This Phase 2b trial is designed to provide a screening evaluation for the hypothesis that, following a 5-day treatment with MetroGel® to treat BV, L. crispatus CTV-05 (LACTIN-V, Osel, Inc.) administered at 2 x 10\^9 cfu/dose using a vaginal applicator reduces the 12-week incidence of BV recurrence when compared to placebo. The primary objectives of this study are: 1) To estimate the efficacy of repeated doses of LACTIN-V (2 x 10\^9 cfu/dose) as compared to placebo in preventing BV recurrence by 12 weeks following treatment of BV with MetroGel vaginal gel (MetroGel). 2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of AEs between individuals randomized to LACTIN-V or placebo.
This is a Phase II-b multicenter randomized double-blind placebo-controlled trial to assess the efficacy of repeated doses of LACTIN-V compared to placebo in preventing BV recurrence in women diagnosed with BV. The study will also assess the safety of LACTIN-V by comparing the incidence of AEs between women randomized to LACTIN-V or placebo. The study plans to enroll 228 non-pregnant, pre-menopausal women age 18 to 45 years. Women will be randomized 2:1 to receive LACTIN-V or placebo. Potentially eligible women will start a standard 5-day course of MetroGel. Women will return to the study clinic within 2 days after completing the 5-day course of MetroGel to re-evaluate eligibility criteria and review the BV test results from the screening visit. Women with Amsel criteria \> /=3 and Nugent score 4-10 will be instructed to administer the LACTIN-V or placebo at home for 5 consecutive days and then twice weekly for 10 weeks. The primary objectives of this study are: 1) To estimate the efficacy of repeated doses of LACTIN-V (2 x109 cfu/dose) as compared to placebo in preventing BV recurrence by 12 weeks following treatment of BV with MetroGel vaginal gel (MetroGel). 2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of AEs between individuals randomized to LACTIN-V or placebo. Secondary objectives are: 1) To investigate the colonization of LACTIN-V (presence of L. crispatus CTV-05 in the vaginal specimen) and fluctuations over 12 weeks, in relation to menses and sexual intercourse 2) To evaluate user acceptability and tolerability of LACTIN-V over 12 weeks, including perceptions around method of delivery and dosing. 3) To measure long-term colonization of LACTIN-V at 24 weeks (12 weeks after last dosing) 4) To estimate the long-term efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as compared to placebo in preventing BV recurrence at 24 weeks (12 weeks after last dosing)
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
228
LACTIN-V is an intravaginal live biotherapeutic product composed of Lactobacillus crispatus CTV-05 (LACTIN-V, Osel Inc) in a vaginal applicator. Subjects receive 2x10\^9 cfu/dose applied vaginally daily x 5 days then twice weekly x 10 weeks.
Metronidazole is a nitroimidazole. Metronidazole gel (MetroGel) is applied vaginally 7.5 mg/gm daily for 5 days
Placebo formulation applied vaginally, daily x 5 days then twice weekly x 10 weeks.
University of California, San Diego - Antiviral Research Center
San Diego, California, United States
San Francisco General Hospital - Infectious Diseases
San Francisco, California, United States
Cook County Health and Hospitals System - Ruth M Rothstein CORE Center
Chicago, Illinois, United States
Washington University School of Medicine in St. Louis - Infectious Disease Clinical Research Unit
St Louis, Missouri, United States
The Proportion of Participants Reporting Product-related Adverse Events (AEs) and Serious Adverse Events (SAEs) in Each Study Arm.
Adverse events and serious adverse events were collected during the entire study period. Relatedness to study product was assessed by the site investigator according to the protocol definition of related as "There is a reasonable possibility that the study product caused the AE. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the AE."
Time frame: Day 1 to Day 168
The Proportion of Participants With a Positive BV Diagnosis in Each Study Arm.
