Probiotic and Antibiotic Therapies in Women With Unexplained Infertility

Phase 2

Withdrawn

• Conditions: Endometriosis; Unexplained Infertility
• Interventions: Drug: SH-DS01 + Metronidazole; Other: Probiotic Placebo + Antibiotic Placebo; Other: SH-DS01 + Antibiotic Placebo

• Registration Number: NCT04955574
• Lead Sponsor: McMaster University

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-06-11
• Study First Submitted QC: 2021-07-05
• Study First Posted: 2021-07-09
• Study Start: 2023-01
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-26
• Last Update Posted: 2023-06-28
• Primary Completion: 2024-01
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: Female
• Target Recruitment: Not specified

Inclusion Criteria

1. Female aged 18-40 at the time of egg retrieval
2. Generally in good health (at physician's discretion)
3. Diagnosed with Unexplained Infertility
4. Diagnosed with or suspected of having endometriosis (at ONE Fertility physician's discretion)
5. Normal uterine cavity as assessed by prior sonohysterogram
6. Planning to undergo Frozen Embryo Transfer with ≥1 frozen blastocyst ≥3BB (grade Gardner) to transfer
7. Able to understand, comply and consent to protocol requirements and instructions
8. Able to attend scheduled study visits and complete required investigations

Exclusion Criteria

1. Any known endometrial pathologies other than endometriosis

2. Polycystic ovary syndrome

3. Ovulatory dysfunction

4. Male factor infertility (Total Motile Sperm Count <5M/mL)

5. Poorly controlled auto-immune disease and/or diabetes (at physician's discretion)

6. Is immune-compromised

7. Cockayne syndrome

8. Allergy to Metronidazole

9. Allergy to rice (bran and hull), pomegranate, Acacia gum, hypromellose, fermented gellan gum, chlorophyllin, or sunflower oil

10. Known intolerance of Lactobacillus and/or Bifidobacterium-containing probiotics

11. Antibiotic use in the past month

12. Use of any of the following:

    1. Oral probiotics
    2. Alcohol
    3. Anticoagulant therapies (Warfarin type)
    4. Drugs containing alcohol
    5. Busulfan
    6. Cyclosporin
    7. Disulfiram
    8. 5-Fluoruracil
    9. Lithium
    10. Phenytoin or Phenobarbital
    11. Vecuronium
    12. Proton pump inhibitors
    13. Histamine H2-receptor antagonists

13. Currently experiencing nausea, fever, vomiting, bloody diarrhea or severe abdominal pain

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Probiotic + Antibiotic	SH-DS01 + Metronidazole	-
Probiotic Placebo + Antibiotic Placebo	Probiotic Placebo + Antibiotic Placebo	-
Probiotic + Antibiotic Placebo	SH-DS01 + Antibiotic Placebo	-

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Difference in implantation rate	Endpoint of interventions to 4 weeks gestation (if applicable)	Evaluated by number of people with a positive beta hCG 2 weeks following frozen embryo transfer (FET), between intervention groups.
Change in uterine microbiota composition	Baseline, immediately after interventions	Evaluated by 16S rRNA sequencing of the uterine microbiota at baseline versus on the day of FET, and compared between experimental groups.
Change in intestinal permeability	Baseline, immediately after interventions	Evaluated by changes in untargeted peripheral blood metabolites at baseline versus on the day of FET, and compared between intervention groups.
Change in serum LPS	Baseline, immediately after interventions	Evaluated by changes in LPS-binding protein (LPS) at baseline versus on the day of FET, and compared between intervention groups.
Difference in ongoing pregnancy rate	Endpoint of interventions to 12 weeks gestation (if applicable)	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.
Change in peripheral cytokines	Baseline, immediately after interventions	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.
Change in urinary metabolites	Baseline, immediately after interventions	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.
Difference in clinical pregnancy rate	Endpoint of interventions to 6 weeks gestation (if applicable)	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.