Infertility, FemaleNCT04686357
RCT to Assess the Impact of Microbiome Status in Infertile IVF Patients at Their First IVF/ICSI Cycle
A study testing EMMA/ALICE in people with Infertility, Female and IVF, run by Peking University Third Hospital.
Trial summary
Although the endometrium has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. The uterine microbiome can be defined as Lactobacillus-dominated (<90% Lactobacillus spp.) or non-Lactobacillus-dominated (<90% Lactobacillus spp. Read more about this study
- Who is it for?
- Ages Up to 37 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Infertility, Female, IVF
- What is being tested?
- EMMA/ALICE
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,018 participants
- Where
- No sites listed yet
- Study dates
- Aug 2021to Sep 2023
- Phase
- Interventional
- 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 Up to 37 years
- Women only
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Patients whose written IC approved by the 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.
- Patients undergoing their first IVF/ICSI cycle (first oocyte pick up, freezing all) with their own oocytes that will receive single embryo transfer of frozen blastocyst stage embryos (day 5/6) on an HRT cycle.
- At least 2 morphologically good quality embryos already vitrified in blastocyst stage (day 5/6).
- Maternal Age: ≤37 years to rule out embryo factor in aging patients.
- BMI: 18.5 - 30.0 kg / m2 (both inclusive).
- Normal ovarian reserve (defined as: AFC ≥ 8; AMH level ≥1.0 ng/ml and/or FSH < 8 mU/ml) before the controlled ovarian stimulation (COS) initiation.
- Serum P levels ≤ 1.5 ng/ml, measured within 24 hours before the hCG administration in the COS cycle.
- Negative serological tests for HIV, HBV, HCV, RPR.
Who cannot join
- Patients with repeated miscarriages (> 2 previous biochemical pregnancies or > 2 spontaneous miscarriages).
- Male partner with severe male factor (spermatozoa < 2 million/ml). Semen donor is allowed.
- Patients who are intrauterine device (IUD) carriers in the last 3 months before sample collection.
- Adenomyosis or any pathological finding affecting the endometrial cavity such as polyps/sub-mucosal myomas, intramural myomas > 4 cm, or hydrosalpinx must be previously operated at least 3 months before the endometrial samples are obtained.(Note: Patients are allowed to participate if the pathology is corrected before performing any study procedure).
- Embryos analysed using preimplantation genetic testing for aneuploidies (PGT-A)
- Women who have received antibiotics in the last month previous to sample collection, except for the prophylaxis for the oocyte retrieval. In the control group, antibiotics cannot be provided during the ET cycle
- Illness or unstable medical condition that may put at risk the patient's safety and her compliance in the study
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Randomized Controlled Trial (RCT) Comparing Microbiome-driven Embryo Transfer (mET) by EMMA/ALICE Test vs Conventional Frozen Embryo Transfer (FET) of Blastocysts in Infertile Women at Their First IVF/ICSI Cycle
Although the endometrium has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. The uterine microbiome can be defined as Lactobacillus-dominated (<90% Lactobacillus spp.) or non-Lactobacillus-dominated (<90% Lactobacillus spp. with >10% of other bacteria). The presence of a pathogenic microbiota in endometrium was associated with significant decrease in implantation, pregnancy, ongoing pregnancy and live birth rates. Some of these pathogens microorganisms can also produce infection and inflammation that may lead to chronic endometritis.
Nowadays, the endometrial microbiome can be investigated with the EMMA test and the most known pathogens related with chronic endometritis can be detected with the ALICE test,both of them developed by Igenomix group. Our goal in this project is to investigate at what extent, if any, the analysis of the endometrial factor, at a microbiome level, in patients at their first IVF cycle improves their clinical outcome.
Read the detailed description
Some authors have reported the existence of an endometrial microbiota present in healthy woman and different from that in the vagina. It is well known that the presence of pathogens (such as Gardnerella and Streptococcus) in the endometrium is related with infertility, pregnancy loss, premature rupture of membranes and preterm birth.
Another factor which has an impact on infertility is Chronic Endometritis (CE). It consists of a persistent inflammation of the endometrial mucosa and its prevalence in infertile patients has been estimated to be between 2.8 and 39%, although this percentage can reach up to 50 and 60% in patients with miscarriages and repeated implantation failure, respectively. The most common cause of CE is bacterial infection, but the traditional methods of diagnosis (histology, hysteroscopy and microbial culture) often give discordant results between them.