A positive BV diagnosis was defined by meeting at least 3 of the 4 Amsel criteria and a Nugent score of 4-10. Amsel criteria are: homogeneous, thin, grayish-white discharge that smoothly coats the vaginal walls; vaginal pH \>4.5; positive whiff-amine test, defined as the presence of a fishy odor when a drop of 10% potassium hydroxide is added to a sample of vaginal discharge; and presence of clue cells (\>20%) on microscopy. The Amsel score ranges from 0-4, where higher scores mean a worse outcome. The Nugent score is calculated by assessing for the presence of large Gram-positive rods scored as 0 to 4, small Gram-variable rods scored as 0 to 4, and curved Gram-variable rods scored as 0 to 2, and adding all component scores. The Nugent score ranges from 0-10, where higher scores mean a worse outcome. All BV diagnoses following 15 days after enrollment (22 days after commencement of MetroGel treatment) were considered a recurrent episode.
Time frame: Day 1 to Day 84
The Proportion of Participants Who Are Compliant With the Complete Dose Regimen as Assessed by Participant Reporting and Applicator Staining.
A subject was considered compliant with the assigned study product if she took 4 of the first 5 daily doses and at least 75% of the scheduled doses overall prior to the first diagnosis of BV or through Week 12, whichever occurred first. Compliance was assessed by subject report via the memory aid and, separately, applicator staining of the returned kit. Compliance was assessed on a weekly basis and the time (week) at which the subject became non-compliant was determined by blinded PI review.
Time frame: Day 1 to Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Categorical Variables on Likert Scale
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by Likert-scale responses of strongly agree, agree, neutral, disagree and strongly disagree.
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Likelihood to Use
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including the question, "If a non-antibiotic, clinically proven lactobacillus product were available for treatment and prevention of BV, what are the chances that you would use it?"
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Current Partner's Reaction to the Product
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including "My current partner's reaction to the product was..." with the options as listed below.
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Current Partner's Reaction as Influence
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including if their current partner's reaction to the product influenced their use of the product.
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Experience Side Effects
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including a Yes/No question about experiencing side effects.
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Experience of Side Effects Make Less Likely to Use
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including a Yes/No question about experiencing side effects. For those participants who answered Yes to experiencing side effects, a follow-up question asked "would these side effects make you less likely to use the product again?"
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Continuous/Discrete Response Regarding Product
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including by rating factors on a 0-10 scale, with 0 being "not at all" and 10 being "extremely".
Time frame: Day 84
Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Continuous/Discrete Response Regarding Product Use
Participants answered a detailed self-administered questionnaire at Week 12 assessing the acceptability of the study product and the applicator. Questionnaire items included rating aspects of the product and applicator by various measures, including by rating factors on use of the product on a 0-10 scale, with 0 being "not at all" and 10 being "extremely so".
Time frame: Day 84
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product in the LACTIN-V Arm Overall.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 1 to Day 84
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 1
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 28
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 56
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 84
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 28
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 56
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 84
The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product Overall.
Colonization of L. crispatus was determined from the concentrations of L. crispatus species and L. crispatus CTV-05 obtained from qPCR. Successful colonization was defined as: If CTV-05 concentration was above the lower limit of detection (LLOD) and the L. crispatus was above the LLOD, then successful colonization had occurred. If either CTV-05 or L. crispatus concentration was below LLOD or indeterminate, then successful colonization had not occurred. The LLOD for CTV-05 was 660 copies/mL and the LLOD for L. crispatus was 953 copies/mL
Time frame: Day 1 to Day 168
The Proportion of Participants With a Positive BV Diagnosis in Each Study Arm.
A positive BV diagnosis was defined by at least 3 of the 4 Amsel criteria and a Nugent score of 4-10. Amsel criteria are: homogeneous, thin, grayish-white discharge that smoothly coats the vaginal walls; vaginal pH \>4.5; positive whiff-amine test, defined as the presence of a fishy odor when a drop of 10% potassium hydroxide is added to a sample of vaginal discharge; and presence of clue cells (\>20%) on microscopy. The Nugent score is calculated by assessing for the presence of large Gram-positive rods scored as 0 to 4, small Gram-variable rods scored as 0 to 4, and curved Gram-variable rods scored as 0 to 2. All BV diagnoses following 15 days after enrollment (22 days after commencement of MetroGel treatment) were considered a recurrent episode.
Time frame: Day 1 to Day 168
The Number of Participants Who Discontinued Study Product Early in Each Study Arm Due to Adverse Events.
Tolerability of LACTIN-V and the applicator was measured by the proportion of participants who discontinued the study product prior to completing the dose schedule due to an adverse event.
Time frame: Day 1 to Day 84
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