Phase 2 Trial of LACTIN-V in Women at High Risk of HIV Acquisition

Phase 2 Placebo-controlled Randomized Trial of LACTIN-V (Lactobacillus Crispatus CTV-05) Among Women at High Risk of HIV Acquisition in Durban, South Africa

The purpose of this study is to assess the impact of LACTIN-V, a vaginally administered live biotherapeutic product (LBP) that contains the human L. crispatus CTV-05 strain, on the vaginal microbiome of Lactobacillus-deficient young women in the South African FRESH study who are at high risk for HIV acquisition.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Bacterial Vaginosis
• Intervention / Treatment: Drug: LACTIN-V; Drug: Placebo

Detailed Description

We will conduct a randomized, placebo-controlled trial of the vaginal live biotherapeutic product LACTIN-V in 60 young South African women.

After being informed about the study and potential risks, all participants giving written informed consent will be enrolled if they meet eligibility criteria. At enrollment on Day 1, they will start a 7-day course of standard oral metronidazole treatment for bacterial vaginosis. Women who completed their metronidazole treatment will be randomized 2:1 to LACTIN-V vs. placebo. Within 8-48 hours of the final metronidazole dose, women will receive the study product for five consecutive days, followed by twice weekly for three additional weeks. Women will be followed during the dosing (4 weeks) and post-dosing phase (4 weeks) for a total of 64 days.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4066
      • FRESH (Females Rising through Education, Support and Health) Clinical Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 23 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. FRESH study participant.
2. Capable of reading and writing English or isiZulu and voluntarily provide written informed consent to participate in the study and comply with all study procedures
3. HIV-negative
4. Nugent score 4-10 on vaginal Gram stain
5. Otherwise healthy women, 18-23 years of age on the day of enrolment
6. Regular predictable menstrual cycles or amenorrhoeic for at least 3 months due to use of a long-acting progestin.
7. Willing to complete 7-day course of oral metronidazole.
8. Willing to be asked questions about personal medical health and sexual history
9. Willing to apply study agent vaginally and comply with study examinations
10. Willing to self-administer Study Product on dosing days that do not coincide with regular FRESH study visits.
11. Agree to try to abstain from sexual intercourse 12 hours prior to study visits that include a gynaecological exam (Randomization Visit 3, Follow-up Visit 11, Final Visit 19).
12. Agree to try to abstain from sexual intercourse for 12 hours after study product administration to ensure that the product will remain inside the vagina.

13. Agree to abstain from the use of any other vaginal product throughout the trial period from the time of enrolment through the end of the study.

    Note: Intravaginal products include contraceptive creams such as Gynol II, gels, foams, sponges, lubricants not approved by the study investigators, tampons and douches.

14. Must be stable on a reliable method of long-acting birth control and agree to remain on, for the duration of the study (if of childbearing potential) or, of non-childbearing potential (permanently sterile).

Exclusion Criteria:

1. Urogenital infection (as tested during the FRESH Week 5 Study Visit, reported within 30 days of detection at the LACTIN-V Enrolment Visit).

   Note: Urogenital infection includes urinary tract infection, Trichomonas (T.) vaginalis, Neisseria (N.) gonorrhoeae, Chlamydia (C.) trachomatis, Mycoplasma genitalium.

