Probiotic and Antibiotic Therapies in Women With Unexplained Infertility

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.

Study Overview

• Status: Withdrawn
• Conditions: Endometriosis; Unexplained Infertility
• Intervention / Treatment: Other: SH-DS01 + Antibiotic Placebo; Drug: SH-DS01 + Metronidazole; Other: Probiotic Placebo + Antibiotic Placebo

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 Type: Interventional
• Phase: Phase 2

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic + Antibiotic Placebo	Other: SH-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.
Experimental: Probiotic + Antibiotic	Drug: SH-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.
Placebo Comparator: Probiotic Placebo + Antibiotic Placebo	Other: Probiotic 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: One Fertility
• Investigators: Principal Investigator: Jocelyn Wessels, PhD, McMaster University

Publications and helpful links

General Publications

• Brook N, Khalaf Y, Coomarasamy A, Edgeworth J, Braude P. A randomized controlled trial of prophylactic antibiotics (co-amoxiclav) prior to embryo transfer. Hum Reprod. 2006 Nov;21(11):2911-5. doi: 10.1093/humrep/del263. Epub 2006 Jul 10.
• Moreno I, Codoner FM, Vilella F, Valbuena D, Martinez-Blanch JF, Jimenez-Almazan J, Alonso R, Alama P, Remohi J, Pellicer A, Ramon D, Simon C. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016 Dec;215(6):684-703. doi: 10.1016/j.ajog.2016.09.075. Epub 2016 Oct 4.
• Fanchin R, Harmas A, Benaoudia F, Lundkvist U, Olivennes F, Frydman R. Microbial flora of the cervix assessed at the time of embryo transfer adversely affects in vitro fertilization outcome. Fertil Steril. 1998 Nov;70(5):866-70. doi: 10.1016/s0015-0282(98)00277-5.
• Eckert LO, Moore DE, Patton DL, Agnew KJ, Eschenbach DA. Relationship of vaginal bacteria and inflammation with conception and early pregnancy loss following in-vitro fertilization. Infect Dis Obstet Gynecol. 2003;11(1):11-7. doi: 10.1155/S1064744903000024.
• Selman H, Mariani M, Barnocchi N, Mencacci A, Bistoni F, Arena S, Pizzasegale S, Brusco GF, Angelini A. Examination of bacterial contamination at the time of embryo transfer, and its impact on the IVF/pregnancy outcome. J Assist Reprod Genet. 2007 Sep;24(9):395-9. doi: 10.1007/s10815-007-9146-5. Epub 2007 Jul 17.
• Kyono K, Hashimoto T, Nagai Y, Sakuraba Y. Analysis of endometrial microbiota by 16S ribosomal RNA gene sequencing among infertile patients: a single-center pilot study. Reprod Med Biol. 2018 May 6;17(3):297-306. doi: 10.1002/rmb2.12105. eCollection 2018 Jul.
• Egbase PE, Udo EE, Al-Sharhan M, Grudzinskas JG. Prophylactic antibiotics and endocervical microbial inoculation of the endometrium at embryo transfer. Lancet. 1999 Aug 21;354(9179):651-2. doi: 10.1016/s0140-6736(99)02415-0.
• Moore DE, Soules MR, Klein NA, Fujimoto VY, Agnew KJ, Eschenbach DA. Bacteria in the transfer catheter tip influence the live-birth rate after in vitro fertilization. Fertil Steril. 2000 Dec;74(6):1118-24. doi: 10.1016/s0015-0282(00)01624-1.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2023
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 11, 2021
• First Submitted That Met QC Criteria: July 5, 2021
• First Posted (Actual): July 9, 2021

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 26, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Endometrial microbiota; Uterine microbiota
• Additional Relevant MeSH Terms: Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Infertility; Endometriosis; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Metronidazole; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: JW-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No