Probiotic and Antibiotic Therapies in Women With Unexplained Infertility

Study Overview
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Brief Summary
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The study is designed as a proof of concept pilot study with 3 study arms to evaluate the safety and feasibility of the use of oral probiotics and/or antibiotics in women with unexplained infertility/endometriosis. Our secondary outcomes will assess In Vitro Fertilization outcomes, and changes in the uterine microbiota (bacteria), intestinal barrier integrity, and urinary metabolites in response to study interventions.

Detailed Description
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Previous research has demonstrated that the uterine microbiota can impact fertility and embryo implantation. This information leads to the hypothesis that prophylactic antibiotic and/or probiotic treatment may improve reproductive outcomes in women with unexplained infertility/endometriosis who are seeking In Vitro Fertilization (IVF). No therapeutic protocols to improve these outcomes currently exist. However, there are safe and easily accessible medications and supplements that may be able to optimally modify the uterine microbiota. Herein we are proposing a proof of concept pilot study of the feasibility, safety and tolerability of administering oral probiotics, or oral probiotics in combination with antibiotics, to women seeking IVF.

Official Title
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Probiotic and Antibiotic Therapies in Women With Unexplained Infertility

Conditions
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Unexplained Infertility, Endometriosis

Intervention / Treatment
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* Other: SH-DS01 + Antibiotic Placebo
* Drug: SH-DS01 + Metronidazole
* Other: Probiotic Placebo + Antibiotic Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged 18-40 at the time of egg retrieval Generally in good health (at physician's discretion) Diagnosed with Unexplained Infertility Diagnosed with or suspected of having endometriosis (at ONE Fertility physician's discretion) Normal uterine cavity as assessed by prior sonohysterogram Planning to undergo Frozen Embryo Transfer with ≥1 frozen blastocyst ≥3BB (grade Gardner) to transfer Able to understand, comply and consent to protocol requirements and instructions Able to attend scheduled study visits and complete required investigations Exclusion Criteria: Any known endometrial pathologies other than endometriosis Polycystic ovary syndrome Ovulatory dysfunction Male factor infertility (Total Motile Sperm Count <5M/mL) Poorly controlled auto-immune disease and/or diabetes (at physician's discretion) Is immune-compromised Cockayne syndrome Allergy to Metronidazole Allergy to rice (bran and hull), pomegranate, Acacia gum, hypromellose, fermented gellan gum, chlorophyllin, or sunflower oil Known intolerance of Lactobacillus and/or Bifidobacterium-containing probiotics Antibiotic use in the past month Use of any of the following: Oral probiotics Alcohol Anticoagulant therapies (Warfarin type) Drugs containing alcohol Busulfan Cyclosporin Disulfiram 5-Fluoruracil Lithium Phenytoin or Phenobarbital Vecuronium Proton pump inhibitors Histamine H2-receptor antagonists Currently experiencing nausea, fever, vomiting, bloody diarrhea or severe abdominal pain

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic + Antibiotic Placebo<br> | Other: SH-DS01 + Antibiotic Placebo<br>* Participants will be instructed to take 2 capsules of SH-DS01 probiotic once daily (at lunch) from cycle day 1 to the day of ovulation/day of luteal progesterone initiation, followed by 2 capsules of SH-DS01 probiotic once daily (at lunch) and 1 capsule of placebo for antibiotic twice daily (at breakfast and dinner) from the day of ovulation/day of luteal progesterone initiation to the day of frozen embryo transfer.<br>|
| Experimental: Probiotic + Antibiotic<br> | Drug: SH-DS01 + Metronidazole<br>* Participants will be instructed to take 2 capsules of SH-DS01 probiotic once daily (at lunch) from cycle day 1 to the day of ovulation/day of luteal progesterone initiation, followed by 2 capsules of SH-DS01 probiotic once daily (at lunch) and 1 capsule of 500mg metronidazole twice daily (at breakfast and dinner) from the day of ovulation/day of luteal progesterone initiation to the day of frozen embryo transfer.<br>|
| Placebo Comparator: Probiotic Placebo + Antibiotic Placebo<br> | Other: Probiotic Placebo + Antibiotic Placebo<br>* Participants will be instructed to take 2 capsules of placebo for probiotic once daily (at lunch) from cycle day 1 to the day of ovulation/day of luteal progesterone initiation, followed by 2 capsules of placebo for probiotic once daily (at lunch) and 1 capsule of placebo for antibiotic twice daily (at breakfast and dinner) from the day of ovulation/day of luteal progesterone initiation to the day of frozen embryo transfer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of study enrollment | Evaluated by number of eligible participants consenting to enrollment in the study. | Screening | 
| Rate of retention of study participants | Evaluated by number of study participants who complete, drop out or withdraw from the study. | Immediately after the intervention | 
| Proportion of participants adhering to study protocol | Evaluated as the percentage of study participants reporting daily administration of study interventions throughout the intervention period. | Immediately after the intervention | 
| Incidence of intervention-emergent adverse events | Evaluated as the percentage of adverse events occurring in each intervention group. | Immediately after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in implantation rate | Evaluated by number of people with a positive beta hCG 2 weeks following frozen embryo transfer (FET), between intervention groups. | Endpoint of interventions to 4 weeks gestation (if applicable) | 
| Difference in clinical pregnancy rate | Evaluated by number of people with a clinical pregnancy (gestational sac with fetal pole and cardiac activity seen on ultrasound at 6 weeks gestation), between intervention groups. | Endpoint of interventions to 6 weeks gestation (if applicable) | 
| Difference in ongoing pregnancy rate | Evaluated by number of people with an ongoing pregnancy (gestational sac with fetal pole and cardiac activity seen on ultrasound at 12 weeks gestation), between intervention groups. | Endpoint of interventions to 12 weeks gestation (if applicable) | 
| Change in uterine microbiota composition | Evaluated by 16S rRNA sequencing of the uterine microbiota at baseline versus on the day of FET, and compared between experimental groups. | Baseline, immediately after interventions | 
| Change in serum LPS | Evaluated by changes in LPS-binding protein (LPS) at baseline versus on the day of FET, and compared between intervention groups. | Baseline, immediately after interventions | 
| Change in intestinal permeability | Evaluated by changes in untargeted peripheral blood metabolites at baseline versus on the day of FET, and compared between intervention groups. | Baseline, immediately after interventions | 
| Change in peripheral cytokines | Evaluated by changes in peripheral cytokines (TNF, IL-6, IL-8, IFNg - in pg/mL) at baseline versus on the day of FET, and compared between intervention groups. | Baseline, immediately after interventions | 
| Change in urinary metabolites | Evaluated by changes untargeted urinary metabolites at baseline versus on the day of FET, and compared between intervention groups. Nontargeted metabolic phenotyping of >100 urinary metabolites will be performed by multisegment injection capillary electrophoresis-mass spectrometry (MSI-CE-MS) as a high throughput platform to analyze metabolites. The fold change for each metabolite will be calculated between baseline vs. after interventions, and the fold changes will be compared between intervention groups. | Baseline, immediately after interventions | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine microbiota, Endometrial microbiota