2. Diagnosis of two or more outbreaks of N. gonorrhoeae, C. trachomatis, T. vaginalis, Mycoplasma genitalium, or herpes simplex virus (herpes genitalis) within 6 months prior to enrolment.
3. Subject is ineligible if menstrual cycle length is less than 21 days
4. Subject is ineligible if deep epithelial disruption is observed on genital examination noted on or before the Randomization Visit
5. Positive for HIV (as tested during the FRESH Week 5 Study Visit, within 30 days of the LACTIN-V Enrolment Visit).
6. Current pregnancy or within 2 months of last pregnancy
7. Vaginal or systemic antibiotic or antifungal therapy within 21 days of enrolment
8. Use of disulfiram within past 2 weeks or other contraindication to use of metronidazole
9. Any condition requiring regular periodic use of systemic antibiotics during participation in the trial
10. Investigational drug use other than LACTIN-V within 30 days or 10 half- lives of the drug, whichever is longer, of Enrolment Visit
11. Other planned participation in an investigational drug study while participating in this study
12. Intrauterine device (IUD) insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser treatment within the last 2 months prior to enrolment
13. Use of vaginal ring (e.g, NuvaRing) within 3 days of enrolment or during the course of the study
14. Hysterectomy
15. Unwilling to complete 7 days of oral metronidazole (twice daily) with the last dose taken no later than 48 hours prior to randomization (minimum of 12 of 14 doses required)
16. Use of new long-acting hormonal treatments. Participant may be enrolled if stable (>1 month) on existing therapy as determined by the principal investigator (PI)
17. Known allergy to any component of LACTIN-V/placebo or metronidazole or to nitroimidazole derivatives or latex (condoms)
18. Any social, medical, or psychiatric condition including history of drug or alcohol abuse that in the opinion of the investigator would make it difficult for the participant to comply with study procedures
19. Any serious or chronic illness, deemed incompatible with study participation by the study doctor, including immunosuppression due to cancer chemotherapy, systemic corticosteroids.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LACTIN-V; LACTIN-V contains a naturally occurring human vaginal strain of Lactobacillus (L.) crispatus CTV- 05. At a potency of 2 x 109 cfu/dose, it is preserved in powder formulation, and applied by a vaginal applicator. Women will receive the study product for five consecutive days, followed by twice weekly for three additional weeks. Women will be followed during the dosing (4 weeks) and post-dosing phase (4 weeks) for a total of 64 days.	Drug: LACTIN-V; administered vaginally; Other Names: Lactobacillus crispatus CTV-05
Placebo Comparator: Placebo; A matching placebo formulation without L. crispatus CTV-05 is supplied in an identical applicator containing just the powder formulation. Women will receive the placebo for five consecutive days, followed by twice weekly for three additional weeks. Women will be followed during the dosing (4 weeks) and post-dosing phase (4 weeks) for a total of 64 days.	Drug: Placebo; administered vaginally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Genital Tract Inflammation	The proportion of participants with decreased genital tract proinflammatory cytokines and HIV target cells over 64 days of follow up, compared to levels at baseline. The outcome will be a change in immune parameters after treatment with LACTIN-V in comparison to placebo (proinflammatory cytokines in genital fluid, activated endocervical HIV target cells and the anti-HIV effect of vaginal secretions), measured as the number and proportions of endocervical CD4+ HIV target cells (i.e., CD4+/CCR5+/HLA-DR+/CD38+ T cells) at Day 64. Decreased inflammation will be defined using a measure of >1 log10 decrease in 3/8 markers between baseline and Day 64.	over 64 days
Number of Participants With Lactobacillus-dominant Vaginal Microbiota	The proportion of participants with Lactobacillus-dominant vaginal microbiota in young South African women. Measured will be dominance of Lactobacillus crispatus (defined as > 50% relative abundance) after the intervention. Our primary outcome is measured at Day 36 (after 4 weeks of treatment with LACTIN-V), and at Day 64 (following the post- dosing phase).	over 64 days
Number of Participants With Vaginal Colonization of L. Crispatus CTV-05	The proportion of participants experiencing successful colonization with L. crispatus CTV-05 following dose of study product through the final visit (Day 64) in the LACTIN-V arm. This primary outcome is measured at Day 36 (after 4 weeks of treatment with LACTIN-V), and at Day 64 (following the post- dosing phase).	over 64 days
Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain	The proportion of participants with a positive test for vaginal dysbiosis (Nugent Score 4-10 on vaginal Gram Stain) in each study arm by Day 36 and Day 64. The Nugent Score has values from 0 -10. 0-3 describes an optimal vaginal microbiome with lactobacilli but little bacterial diversity, 4-6 is an intermediate score, and 7-10 characterizes a vaginal microbiome with few lactobacilli and an overgrowth of pathogens.	over 64 days
Number of Participants Reporting Any Solicited Adverse Events (AEs) Through the Final Visit	Overall Safety of LACTIN-V and the applicator will be measured by the proportion of participants reporting any solicited Adverse Events (AEs) through the final visit on Day 64, compared between study arms.	over 64 days
Number of Participants Willing to Use This Type of Product in the Future	Acceptability of LACTIN-V and the applicator will be measured by standardized questionnaire about acceptability of the study product and participants' stated willingness to use this type of product in the future, in each study arm. (Question "I would use the product again", on Day 36)	over 36 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Aurum Institute; Harvard University; University of KwaZulu; Osel, Inc.; Health Systems Trust
• Investigators: Principal Investigator: Craig R Cohen, MD MPH, University of California, San Francisco

Publications and helpful links

General Publications

• Mitchell C, Manhart LE, Thomas K, Fiedler T, Fredricks DN, Marrazzo J. Behavioral predictors of colonization with Lactobacillus crispatus or Lactobacillus jensenii after treatment for bacterial vaginosis: a cohort study. Infect Dis Obstet Gynecol. 2012;2012:706540. doi: 10.1155/2012/706540. Epub 2012 May 30.
• Gosmann C, Anahtar MN, Handley SA, Farcasanu M, Abu-Ali G, Bowman BA, Padavattan N, Desai C, Droit L, Moodley A, Dong M, Chen Y, Ismail N, Ndung'u T, Ghebremichael MS, Wesemann DR, Mitchell C, Dong KL, Huttenhower C, Walker BD, Virgin HW, Kwon DS. Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women. Immunity. 2017 Jan 17;46(1):29-37. doi: 10.1016/j.immuni.2016.12.013. Epub 2017 Jan 10.
• 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.
• Hemmerling A, Harrison W, Schroeder A, Park J, Korn A, Shiboski S, Cohen CR. Phase 1 dose-ranging safety trial of Lactobacillus crispatus CTV-05 for the prevention of bacterial vaginosis. Sex Transm Dis. 2009 Sep;36(9):564-9. doi: 10.1097/OLQ.0b013e3181a74924.
• Hemmerling A, Harrison W, Schroeder A, Park J, Korn A, Shiboski S, Foster-Rosales A, Cohen CR. Phase 2a study assessing colonization efficiency, safety, and acceptability of Lactobacillus crispatus CTV-05 in women with bacterial vaginosis. Sex Transm Dis. 2010 Dec;37(12):745-50. doi: 10.1097/OLQ.0b013e3181e50026.
• Cohen CR, Duerr A, Pruithithada N, Rugpao S, Hillier S, Garcia P, Nelson K. Bacterial vaginosis and HIV seroprevalence among female commercial sex workers in Chiang Mai, Thailand. AIDS. 1995 Sep;9(9):1093-7. doi: 10.1097/00002030-199509000-00017.
• Mitchell C, Fredricks D, Agnew K, Hitti J. Hydrogen Peroxide-Producing Lactobacilli Are Associated With Lower Levels of Vaginal Interleukin-1beta, Independent of Bacterial Vaginosis. Sex Transm Dis. 2015 Jul;42(7):358-63. doi: 10.1097/OLQ.0000000000000298.
• Ngugi BM, Hemmerling A, Bukusi EA, Kikuvi G, Gikunju J, Shiboski S, Fredricks DN, Cohen CR. Effects of bacterial vaginosis-associated bacteria and sexual intercourse on vaginal colonization with the probiotic Lactobacillus crispatus CTV-05. Sex Transm Dis. 2011 Nov;38(11):1020-7. doi: 10.1097/OLQ.0b013e3182267ac4.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2021
• Primary Completion (Actual): March 31, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 26, 2021

Study Record Updates

• Last Update Posted (Actual): August 13, 2024
• Last Update Submitted That Met QC Criteria: July 18, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: HIV infections; Vaginal microbiome; bacterial Vaginosis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Vaginitis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; HIV Infections; Vaginal Diseases; Vaginosis, Bacterial
• Other Study ID Numbers: LV-007; 1R01HD098978 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes