LACTIN-V Study for Recurrent Bacterial Vaginosis

• ClinicalTrials.gov Identifier: NCT02766023
• Recruitment Status: Completed
• First Posted: May 9, 2016
• Results First Posted: February 11, 2020
• Last Update Posted: March 4, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Bacterial Vaginosis	Biological: Lactobacillus crispatus CTV-05; Drug: Metronidazole; Other: Placebo	Phase 2

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 228 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Phase II-b Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus Crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis
• Actual Study Start Date: June 3, 2016
• Actual Primary Completion Date: February 11, 2019
• Actual Study Completion Date: February 11, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: LACTIN-V; Subjects receive 5-day course of metronidazole gel 7.5 mg/gm daily applied vaginally. Subjects then receive LACTIN-V 2x10^9 cfu/dose applied vaginally for 5 days then twice weekly for 10 weeks. N=152	Biological: Lactobacillus crispatus CTV-05; 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.; Drug: Metronidazole; Metronidazole is a nitroimidazole. Metronidazole gel (MetroGel) is applied vaginally 7.5 mg/gm daily for 5 days
Placebo Comparator: Placebo; Subjects receive 5-day course of metronidazole gel 7.5 mg/gm daily applied vaginally. Subjects then receive placebo applied vaginally for 5 days then twice weekly for 10 weeks. N=76	Drug: Metronidazole; Metronidazole is a nitroimidazole. Metronidazole gel (MetroGel) is applied vaginally 7.5 mg/gm daily for 5 days; Other: Placebo; Placebo formulation applied vaginally, daily x 5 days then twice weekly x 10 weeks.

Outcome Measures

Primary Outcome Measures :

1. The Proportion of Participants Reporting Product-related Adverse Events (AEs) and Serious Adverse Events (SAEs) in Each Study Arm. [ Time Frame: Day 1 to Day 168 ]
   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."
2. The Proportion of Participants With a Positive BV Diagnosis in Each Study Arm. [ Time Frame: Day 1 to Day 84 ]
   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.

Secondary Outcome Measures :

1. The Proportion of Participants Who Are Compliant With the Complete Dose Regimen as Assessed by Participant Reporting and Applicator Staining. [ Time Frame: Day 1 to Day 84 ]
   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.
2. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Categorical Variables on Likert Scale [ Time Frame: Day 84 ]
   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.
3. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Likelihood to Use [ Time Frame: Day 84 ]
   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?"
4. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Current Partner's Reaction to the Product [ Time Frame: Day 84 ]
   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.
5. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Current Partner's Reaction as Influence [ Time Frame: Day 84 ]
   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.
6. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Experience Side Effects [ Time Frame: Day 84 ]
   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.
7. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Experience of Side Effects Make Less Likely to Use [ Time Frame: Day 84 ]
   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?"
8. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Continuous/Discrete Response Regarding Product [ Time Frame: Day 84 ]
   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".
9. Acceptability of LACTIN-V and the Applicator Measured by Self-administered Questionnaires About Acceptability - Continuous/Discrete Response Regarding Product Use [ Time Frame: Day 84 ]
   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".
10. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product in the LACTIN-V Arm Overall. [ Time Frame: Day 1 to Day 84 ]
    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
11. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse. [ Time Frame: Day 1 ]
    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
12. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse. [ Time Frame: Day 28 ]
    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
13. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse. [ Time Frame: Day 56 ]
    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
14. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Intercourse. [ Time Frame: Day 84 ]
    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
15. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses. [ Time Frame: Day 28 ]
    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
16. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses. [ Time Frame: Day 56 ]
    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
17. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product by Occurrence of Menses. [ Time Frame: Day 84 ]
    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
18. The Proportion of Participants Experiencing Successful Colonization With L. Crispatus CTV-05 Following Dose of Study Product Overall. [ Time Frame: Day 1 to Day 168 ]
    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
19. The Proportion of Participants With a Positive BV Diagnosis in Each Study Arm. [ Time Frame: Day 1 to Day 168 ]
    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.
20. The Number of Participants Who Discontinued Study Product Early in Each Study Arm Due to Adverse Events. [ Time Frame: Day 1 to Day 84 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Capable of reading and writing English and voluntarily provide written informed consent to participate in the study and comply with all study procedures 2. Untreated BV (asymptomatic or symptomatic) as diagnosed during the screening visit defined by >/=3 Amsel criteria. Note: Amsel criteria include the following: --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 (KOH) is added to a sample of vaginal discharge; --Presence of clue cells (>20% on microscopy). 3. Untreated BV(asymptomatic or symptomatic) as confirmed in the laboratory using the Nugent scoring system (Nugent Score >/= 4) 4. Otherwise healthy pre-menopausal women 18-45 years of age on the day of screening 5. Regular predictable menstrual cycles or amenorrheic for at least 3 months due to use of a long-acting progestin or continuous use of oral contraceptives 6. Willing to be asked questions about personal medical health and sexual history. 7. Willing to apply study agent vaginally and comply with study examinations. 8. Agree to abstain from sexual intercourse during the first 5 consecutive days of study product administration, 12 hours prior to study visits and for 12 hours after each study product application 9. Agree to abstain from the use of any other intravaginal product throughout the trial period from the time of screening through Visit 7 (Week 24, Day 168) Note: Intravaginal products include contraceptive creams such as Gynol II, gels, foams, sponges, lubricants not approved by the study investigators, and douches. Limit use of tampons during menstruation to unscented products. 10. Must be of non-childbearing potential or if of childbearing potential, must agree to use a reliable method of birth control for the duration of the study Note: Reliable methods of birth control include tubal ligation, male partner with a vasectomy, a steroidal contraceptive (oral, patch, injectable or implantable), IUD, condoms or abstinence.

