NCT04686357

RCT to Assess the Impact of Microbiome Status in Infertile IVF Patients at Their First IVF/ICSI Cycle

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

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 1,018 (estimated)
• Sponsor: Peking University Third Hospital · Academic / Other
• Sex: Female
• Age: 37 Years
• Healthy volunteers: Accepted

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. 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.

Conditions

• Infertility, Female
• IVF

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	EMMA/ALICE	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: 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	EMMA/ALICE	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.

Timeline

• Start date: 2021-08-01
• Primary completion: 2023-09-01
• Completion: 2023-09-01
• First posted: 2020-12-28
• Last updated: 2021-07-08