Endometriosis, Unexplained Infertility
Conditions
Keywords
Uterine microbiota, Endometrial microbiota
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.
Interventions
OTHERSH-DS01 + Antibiotic Placebo
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.
DRUGSH-DS01 + Metronidazole
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.
OTHERProbiotic Placebo + Antibiotic Placebo
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.
Sponsors
One Fertility
McMaster University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of study enrollment | Screening | Evaluated by number of eligible participants consenting to enrollment in the study. |
| 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. |
| Incidence of intervention-emergent adverse events | Immediately after the intervention | Evaluated as the percentage of adverse events occurring in each intervention group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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. |
| 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. |
| 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. |
| 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 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. |
Outcome results
None listed