Suppression Of Bacterial Vaginosis (BV) [SUBVert]

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.

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.