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.

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.

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.