Back to resultsProbiotic and Antibiotic Therapies in Women With Unexplained Infertility
Primary Purpose
Unexplained Infertility, Endometriosis
Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
SH-DS01 + Antibiotic Placebo
SH-DS01 + Metronidazole
Probiotic Placebo + Antibiotic Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Unexplained Infertility focused on measuring Uterine microbiota, Endometrial microbiota
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Probiotic + Antibiotic Placebo
Probiotic + Antibiotic
Probiotic Placebo + Antibiotic Placebo
Arm Description
Outcomes
Primary Outcome Measures
Rate of study enrollment
Evaluated by number of eligible participants consenting to enrollment in the study.
Rate of retention of study participants
Evaluated by number of study participants who complete, drop out or withdraw from the study.
Proportion of participants adhering to study protocol
Evaluated as the percentage of study participants reporting daily administration of study interventions throughout the intervention period.
Incidence of intervention-emergent adverse events
Evaluated as the percentage of adverse events occurring in each intervention group.
Secondary Outcome Measures
Difference in implantation rate
Evaluated by number of people with a positive beta hCG 2 weeks following frozen embryo transfer (FET), between intervention groups.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT04955574
First Posted
June 11, 2021
Last Updated
June 26, 2023
Sponsor
McMaster University
Collaborators
One Fertility
1. Study Identification
Unique Protocol Identification Number
NCT04955574
Brief Title
Probiotic and Antibiotic Therapies in Women With Unexplained Infertility
Official Title
Probiotic and Antibiotic Therapies in Women With Unexplained Infertility
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Withdrawn
Why Stopped
Change in departmental research focus.
Study Start Date
January 2023 (Anticipated)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
McMaster University
Collaborators
One Fertility
4. Oversight
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
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Unexplained Infertility, Endometriosis
Keywords
Uterine microbiota, Endometrial microbiota
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Probiotic + Antibiotic Placebo
Arm Type
Experimental
Arm Title
Probiotic + Antibiotic
Arm Type
Experimental
Arm Title
Probiotic Placebo + Antibiotic Placebo
Arm Type
Placebo Comparator
Intervention Type
Other
Intervention Name(s)
SH-DS01 + Antibiotic Placebo
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
SH-DS01 + Metronidazole
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Probiotic Placebo + Antibiotic Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Rate of study enrollment
Description
Evaluated by number of eligible participants consenting to enrollment in the study.
Time Frame
Screening
Title
Rate of retention of study participants
Description
Evaluated by number of study participants who complete, drop out or withdraw from the study.
Time Frame
Immediately after the intervention
Title
Proportion of participants adhering to study protocol
Description
Evaluated as the percentage of study participants reporting daily administration of study interventions throughout the intervention period.
Time Frame
Immediately after the intervention
Title
Incidence of intervention-emergent adverse events
Description
Evaluated as the percentage of adverse events occurring in each intervention group.
Time Frame
Immediately after the intervention
Secondary Outcome Measure Information:
Title
Difference in implantation rate
Description
Evaluated by number of people with a positive beta hCG 2 weeks following frozen embryo transfer (FET), between intervention groups.
Time Frame
Endpoint of interventions to 4 weeks gestation (if applicable)
Title
Difference in clinical pregnancy rate
Description
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.
Time Frame
Endpoint of interventions to 6 weeks gestation (if applicable)
Title
Difference in ongoing pregnancy rate
Description
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.
Time Frame
Endpoint of interventions to 12 weeks gestation (if applicable)
Title
Change in uterine microbiota composition
Description
Evaluated by 16S rRNA sequencing of the uterine microbiota at baseline versus on the day of FET, and compared between experimental groups.
Time Frame
Baseline, immediately after interventions
Title
Change in serum LPS
Description
Evaluated by changes in LPS-binding protein (LPS) at baseline versus on the day of FET, and compared between intervention groups.
Time Frame
Baseline, immediately after interventions
Title
Change in intestinal permeability
Description
Evaluated by changes in untargeted peripheral blood metabolites at baseline versus on the day of FET, and compared between intervention groups.
Time Frame
Baseline, immediately after interventions
Title
Change in peripheral cytokines
Description
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.
Time Frame
Baseline, immediately after interventions
Title
Change in urinary metabolites
Description
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.
Time Frame
Baseline, immediately after interventions
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jocelyn Wessels, PhD
Organizational Affiliation
McMaster University
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
12839628
Citation
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.
Results Reference
background
PubMed Identifier
17636439
Citation
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.
Results Reference
background
PubMed Identifier
27717732
Citation
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.
Results Reference
background
PubMed Identifier
30013432
Citation
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.
Results Reference
background
PubMed Identifier
9806568
Citation
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.
Results Reference
background
PubMed Identifier
10466674
Citation
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.
Results Reference
background
PubMed Identifier
11119737
Citation
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.
Results Reference
background
PubMed Identifier
16832124
Citation
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.
Results Reference
background
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Probiotic and Antibiotic Therapies in Women With Unexplained Infertility
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