Vaginal lIve Biotherapeutic RANdomized Trial

Study Overview
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Brief Summary
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The goal of this randomized clinical trial is to evaluate safety and biologic effect of a multi-strain vaginal L. crispatus live biotherapeutic product (LBP) in people receiving antibiotic treatment for bacterial vaginosis (BV). The main question[s] it aims to answer are whether the intervention is safe, and whether the strains of L. crispatus will colonize recipients' vagina. The study will evaluate one LBP with 6 strains of L. crispatus (LC106) and one LBP with 15 strains (LC115) vs. placebo. Participants will: be treated with oral antibiotics for BV receive 7 days of vaginal study product collect daily home swabs and make short daily diary entries for 5 weeks, including the week of antibiotic treatment and the week of study product treatment. Researchers will compare the 3 groups receiving different dosing strategies of LC106 and 1 group receiving LC115 vs. 1 group receiving placebo to see if the live biotherapeutic strains colonize the vagina after antibiotic treatment for BV.

Detailed Description
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This is a Phase I randomized trial of a novel live biotherapeutic intervention containing multiple strains of L. crispatus. L. crispatus is a species of Lactobacillus commonly found in the human vagina, which is associated with optimal reproductive health outcomes. Detection of, and dominance of the community by, L. crispatus is associated with lower risk for bacterial vaginosis (BV), but no intervention to date has demonstrated the ability to durably shift the vaginal microbiome to L. crispatus dominance in a majority of treated people. In this study, we will compare safety and biologic effects of two formulations of a consortia of L. crispatus strains, and a variety of dosing strategies in women with BV who receive antibiotic treatment. Our primary outcome is colonization with any of the L. crispatus strains contained in the live biotherapeutic product. All participants will have menses suppressed with either injectable progesterone contraception or continuous oral contraceptive pills for the duration of the study. All participants will receive 7 days of oral metronidazole (500mg twice daily) and will be randomized to one of five groups: Placebo daily for 7d after metronidazole treatment LC-106 daily for 7d after metronidazole treatment LC-106 daily for 3d + 4 days of placebo, starting after metronidazole treatment LC-106 daily for 7d, starting on day 3 of metronidazole treatment LC-115 daily for 7d after metronidazole treatment

Official Title
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Phase 1 Trial of Multi-strain Lactobacillus Crispatus Vaginal Live Biotherapeutic Product

Conditions
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Bacterial Vaginosis

Intervention / Treatment
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* Drug: LC106
* Drug: LC115
* Drug: Placebo
* Drug: Metronidazole Oral


