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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Bacterial Vaginosis, HIV Infections

Intervention / Treatment
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* Drug: LACTIN-V
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FRESH study participant. 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 HIV-negative Nugent score 4-10 on vaginal Gram stain Otherwise healthy women, 18-23 years of age on the day of enrolment Regular predictable menstrual cycles or amenorrhoeic for at least 3 months due to use of a long-acting progestin. Willing to complete 7-day course of oral metronidazole. Willing to be asked questions about personal medical health and sexual history Willing to apply study agent vaginally and comply with study examinations Willing to self-administer Study Product on dosing days that do not coincide with regular FRESH study visits. 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). 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. 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. 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: 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. 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. Subject is ineligible if menstrual cycle length is less than 21 days Subject is ineligible if deep epithelial disruption is observed on genital examination noted on or before the Randomization Visit Positive for HIV (as tested during the FRESH Week 5 Study Visit, within 30 days of the LACTIN-V Enrolment Visit). Current pregnancy or within 2 months of last pregnancy Vaginal or systemic antibiotic or antifungal therapy within 21 days of enrolment Use of disulfiram within past 2 weeks or other contraindication to use of metronidazole Any condition requiring regular periodic use of systemic antibiotics during participation in the trial Investigational drug use other than LACTIN-V within 30 days or 10 half- lives of the drug, whichever is longer, of Enrolment Visit Other planned participation in an investigational drug study while participating in this study Intrauterine device (IUD) insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser treatment within the last 2 months prior to enrolment Use of vaginal ring (e.g, NuvaRing) within 3 days of enrolment or during the course of the study Hysterectomy 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) 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) Known allergy to any component of LACTIN-V/placebo or metronidazole or to nitroimidazole derivatives or latex (condoms) 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 Any serious or chronic illness, deemed incompatible with study participation by the study doctor, including immunosuppression due to cancer chemotherapy, systemic corticosteroids.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 23 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: We will conduct a randomized, placebo-controlled trial of the vaginal live biotherapeutic product LACTIN-V in 60 young South African women, randomizing women 2:1 to LACTIN-V vs. placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LACTIN-V<br>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<br>* administered vaginally<br>* Other names: Lactobacillus crispatus CTV-05;|
| Placebo Comparator: Placebo<br>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<br>* administered vaginally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the effect of repeat dosing of LACTIN-V (2 x 109 cfu/dose) on genital tract inflammation in young South African women at risk of HIV. | 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 Our 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). | over 64 days | 
| Determine the ability of LACTIN-V to promote a Lactobacillus-dominant vaginal microbiota in young South African women at risk of HIV. | The proportion of participants with increased Lactobacillus-dominant vaginal microbiota in young South African women, compared to levels at randomization (Day 8) after completion of metronidazole. Measured will be overall Lactobacillus species, as well as Lactobacillus crispatus, Lactobacillus jensenii, Lactobacillus gasseri, and Lactobacillus iners. Our primary outcome is the presence of Lactobacillus-dominant vaginal microbial cervico-types after 4 weeks of treatment with LACTIN-V, and following the post- dosing phase at Day 64. | over 64 days | 
| Determine the ability of LACTIN-V for vaginal colonization of L. crispatus CTV-05 in young South African women at risk of HIV. | 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. | over 64 days | 
| Determine the ability of LACTIN-V for preventing bacterial vaginosis in young South African women at risk of HIV. | The proportion of participants with a positive Bacterial Vaginosis (BV) diagnosis in each study arm by Day 64. | over 64 days | 
| Determine the safety of LACTIN-V in a population of young South African women at risk for HIV. | Safety of LACTIN-V and the applicator will be measured by: The proportion of participants reporting product-related Adverse Events (AEs) and Serious Adverse Events (SAEs) through the final visit that are likely related to use of study product compared by study arm, in particular Grade 3 AEs and SAEs. | over 64 days | 
| Determine the acceptability of LACTIN-V in a population of young South African women at risk for HIV. | 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. | over 64 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vaginal microbiome, bacterial Vaginosis, HIV infections