluid collectionReceptive patients by the ERA test with an endometrial microbiota mainly composed of different species of the genus Lactobacillus, determined by NGS sequencing. |
| NLD microbiome receptive to the ERA test | – | Procedure: Endometrial biopsy and endometrial fluid collectionReceptive patients by the ERA test with an endometrial microbiota composed of different pathogenic bacteria such as Streptococcus and Gardnerella, or not dominated by bacteria of the genus Lactobacillus, determined by NGS sequencing. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- ART patients, with indication of diagnosis of endometrial receptivity by ERA that will receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6).
Key inclusion criteria (7 listed)
- Patients in In Vitro Fertilization (IVF) / IntraCytoplasmic Sperm Injection (ICSI) or OVODON with indication of ERA, with or without Preimplantation genetic screening (PGS) indication, which receive embryo transfer with frozen blastocyst stage embryos (day 5/day 6) on a hormone replacement therapy (HRT) cycle.
- Maternal Age: ≤40 years (IVF/ICSI patients)
- Maternal Age: ≤50 years (OVODONATION patients)
- Body Mass Index (BMI): 18.5 - 30 kg / m2 (both inclusive)
- Negative serological tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), Rapid plasma reagin (RPR) for syphilis
Key exclusion criteria (5 listed)
- Patients who are Intra-Uterine Device (IUD) carriers in the last 3 months
- Patients who have taken prescribed antibiotics in the last 3 months before the sample collection. (May be accepted those cases where the patient has received previous prophylactic antibiotics to ovarian puncture in the stimulation cycle, according to the standard clinical practice of the centre. The administration of this antibiotic should be at least 1 month before the sample collection).
- Adnexal or uterine pathologies as uterine malformations that may affect the implantation rate (e.g: Polyps, intramural myoma ≥ 4cm or submucosal, septum, hydrosalpinx, etc). Patients affected (before or after of their inclusion) with any of the previously described pathologies, will be allowed to participate in this study as long as they are surgically treated before any study procedure.
- Existence of bacterial, fungal or viral infections severe or uncontrolled that, in the opinion of the principal investigator, could interfere with the patient's participation in the study or the assessments of the study results.
- Any illness or medical condition that is unstable or can put patient safety at risk and compliance in the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Endometrial biopsy and endometrial fluid collectionOn the same day that the EB for ERA is indicated, in day 5 of a HRT cycle with 5 days of progesterone, according to the common clinical practice, a sample of EF will be aspirated immediately prior to EB for ERA. This EF sample will be used for the non-invasive diagnosis of the microbiome, also a small portion of the endometrial tissue obtained for the endometrial receptivity diagnosis by ERA will be used as a control for the study of the endometrial microbiome. Those patients with a receptive endometrium will continue their ART according to the standard clinical protocol. Those patients with non-receptive endometrium will follow the recommendation derived of the ERA test for the election of the day for a second EB sample, in which the collection of EF sample will be repeated. Finally, the receptivity and microbiome results in EF will be correlated with that on the endometrial tissue, and with the reproductive outcomes of these patients after the embryo transfer. | Procedure or surgery | LD microbiome receptive to the ERA test, NLD microbiome receptive to the ERA test |
Primary outcome
Development of a new non-invasive diagnosis test of Endometrial Microbiome (EM) in infertile patients
Time frame: 24 months
Bacterial DNA analysis by Next Generation Sequencing (NGS) using endometrial fluid for the EM diagnose. This will be measured by the percentage of each bacterial DNA in EF samples
7 secondary outcomes
Live birth rate
Time frame: 40 weeks
Implantation rate
Time frame: 12 weeks
Pregnancy rate
Time frame: 20 weeks
Biochemical pregnancies
Time frame: 20 weeks
Ectopic pregnancies
Time frame: 20 weeks
Clinical miscarriages
Time frame: 20 weeks
Ongoing pregnacy rate
Time frame: 40 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carlos Simón, MD PhD study chair
Igenomix
13 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Infertility of Uterine Origin, run by Igenomix at 13 sites in 8 countries.
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 7 inclusion and 5 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: finished, as of the sponsor's last update on 9 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, Argentina, Spain, Canada, Japan and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Development of a new non-invasive diagnosis test of Endometrial Microbiome (EM) in infertile patients (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 9 Oct 2020.