Exploring the Effects of an Intravaginal Lactic Acid Gel on the Vaginal Microbiome

Study Overview
=================
Brief Summary
-----------------
This project aims to investigate if the contraceptive method, Phexxi, causes changes to the composition of the vaginal microbiome. The investigators hypothesize that regular use of Phexxi will cause increased colonization of lactic acid-producing lactobacilli, which could have positive effects in the way of preventing recurrent episodes of BV and candida infections.

Detailed Description
-----------------
This is a single center, prospective trial, which comprises of a pre-post study design that will be looking at the vaginal microbiome makeup of participants before and after a four-week course of Phexxi. The primary outcomes will be an increase in lactic acid-forming lactobacilli, as well as a decrease in patient-reported symptoms of vulvovaginitis. This study will be based at the Queen's Medical Center (QMC), POB1 Suite 1004. Eligible patients will be approached by participating clinicians (all doctors providing care at the 1004 clinic) to assess interest in study participation.. The principal investigator will review the weekly schedule for the 1004 clinic and alert the attending physicians of patients who may be eligible for the study based on chart review. A HIPAA waiver will be required for this stage of recruitment, as the principal investigator would otherwise not be accessing these patient's charts. The attending physician staffing the 1004 clinic will ask the flagged patients if they are interested in learning about the study and review general study objectives with patients. If the patient is interested in participating, the research associates will approach the patient to more thoroughly screen, then conduct the informed consent process. Informed consent will be collected from every participant prior to the start of the study. After obtaining informed consent, the research team will review standardized instructions for using the study medication with the patient and the research associate will provide a take-home kit including all of the study materials, including instructions for collecting each swab and for returning the samples. Samples will be self-collected by participants at their home at intervals specified in the study instructions. All materials provided to the patient will be pre-labeled with their study ID, protecting each participant's PHI. No collections will take place in-clinic. These materials include all surveys, patient's diary, and all swab vials. The three collection points are as follows: 1) baseline, prior to starting intervention (see below for recommendations on collecting baseline swab), 2) after completion of the intervention (30 days after baseline collection), and 3) 30 days after completion of the intervention (60 days after baseline collection). All vaginal swabs must be frozen within 48 hours of collection. As such, the participants will be asked to send their samples within 24 hours in order to give adequate time for delivery to the storage facility and be asked to collect their specimens between Sunday and Thursday so samples can reach the facility during business hours. Freezing will occur at the research site. Each patient's study kit will include a prepaid shipping envelope, which the participant can use to mail or drive their specimen to the research team who will then place it in the freezer until it is ready for analysis. The first phase of the study will include an assessment and classification of patients' vaginal microbiome prior to receipt of the intervention. To get the best representation of the participant's baseline microbiome, the participant will be asked to collect their baseline swab no sooner than 10 days after menses, as menses-induced changes in the microbiome have been shown to resolve after this time12. For similar reasons, if participants are being treated with an acute course of antibiotics or antifungals at the time of recruitment, they will be asked to wait 10 days after the completion of their medication course before collecting their baseline swab. There will be two additional time points for collection: collection 2) at the end of the 30 day intervention, and collection 3) 30 days after completion of the intervention. Once received at the research site, samples will be stored in a specimen freezer at -80 degrees F until all specimens are received, at which point they will analyzed using NextGen sequencing, a DNA sequencing technology that will identify the genetic makeup of their specimens. This will be done to sequence the genome of the bacteria of the microbiome, not the patient's genetic material. The first phase of the study will also include a survey, which will collect demographic information from each participant, as well as assess patients' current acceptability of a vaginal gel for prophylactic use, their most bothersome symptoms, and how their quality of life is affected by recurrent vulvovaginitis. The specific information collected from each participant can be found below in Data Analysis. The survey used to measure this will be the Vulvovaginal Symptom Questionnaire (VSQ), which has been validated for the purposes stated above. There will also be an added space in the survey provided for open-ended answers and comments. Measurement for primary outcomes will be done using two separate methods. In order to assess for the presence of lactic acid-forming organisms before and after the lactic acid gel intervention, NextGen DNA sequencing will be completed on self-collected samples submitted by participants. The analysis of these samples will be performed by Dr. Miller, at an in-house lab run by the UH Maternal Fetal Medicine division. In order to assess for patient-experienced symptoms, survey B will be administered prior to, immediately after, and 30 days after intervention. In order to measure our secondary outcome, Survey C will be administered at collection points 2 and 3 of the vaginal swabs. This survey is a validated tool to assess for the acceptability, appropriateness, and feasability of an intervention (Acceptability of Intervention Measure, or AIM, Intervention Appropriateness measure, or IAM, and Feasibility of Intervention Measure, or FIM). The intervention will take place on a rolling basis, as patient participation will have no bearing on other participants. The intervention itself will take place over thirty days. 8 pre-filled vaginal inserters with vaginal gel, will be provided to each of the participants with verbal and written instructions for application. Patients will be instructed to use Phexxi twice per week, on the same days every week. Throughout the 30 days, participants will also be asked to keep a diary of events occurring when they used the product, such as intercourse or menses, as well as record any symptoms or side effects they noticed when using the product. The diary can be sent back with the second specimen vial. Disposal of the product may be done in a regular waste basket. Approximately 30 days after completion of the intervention, participants will receive an email reminder to collect and send a third collection swab in for analysis. This email will also include the link for the third and final set of surveys.