Based on all mentioned above, two molecular tests have been respectively developed by Igenomix (an international company that provides leading advanced services in reproductive genetics and infertility) to assess endometrial microbiome: EMMA (Endometrial Microbiome Metagenomic Analysis) and ALICE (Analysis of Infectious Chronic Endometritis). EMMA test analyses and quantifies all the bacteria present in the endometrium, showing the main bacterial genera present in significant amount in an endometrial sample; while ALICE test quantifies the amount of pathogens more often causing CE (Enterococcus spp., Enterobacteriaceae (Escherichia and Klebsiella), Streptococcus spp., Staphylococcus spp., Mycoplasma spp., and Ureaplasma spp.), Chlamydia and Neisseria, also in an endometrial sample.
The current project aims to investigate in a randomized way the potential improvement on the clinical outcome of Chinese infertile patients at their first IVF cycle considering a personalized diagnosis and treatment (when applicable) of their endometrial microbiome status with the EMMA/ALICE. To do that, only the outcomes of the first single embryo transfers performed after the inclusion of each patient will be considered.
Considering a 30% of possible drop-outs, a total of 1018 patients will be recruited (509 randomized in each group). They will be allocated on a balanced way (assigned by chance like the flip of a coin) in one of the two arms described below. Reproductive outcomes (defined following The International Glossary on Infertility and Fertility Care, 2017) will be compared between the two groups.
Data exported from the source documents will be duly codified and treated in order to protect the clinical and personal information of participants in accordance with the current local legislation.
All the statistical analysis performed on the data, as well as the procedures, will be registered in a detailed Statistical Analysis Plan (SAP) that will be developed during the study and before starting data analysis.
An interim analysis of this data is planned once 50% of the recruitment has been achieved. Besides and at that same moment, the study will be overseen by an independent Data Monitoring Committee.
All of the statistical procedures will be done systematically by both, intention to treat analysis (ITT) and per protocol analysis (PP). The ITT analysis will include all randomized patients recruited and assigned to one of the two groups after biopsy collection and before randomization. The PP analysis will be applied to those patients who adequately follow the protocol assigned according to their group and in whom the transfer of the good quality blastocyst is performed.
- Conditions
- Infertility, Female, IVF
- Being tested
- EMMA/ALICE
- Keywords
- Endometrial microbiota, microbiome treated embryo transfer, frozen embryo transfer, randomized clinical trial, endometrial microbiome metagenomic analysis, analysis of infectious chronic endometritis
- Medical subject headings
- Infertility, Female
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EMMA/ALICEDiagnostic test
Before randomization, an endometrial biopsy (EB) sample will be collected from all participants between day 15 and 25 of a natural cycle or after around 120 hours of progesterone (P) impregnation during a standard HRT cycle. The results of the EMMA/ALICE test will be provided to participants and their gynecologists. Depending on the test results, there are 3 different possibilities:
- Normal result
- Ultralow or Dysbiotic result
- Abnormal result (pathogens) All probiotics and antibiotics that will be used in the study are already authorized by the local health authorities and will be prescribed under their technical data sheet/brochure conditions following the medical indications.
EMMA/ALICEDiagnostic test
Before randomization, an endometrial biopsy (EB) sample will be collected from all participants between day 15 and 25 of a natural cycle or after around 120 hours of progesterone (P) impregnation during a standard HRT cycle. The results of the diagnosis will not be disclosed with the patients randomized into this arm nor with their gynecologists.
| Study group | Role | What they receive |
|---|---|---|
| Intervention group (mET) | Experimental | Microbiome-driven embryo transfer of a single vitrified blastocyst in an HRT cycle according to the EMMA/ALICE test results. Receives: Diagnostic Test: EMMA/ALICE |
| Control group (FET) | Active comparator | Frozen embryo transfer of a single vitrified blastocyst in an HRT cycle according to the clinical standard practice. Receives: Diagnostic Test: EMMA/ALICE |
What is being measured
The primary outcome is the main question the study is designed to answer.
Live birth rate
The number of deliveries that resulted in at least one live birth per ET (transferred patient). Live birth is defined as the complete expulsion or extraction from a woman of a product of conception after 22 weeks of gestation, which, after such separation, breathes or shows any other evidence of life, such as heartbeat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached.
Measured: From date of embryo transfer until 40 weeks
Secondary outcomes (9)
Implantation rate
The number of gestational sacs observed by vaginal ultrasound at the 5th gestational week divided by the number of embryos transferred.
Measured: From date of embryo transfer until 5-6 weeks
Clinical miscarriage rate
Number of spontaneous pregnancy losses in which a gestational sac/s was previously observed, per number of pregnancies.
Measured: From date of embryo transfer until 20 weeks
Biochemical pregnancy rate
Number of pregnancies diagnosed only by βhCG detection without a gestational sac visualized by vaginal ultrasound at the 5th week of pregnancy, per number of pregnancies.
Measured: From date of embryo transfer until 5-6 weeks
Ectopic pregnancy rate
Number of pregnancies outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology, per number of pregnancies.