Exclusion Criteria:

1. Urogenital infection at screening Note: Urogenital infection includes urinary tract infection, Trichomonas (T.) vaginalis, Neisseria (N.) gonorrhoeae, Chlamydia (C.) trachomatis, Treponema (T.) pallidum, or vulvo-vaginal candidiasis. 2. Diagnosis of two or more outbreaks of N. gonorrhoeae, C. trachomatis, T. pallidum, T. vaginalis, or herpes simplex virus (herpes genitalis) within 6 months prior to screening 3. Positive for syphilis or HIV at screening 4. Current pregnancy or within 2 months of last pregnancy and/or currently breastfeeding**. Criteria will be assessed at screening and enrollment. 5. Vaginal or systemic antibiotic or antifungal therapy (other than MetroGel given as part of study procedures) within 21 days of screening or within 30 days of enrollment** 6. Use of disulfiram within past 2 weeks or other contraindication to use of MetroGel** 7. Any condition requiring regular periodic use of systemic antibiotics during participation in the trial 8. Active genital herpes lesion** (if not resolved by enrollment)** 9. Investigational drug use other than LACTIN-V within 30 days or 10 half-lives of the drug, whichever is longer, of enrollment visit** 10. Other planned participation in an investigational drug study while participating in this study** 11. Menopause defined as more than 12 consecutive months of amenorrhea without another known cause including pregnancy 12. IUD insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser treatment within the last 2 months prior to screening 13. Use of vaginal ring (eg, NuvaRing) within 3 days of screening or during the course of the study** 14. Failure to complete 5 days of MetroGel with the last dose taken no later than 48 hours prior to randomization*** 15. Use of new long-acting hormonal treatments. Participant may be enrolled if stable (>3 months) on existing therapy as determined by the principal investigator** 16. Known allergy to any component of LACTIN-V/placebo or MetroGel or to nitroimidazole derivatives or latex (condoms) 17. Any social, medical, or psychiatric condition, including history of drug or alcohol abuse that in the opinion of the investigator would make it unlikely for the participant to comply with the study ** Note: Criteria will be assessed at screening and enrollment. ***Note: Criteria will be assessed at enrollment

Contacts and Locations

Locations

United States, California

University of California, San Diego - Antiviral Research Center

San Diego, California, United States, 92103-8208

San Francisco General Hospital - Infectious Diseases

San Francisco, California, United States, 94110-3518

United States, Illinois

Cook County Health and Hospitals System - Ruth M Rothstein CORE Center

Chicago, Illinois, United States, 60612

United States, Missouri

Washington University School of Medicine in St. Louis - Infectious Disease Clinical Research Unit

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] February 19, 2016

Statistical Analysis Plan  [PDF] May 11, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Armstrong E, Hemmerling A, Miller S, Burke KE, Newmann SJ, Morris SR, Reno H, Huibner S, Kulikova M, Liu R, Crawford ED, Castaneda GR, Nagelkerke N, Coburn B, Cohen CR, Kaul R. Metronidazole treatment rapidly reduces genital inflammation through effects on bacterial vaginosis-associated bacteria rather than lactobacilli. J Clin Invest. 2022 Mar 15;132(6):e152930. doi: 10.1172/JCI152930.

Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, Green L, Miller S, Powell J, Parks T, Hemmerling A. Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis. N Engl J Med. 2020 May 14;382(20):1906-1915. doi: 10.1056/NEJMoa1915254.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02766023
• Other Study ID Numbers: 14-0029; HHSN272201300014I
• First Posted: May 9, 2016
• Results First Posted: February 11, 2020
• Last Update Posted: March 4, 2020
• Last Verified: April 5, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

CTV-05; LACTIN-V; Lactobacillus; MetroGel®; Vaginitis

Additional relevant MeSH terms:

Vaginosis, Bacterial; Vaginal Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Vaginitis; Metronidazole; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents