Suppression Of Bacterial Vaginosis (BV) [SUBVert]

Study Overview
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Brief Summary
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A Phase II randomized, double-blind, placebo-controlled study screening approximately 600 adult females, aged 18-55, with a goal to enroll approximately 250 participants to achieve 200 evaluable participants at the test of cure (TOC) visit. The study is designed to determine the clinical efficacy of an investigational product (IP), TOL-463 Insert, in suppressing Recurrent Bacterial Vaginosis (RBV) when administered to women who have a history of RBV and have been successfully cleared of their current Bacterial Vaginosis (BV) infection administering 500 mg of oral metronidazole, twice a day for 7 days or another CDC-recommended BV treatment. Patient participation will be approximately 100 days while the study is conducted at 4 sites within the United States. The primary objective of the study is to evaluate the clinical efficacy of a twice-weekly application of TOL-463 vaginal insert in suppression of BV in women with a history of RBV following successful induction with oral metronidazole or a CDC-recommended BV treatment.

Detailed Description
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This is a Phase II randomized, double-blind, placebo-controlled study screening approximately 600 adult females, aged 18-55, with a goal to enroll approximately 250 participants to achieve 200 evaluable participants at the test of cure (TOC) visit. The study is designed to determine the clinical efficacy of an investigational product (IP), TOL-463 Insert, in suppressing Recurrent Bacterial Vaginosis (RBV) when administered to women who have a history of RBV and have been successfully cleared of their current Bacterial Vaginosis (BV) infection administering 500 mg of oral metronidazole, twice a day for 7 days or another CDC-recommended BV treatment. Patient participation will be approximately 100 days while the study is conducted at 4 sites within the United States. The primary objective of the study is to evaluate the clinical efficacy of a twice-weekly application of TOL-463 vaginal insert in suppression of BV in women with a history of RBV following successful induction with oral metronidazole or a CDC-recommended BV treatment. Secondary objectives of the study are: 1) to evaluate the time to BV recurrence as defined by clinical criteria, 2) to evaluate the incidence of vaginal symptoms over study participation, 3) to evaluate acceptability of a twice-weekly application of TOL-463 vaginal insert in suppression of BV, and 4) to evaluate the safety of TOL-463 vaginal insert compared to placebo, including the incidence of secondary vulvovaginal candidiasis (VVC). The null hypothesis for the comparison is that there is no difference in cure rates between treatments, with a two-sided alternative.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial Of TOL-463 Insert for Suppression Of Bacterial Vaginosis (BV) [SUBVert]

Conditions
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Bacterial Vaginosis

Intervention / Treatment
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* Other: Placebo
* Drug: TOL-463


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening Visit(s) Inclusion Criteria: Women with a current Bacterial Vaginosis (BV) infection and a history of at least two previous episodes of BV by documentation or self-report in the past year. Screening (V0) diagnosis is based on the presence of > / = 3 Amsel criteria*; Homogeneous vaginal discharge; positive potassium hydroxide (KOH) whiff test; vaginal pH of > 4.5; and > / = 20% clue cells. Willing and able to provide written informed consent; Age 18-55 years of age at the time of V0; General good health based on medical history, targeted physical examination, and pelvic examination; For participants 21 years of age or older, Pap test performed within the past 3 years, with the most recent result being normal or Atypical Squamous Cells of Undetermined Significance (ASCUS) Human Papillomavirus (HPV) negative or Pap smear collected at V0*; *Consistent with current Pap screening guidelines, a Pap smear must be performed at V0, for women who meet the following criteria and cannot provide documentation or self-report of a normal or ASCUS HPV negative Pap smear, conducted within the prior 3 years: (a) has not had a hysterectomy or (b) has had a hysterectomy and has a history of cervical intraepithelial neoplasia grade 2 plus (CIN2plus) in the past 20 years. Note: If a Pap smear is conducted at V0, the results are not required prior to enrollment. Have a negative urine pregnancy test at V0, if of childbearing potential; Must be of non-childbearing potential* or must be using an effective method of birth control** and must be willing to continue the method through the end of Investigational Product (IP) administration; *Defined as post-menopausal or status post bilateral tubal ligation, or status post bilateral oophorectomy or status post hysterectomy. **Acceptable methods are defined as: Intrauterine Devices (IUDs) or hormonal contraceptives for at least 22 days prior to screening. Note: Intravaginal contraceptive rings (e.g., NuvaRing) are not acceptable forms of birth control for this study. Consistent use of a barrier method, including diaphragms or condoms, for at least 13 days prior to screening. Abstinence from vaginal sexual intercourse for at least 13 days prior to screening. Exclusively same-sex relationship. Monogamous relationship with vasectomized partner. Willing and able to cooperate to the extent and degree required by this protocol at the discretion of the investigator; Enrollment Visit Inclusion Criteria: In addition to confirming all relevant Screening Visit Inclusion Criteria, women must meet all of the following criteria to be eligible for enrollment in the study. Willing and able to provide Enrollment written informed consent; After completion of metronidazole induction therapy or another CDC-recommended BV treatment, no clinical evidence of BV* and absence of symptoms of BV** at Visit 1, Enrollment (V1); As defined by < / = 2 of 4 Amsel criteria. **Defined as absence of vaginal discharge and odor consistent with BV. Must have a negative urine pregnancy test at V1, if of childbearing potential; Willing to refrain from any intravaginal products/medications* other than the IP throughout the course of the trial; *For example: douches, antifungal or antibacterial preparations, lubricants, contraceptive creams, gels, foams, sponges, spermicides. Must agree to abstain from receptive oral, anal, and vaginal sexual intercourse one hour prior to IP administration and for 24 hours after; Willing to refrain from using tampons or menstrual cups for 24 hours after IP administration; Must be of non-childbearing potential* OR must be using an effective method of birth control** and must be willing to continue the method through the end of IP administration; *Defined as post-menopausal or status post bilateral tubal ligation, or status post bilateral oophorectomy or status post hysterectomy. Acceptable methods are defined as: IUDs or hormonal contraceptives for at least 30 days prior to using IP. Note: Intravaginal contraceptive rings (e.g., NuvaRing) are not acceptable forms of birth control for this study. Consistent use of a barrier method, including diaphragms or condoms, for at least 21 days prior to using IP. Abstinence from vaginal sexual intercourse for at least 21 days prior to using IP. Exclusively same-sex relationship. Monogamous relationship with vasectomized partner. Exclusion Criteria: Screening Visit(s) Exclusion Criteria: Diagnosis of another vaginal or vulvar condition that may confuse interpretation of response to Investigational product (IP)*; For example: erosive lichen planus, desquamative inflammatory vaginitis, or contact dermatitis involving the vulvar epithelium. Concurrent Vulvovaginal Candidiasis (VVC) infection with inability to be treated with oral fluconazole; Infectious cause of cervicitis (e.g., N. gonorrhoeae, C. trachomatis, or T. vaginalis) confirmed on physical examination and/or with laboratory testing*, **; *Women may be rescreened for eligibility following successful treatment of confounding Sexually Transmitted Infection (STI). **Results of Nucleic Acid amplification Test (NAAT) testing will be reviewed prior to enrollment. Active genital lesions, including ulcers or vesicles consistent with herpes or warts; Planned ongoing immunosuppressive therapy or systemic antibiotic treatment during the course of the study; History of hypersensitivity, allergy or other contraindication(s) to metronidazole or other CDC-recommended BV treatment used to treat subject; History of hypersensitivity to any TOL-463 formulation components; Current or untreated cervical intraepithelial neoplasia (CIN) or cervical carcinoma; Currently pregnant or nursing; Any other condition that, in the opinion of the investigator, would interfere with participation in the study; Previous enrollment in the study or at the investigator's discretion; Enrollment Visit Exclusion Criteria: In addition to confirming all Screening Visit Exclusion Criteria, women who meet any of the following criteria will not be eligible for enrollment in the study. Active menses or significant vaginal bleeding as determined by the study clinician at V1*; *Note: women who are menstruating may be reevaluated for study enrollment within the enrollment window. Use of vaginal or systemic antibiotic or antifungal since V0, other than oral metronidazole, CDC-recommended BV treatment, or oral fluconazole, as per protocol; Evidence or suspicion of infectious cause of cervicitis or active genital lesion on pelvic examination at Visit 1, Enrollment (V1); Concurrent VVC infection at V1 with inability to treat with oral fluconazole; Use of any investigational drug within 30 days prior to V1 or planned/anticipated use during study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>TOL-463 insert administered vaginally twice a week for twelve weeks. N=125 | Drug: TOL-463<br>* TOL-463 is a non-azole vaginal anti-infective drug candidate designed as a dual-indication therapy for BV and VVC.<br>|
| Placebo Comparator: Arm 2<br>Matching placebo insert administered vaginally twice a week for twelve weeks. N=125 | Other: Placebo<br>* Placebo vaginal inserts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Recurrent Bacterial Vaginosis (RBV) by Visit 4, as Defined by Presence of at Least 3 Amsel Criteria | Recurrent bacterial vaginosis (RBV) was defined as the presence of at least three out of the following four Amsel criteria: positive KOH whiff test, homogeneous discharge characteristic of BV, clue cells comprising at least 20% of vaginal squamous epithelial cells, and vaginal pH > 4.5. Participants who had post-baseline efficacy results but were lost to follow-up before study completion were considered treatment failures and counted toward the number of participants with recurrence of BV. | Day 1 through Day 91 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Bacterial Vaginosis (BV) Recurrence, as Defined by Presence of at Least 3 Amsel Criteria | Recurrent bacterial vaginosis (RBV) was defined as the presence of at least three out of the following four Amsel criteria: positive KOH whiff test, homogeneous discharge characteristic of BV, clue cells comprising at least 20% of vaginal squamous epithelial cells, and vaginal pH > 4.5. Participants who had post-baseline efficacy results but were lost to follow-up before study completion were censored in secondary time-to-event analyses. Participants with off-study diagnosis of BV were excluded from secondary time-to-event analyses. The median time to BV recurrence was calculated as the first event time at which the Kaplan-Meier estimator drops to or below 0.5. | Day 1 through Day 91 | 
| Proportion of Participants Reporting Bacterial Vaginosis (BV) Symptoms - Abnormal Vaginal Discharge | The BV symptoms evaluated for efficacy at each clinic visit included abnormal vaginal discharge and vaginal odor. Both symptoms were assessed by a clinician as either consistent with BV, not consistent with BV, or absent. Only symptoms deemed consistent with BV were reported as BV symptoms. | Assessed at Visit 1 (Day 1), Visit 2 (Window: Days 29-35), Visit 3 (Window: Days 57-63) and Visit 4 (Window: Days 85-91). | 
| Proportion of Participants Reporting Bacterial Vaginosis (BV) Symptoms - Vaginal Odor | The BV symptoms evaluated for efficacy at each clinic visit included abnormal vaginal discharge and vaginal odor. Both symptoms were assessed by a clinician as either consistent with BV, not consistent with BV, or absent. Only symptoms deemed consistent with BV were reported as BV symptoms. | Assessed at Visit 1 (Day 1), Visit 2 (Window: Days 29-35), Visit 3 (Window: Days 57-63) and Visit 4 (Window: Days 85-91). | 
| Number of Participants Satisfied With the Study Treatment as Assessed by Satisfaction Questionnaire Responses | The satisfaction questionnaire contained five questions assessing participant satisfaction with the study treatment. For questions regarding ease of use, frequency of use, and overall satisfaction, participants could respond on a scale ranging from Extremely dissatisfied to Extremely satisfied. Participants who responded with Somewhat satisfied through Extremely satisfied were considered Satisfied with those categories. For the question regarding convenience of use, participants could respond on a scale ranging from Extremely inconvenient to Extremely convenient. Participants who responded with Somewhat convenient through Extremely convenient were considered Satisfied with study treatment convenience. For the question of whether the participant would use the study treatment again, participants who responded with Yes were considered Satisfied with the study treatment. | Assessed at study completion (the visit at which the participant was diagnosed with BV, or Visit 4 for participants remaining BV suppressed). This may occur at Visit 2 (Window: Days 29-35), Visit 3 (Window: Days 57-63) or Visit 4 (Window: Days 85-91). | 
| Number of Participants With Adverse Events (AEs) Considered Product-related Following Initiation of Study Treatment | Safety was monitored throughout the study, including via participant reporting. Study clinicians assessed whether or not reported adverse events (AEs) were related to study treatment. | Day 1 through Day 91 | 
| Number of Participants With Culture Confirmed Secondary VVC Following Initiation of Study Treatment | Assessment of vulvovaginal candidiasis (VVC) was performed by pelvic examination at baseline and at each follow-up visit. If clinical diagnosis of VVC was determined at any visit, then a confirmatory Candida culture was performed. | Day 1 through Day 91 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bacterial vaginosis, Candida albicans, Double-Blind, Gardnerella vaginalis, Phase II, Placebo, Randomized, Suppression, TOL-463 insert