Measured: From date of embryo transfer until 8 weeks
Pregnancy rate
Pregnancy rate is the number of patients with positive serum level of beta-HCG per embryo transfer.
Measured: From date of embryo transfer until 2 weeks
Obstetric complications
Type and number of obstetric complications during pregnancy
Measured: From date of embryo transfer until 40 weeks
Delivery complications
Type and number of delivery complications
Measured: From date of embryo transfer until 40 weeks
Cost-effectiveness between mET and FET groups
To estimate the average cost per patient in each treatment to achieve a live newborn.
Measured: 30 months
Proportion of microorganism in the infertile study population
Relative abundance of each microorganism identified in EB samples
Measured: From date of EB collection until 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2020
- Study startAug 2021 (estimated)
- Primary completionSep 2023 (estimated)
- Study completionSep 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Infertility, FemaleStudies of the same condition, open and under way.
- More trials run by Peking University Third HospitalThe sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 1,018 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Peking University Third Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Reproductive & Genetic Hospital of CITIC-Xiangya, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
- Responsible party
- Sponsor
- Investigators
- Jie Qiao, Principal investigator, Peking university Third Hospital, BeijingQingXue Zhang, Principal investigator, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityFei Gong, Principal investigator, Reproductive & Genetic Hospital of CITIC-Xiangya
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04686357
- Sponsor's protocol ID
- PUTH EMMA 1.0
- Status last verified
- Mar 2021
- First submitted
- 18 Dec 2020
- Last updated
- 8 Jul 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Controlled Trial (RCT) Comparing Microbiome-driven Embryo Transfer (mET) by EMMA/ALICE Test vs Conventional Frozen Embryo Transfer (FET) of Blastocysts in Infertile Women at Their First IVF/ICSI Cycle
- ClinicalTrials.gov ID
- NCT04686357
- Acronym / sponsor ID
- PUTH EMMA 1.0
- Conditions
- Infertility, Female, IVF
- Keywords
- Endometrial microbiota, microbiome treated embryo transfer, frozen embryo transfer, randomized clinical trial, endometrial microbiome metagenomic analysis, analysis of infectious chronic endometritis
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,018 participants (estimated)
- Lead sponsor
- Peking University Third HospitalUniversity, hospital or other
- Collaborators
- Reproductive & Genetic Hospital of CITIC-Xiangya, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
- Study start
- Aug 2021 (estimated)
- Primary completion
- Sep 2023 (estimated)
- Study completion
- Sep 2023 (estimated)
- First posted
- 28 Dec 2020 (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 has been traditionally considered free of bacteria, recent studies have documented the presence of an endometrial microbiome. The uterine microbiome can be defined as Lactobacillus-dominated (<90% Lactobacillus spp.) or non-Lactobacillus-dominated (<90% Lactobacillus spp. with >10% of other bacteria). The presence of a pathogenic microbiota in endometrium was associated with significant decrease in implantation, pregnancy, ongoing pregnancy and live birth rates. Some of these pathogens microorganisms can also produce infection and inflammation that may lead to chronic endometritis.
Nowadays, the endometrial microbiome can be investigated with the EMMA test and the most known pathogens related with chronic endometritis can be detected with the ALICE test,both of them developed by Igenomix group. Our goal in this project is to investigate at what extent, if any, the analysis of the endometrial factor, at a microbiome level, in patients at their first IVF cycle improves their clinical outcome.
Detailed description
Some authors have reported the existence of an endometrial microbiota present in healthy woman and different from that in the vagina. It is well known that the presence of pathogens (such as Gardnerella and Streptococcus) in the endometrium is related with infertility, pregnancy loss, premature rupture of membranes and preterm birth.
Another factor which has an impact on infertility is Chronic Endometritis (CE). It consists of a persistent inflammation of the endometrial mucosa and its prevalence in infertile patients has been estimated to be between 2.8 and 39%, although this percentage can reach up to 50 and 60% in patients with miscarriages and repeated implantation failure, respectively. The most common cause of CE is bacterial infection, but the traditional methods of diagnosis (histology, hysteroscopy and microbial culture) often give discordant results between them.
Based on all mentioned above, two molecular tests have been respectively developed by Igenomix (an international company that provides leading advanced services in reproductive genetics and infertility) to assess endometrial microbiome: EMMA (Endometrial Microbiome Metagenomic Analysis) and ALICE (Analysis of Infectious Chronic Endometritis). EMMA test analyses and quantifies all the bacteria present in the endometrium, showing the main bacterial genera present in significant amount in an endometrial sample; while ALICE test quantifies the amount of pathogens more often causing CE (Enterococcus spp., Enterobacteriaceae (Escherichia and Klebsiella), Streptococcus spp., Staphylococcus spp., Mycoplasma spp., and Ureaplasma spp.), Chlamydia and Neisseria, also in an endometrial sample.