Official Title
-----------------
Exploring the Effects of an Intravaginal Lactic Acid Gel on the Vaginal Microbiome

Conditions
-----------------
Bacterial Vaginosis, Vulvovaginal Candidiasis

Intervention / Treatment
-----------------
* Drug: Phexxi


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-54 Female Pre-menopausal Can speak and read in English Displays capacity for informed consent Has had 2 or more documented and/or self-reported episodes of symptomatic BV or candida infection in the last year, requiring, over-the-counter or prescription treatment Exclusion Criteria: Pregnant or trying to become pregnant Post-menopausal Using NuvaRing device A past medical history of kidney disease, recurrent UTI, and/or urinary tract abnormalities Current UTI Using Phexxi as a contraceptive during the collection period of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 54 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>This is a single-arm study. all participants are assigned to this arm. all study participants will receive Phexxi, the study drug. 8 pre-filled vaginal inserters with vaginal gel, Phexxi, will be provided to each of the participants with verbal and written instructions for application. Patients will be instructed to use Phexxi twice per week, on the same days every week. | Drug: Phexxi<br>* intravaginal gel twice weekly for 4 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess participant's baseline vaginal microbiome makeup | NextGen analysis pre-intervention | Within one week of recruitment, unless menstruating. If this is the case, the participant will be asked to wait 10 days from the cessation of menses in order to allow restoration of baseline vaginal microbiome | 
| To assess if the use of Phexxi causes changes in the vaginal microbiome from baseline after thirty days of use | NextGen analysis immediately post-intervention | 30 days after baseline vaginal swab collection | 
| To assess if the use of Phexxi causes changes in the vaginal microbiome | NextGen analysis 30 days post-completion of intervention | 60 days after baseline vaginal swab collection | 
| To assess participant's baseline vulvovaginitis symptoms | Survey to be completed pre-intervention | On day of recruitment to the study | 
| To assess if the use of Phexxi decreases vulvovaginitis symptoms in study participants | Survey to be completed immediately post-intervention. This survey is a validated tool to assess for symptoms of vulvovaginitis (Vulvovaginal Symptoms Questionnaire, or VSQ). It employs a binary scoring system, giving 0 points for no and 1 point for yes, with 21 questions which assess vulvovaginitis symptoms. | 30 days after baseline vaginal swab collection | 
| To assess if the use of Phexxi decreases vulvovaginitis symptoms in study participants | Survey to be completed 30 days post-completion of intervention. This survey is a validated tool to assess for symptoms of vulvovaginitis (Vulvovaginal Symptoms Questionnaire, or VSQ). It employs a binary scoring system, giving 0 points for no and 1 point for yes, with 21 questions which assess vulvovaginitis symptoms. | 60 days after baseline vaginal swab collection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess patient satisfaction/acceptability of this intervention as a therapeutic/prophylactic agent for recurrent vulvovaginitis | Survey at 2 time points: immediately post-intervention, and 30 days post-completion of intervention. This survey is a validated tool to assess for the acceptability, appropriateness, and feasability of an intervention (Acceptability of Intervention Measure, or AIM, Intervention Appropriateness measure, or IAM, and Feasibility of Intervention Measure, or FIM). It lists a number of statements to assess the above measures and asks the participant to circle the ones which apply to them. | 30 and 60 days after baseline swab collection |