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal individuals, 18- 40 years old BV by Amsel criteria (at least 3 of 4 criteria must be present) Abnormal Nugent score: ≥ 7 Willing and able to provide written informed consent. HIV uninfected (by HIV Ab/Ag test at enrollment) Not pregnant by pregnancy test at enrollment, and unlikely to have an early pregnancy per clinician's assessment of last menstrual period and recent sexual activity. On continuous oral contraceptives (US site) or injectable progestin contraceptives (South African site) that suppress menstrual cycles, or willing to suppress menstrual cycles with one of these types of hormonal contraceptives Willing and able to attend study visits and comply with study procedures Exclusion Criteria: History of clinically significant vaginal, cervical, or uterine disease including but not limited to: cancer of the female reproductive tract Prior hysterectomy Diagnosed with cervicovaginal infection (inclusive of gonorrhoeae, chlamydia, trichomonas) within the 30 days prior (or at enrollment visit). Yeast and bacterial vaginosis are not exclusionary. Use of antibiotics in the past 30 days Syphilis (positive screen at enrollment) Vulvovaginal candidiasis (positive microscopy at enrollment) Allergy to or contraindication to use of oral metronidazole High grade abnormal Pap (HSIL, AGC [Atypical Glandular Cells], ASCUS-H) at enrollment (LSIL, ASCUS, or HPV+ are all non-exclusionary) Currently participating in another study of an investigational product (excluding COVID vaccine studies) Use of long-acting systemic investigational product (e.g. injectable PrEP) within the past year Subject taking any of the following medications currently or in the past 30 days: systemic steroids (inhaled or nasal steroid therapy is permitted), interleukins, systemic interferons (e.g. local injection of interferon alpha for treatment of human papillomavirus is permitted) or systemic chemotherapy. History of coronary artery disease, myocardial infarction, chronic obstructive pulmonary disease, chronic renal failure, decompensated cirrhosis, or any other condition that in the opinion of the investigator will compromise ability to participate in the study. Use of an IUD (intrauterine device) Use of probiotics, prebiotics or synbiotics (supplements and products, oral or vaginal) within past 30 days. (NOTE: Oral yogurt with live cultures is allowed, as are fermented foods.) Active COVID-19 infection (determined by a positive PCR test of a nasal or nasopharyngeal swab) or recent exposure (< 14 days) to someone with confirmed COVID-19 infection (an exposure is considered being within 6 feet/180 cm of someone without a mask for more than 15 minutes). Potential participants who meet these criteria can delay screening until they have completed isolation or quarantine. Vaginal cleansing practices in the past 30 days (i.e. vaginal products for cleaning or drying, vaginal douching) (by eligibility questionnaire) Any other condition or situation that in the opinion of the investigator will compromise ability to participate in the study. Menopause: surgical; or absence of periods not due to hormonal contraception and in the setting of prior chemotherapy Use of testosterone for any reason Systolic blood pressure > 180 or diastolic blood pressure > 110 at screening or enrollment Hemoglobin < 9 Less than 2 weeks since 2nd COVID vaccination (mRNA) or 1st vaccination (J&J) or booster Either breastfeeding/lactating or pregnant within 8 weeks prior to study entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized trial with 5 arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Vaginal placebo tablet administered daily for 7 days starting after antibiotic treatment | Drug: Placebo<br>* Vaginal tablets containing primarily microcrystalline cellulose and no live bacteria<br>Drug: Metronidazole Oral<br>* Metronidazole tablet orally twice daily for 7 days<br>|
| Experimental: LC106 7 days<br>Vaginal live biotherapeutic product with 6 strains of L. crispatus, administered daily for 7 days after antibiotic treatment | Drug: LC106<br>* Tablet containing at least 2 x 10^6 CFU/tablet, and comprised of 6 strains of Lactobacillus crispatus<br>Drug: Metronidazole Oral<br>* Metronidazole tablet orally twice daily for 7 days<br>|
| Experimental: LC106 3 days<br>Vaginal live biotherapeutic product with 6 strains of L. crispatus, administered daily for 3 days after antibiotic treatment and packaged with 4 tablets of placebo to maintain masking (so a total of 7 tablets) | Drug: LC106<br>* Tablet containing at least 2 x 10^6 CFU/tablet, and comprised of 6 strains of Lactobacillus crispatus<br>Drug: Metronidazole Oral<br>* Metronidazole tablet orally twice daily for 7 days<br>|
| Experimental: LC106 7 days, early start<br>Vaginal live biotherapeutic product with 6 strains of L. crispatus, administered daily for 7 days starting on the 3rd day of antibiotic treatment | Drug: LC106<br>* Tablet containing at least 2 x 10^6 CFU/tablet, and comprised of 6 strains of Lactobacillus crispatus<br>Drug: Metronidazole Oral<br>* Metronidazole tablet orally twice daily for 7 days<br>|
| Experimental: LC115<br>Vaginal live biotherapeutic product with 15 strains of L. crispatus, administered daily for 7 days after antibiotic treatment | Drug: LC115<br>* Tablet containing at least 2 x 10^6 CFU/tablet, and comprised of 15 strains of Lactobacillus crispatus<br>Drug: Metronidazole Oral<br>* Metronidazole tablet orally twice daily for 7 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of LBP strains by metagenomic sequencing | Detection of any one strain from the LBP at 5% relative abundance or greater, or any combination of strains at 10% relative abundance or greater using shotgun metagenomic sequencing | Over 5 weeks | 
| Adverse events | Assessment of safety by comparing number and severity of adverse events | Over 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of colonization | Presence and quantity of each strain contained in the LBP measured by strain-specific quantitative PCR | Over 12 weeks | 
| Recurrent BV by Amsel and Nugent criteria | Presence of BV by Amsel criteria and/or Nugent criteria | Over 12 weeks | 
| Non-iners Lactobacillus dominance and abundance | Using 16S rRNA sequencing, relative abundance of non-iners Lactobacillus species in the vaginal fluid, and proportion with dominance by these species (> 50% relative abundance) | Over 12 weeks | 
| Alpha and beta diversity of the microbial community | Comparison of alpha and beta diversity metrics between arms before and after treatment with LBP | Over 12 weeks | 
| Proportion of participants reporting product was acceptable to use | Participant perceptions of and preferences for the vaginal LBP treatment | Over 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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live biotherapeutic, bacterial vaginosis, vaginitis