The current project aims to investigate in a randomized way the potential improvement on the clinical outcome of Chinese infertile patients at their first IVF cycle considering a personalized diagnosis and treatment (when applicable) of their endometrial microbiome status with the EMMA/ALICE. To do that, only the outcomes of the first single embryo transfers performed after the inclusion of each patient will be considered.
Considering a 30% of possible drop-outs, a total of 1018 patients will be recruited (509 randomized in each group). They will be allocated on a balanced way (assigned by chance like the flip of a coin) in one of the two arms described below. Reproductive outcomes (defined following The International Glossary on Infertility and Fertility Care, 2017) will be compared between the two groups.
Data exported from the source documents will be duly codified and treated in order to protect the clinical and personal information of participants in accordance with the current local legislation.
All the statistical analysis performed on the data, as well as the procedures, will be registered in a detailed Statistical Analysis Plan (SAP) that will be developed during the study and before starting data analysis.
An interim analysis of this data is planned once 50% of the recruitment has been achieved. Besides and at that same moment, the study will be overseen by an independent Data Monitoring Committee.
All of the statistical procedures will be done systematically by both, intention to treat analysis (ITT) and per protocol analysis (PP). The ITT analysis will include all randomized patients recruited and assigned to one of the two groups after biopsy collection and before randomization. The PP analysis will be applied to those patients who adequately follow the protocol assigned according to their group and in whom the transfer of the good quality blastocyst is performed.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intervention group (mET) | Experimental | Diagnostic Test: EMMA/ALICEMicrobiome-driven embryo transfer of a single vitrified blastocyst in an HRT cycle according to the EMMA/ALICE test results. |
| Control group (FET) | Active comparator | Diagnostic Test: EMMA/ALICEFrozen embryo transfer of a single vitrified blastocyst in an HRT cycle according to the clinical standard practice. |
Who may qualify
- Ages
- Up to 37 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (8 listed)
Key exclusion criteria (7 listed)
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 |
|---|---|---|
| EMMA/ALICEBefore randomization, an endometrial biopsy (EB) sample will be collected from all participants between day 15 and 25 of a natural cycle or after around 120 hours of progesterone (P) impregnation during a standard HRT cycle. The results of the EMMA/ALICE test will be provided to participants and their gynecologists. Depending on the test results, there are 3 different possibilities: 1. Normal result 2. Ultralow or Dysbiotic result 3. Abnormal result (pathogens) All probiotics and antibiotics that will be used in the study are already authorized by the local health authorities and will be prescribed under their technical data sheet/brochure conditions following the medical indications. | Diagnostic test | Intervention group (mET) |
| EMMA/ALICEBefore randomization, an endometrial biopsy (EB) sample will be collected from all participants between day 15 and 25 of a natural cycle or after around 120 hours of progesterone (P) impregnation during a standard HRT cycle. The results of the diagnosis will not be disclosed with the patients randomized into this arm nor with their gynecologists. | Diagnostic test | Control group (FET) |
Primary outcome
Live birth rate
Time frame: From date of embryo transfer until 40 weeks
The number of deliveries that resulted in at least one live birth per ET (transferred patient). Live birth is defined as the complete expulsion or extraction from a woman of a product of conception after 22 weeks of gestation, which, after such separation, breathes or shows any other evidence of life, such as heartbeat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached.
9 secondary outcomes
Implantation rate
Time frame: From date of embryo transfer until 5-6 weeks
Clinical miscarriage rate
Time frame: From date of embryo transfer until 20 weeks
Biochemical pregnancy rate
Time frame: From date of embryo transfer until 5-6 weeks
Ectopic pregnancy rate
Time frame: From date of embryo transfer until 8 weeks
Pregnancy rate
Time frame: From date of embryo transfer until 2 weeks
Obstetric complications
Time frame: From date of embryo transfer until 40 weeks
Delivery complications
Time frame: From date of embryo transfer until 40 weeks
Cost-effectiveness between mET and FET groups
Time frame: 30 months
Proportion of microorganism in the infertile study population
Time frame: From date of EB collection until 3 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jul 2021.
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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.
Jie Qiao principal investigator
Peking university Third Hospital, Beijing
QingXue Zhang principal investigator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Fei Gong principal investigator
Reproductive & Genetic Hospital of CITIC-Xiangya
Questions about this trial
What is this clinical trial studying?
A study testing EMMA/ALICE in people with Infertility, Female and IVF, run by Peking University Third Hospital.
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 8 inclusion and 7 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: status not confirmed, as of the sponsor's last update on 8 Jul 2021. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jie Qiao (+86 010-82266699, Jie.quiao@263.net), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Live birth rate (time frame: From date of embryo transfer until 40 weeks). 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 8 Jul 2021.