Clinical trial NCT04955574: Probiotic and Antibiotic Therapies in Women With Unexplained Infertility
Official title: Probiotic and Antibiotic Therapies in Women With Unexplained Infertility
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Unexplained Infertility
Endometriosis
Keywords: Uterine microbiota
Endometrial microbiota
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: One Fertility
First posted: 2021-07-09
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of study enrollment
timeFrame: Screening
measure: Rate of retention of study participants
timeFrame: Immediately after the intervention
measure: Proportion of participants adhering to study protocol
timeFrame: Immediately after the intervention
measure: Incidence of intervention-emergent adverse events
timeFrame: Immediately after the intervention
Secondary outcomes:
measure: Difference in implantation rate
timeFrame: Endpoint of interventions to 4 weeks gestation (if applicable)
measure: Difference in clinical pregnancy rate
timeFrame: Endpoint of interventions to 6 weeks gestation (if applicable)
measure: Difference in ongoing pregnancy rate
timeFrame: Endpoint of interventions to 12 weeks gestation (if applicable)
measure: Change in uterine microbiota composition
timeFrame: Baseline, immediately after interventions
measure: Change in serum LPS
timeFrame: Baseline, immediately after interventions
measure: Change in intestinal permeability
timeFrame: Baseline, immediately after interventions
measure: Change in peripheral cytokines
timeFrame: Baseline, immediately after interventions
measure: Change in urinary metabolites
timeFrame: Baseline, immediately after interventions
Other outcomes:
Locations:
Study officials:
affiliation: McMaster University
name: Jocelyn Wessels, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.