Bacterial Vaginosis, HIV Infections
Conditions
Keywords
Vaginal microbiome, bacterial Vaginosis, HIV infections
Brief summary
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
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.
Interventions
DRUGLACTIN-V
administered vaginally
DRUGPlacebo
administered vaginally
Sponsors
University of KwaZulu
Harvard University
Aurum Institute
Health Systems Trust
Osel, Inc.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 23 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Lactobacillus-dominant Vaginal Microbiota | over 64 days | 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). |
| Number of Participants With Genital Tract Inflammation | over 64 days | 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. |
| Number of Participants With Vaginal Colonization of L. Crispatus CTV-05 | over 64 days | 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). |
| Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain | over 64 days | 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. |
| Number of Participants Reporting Any Solicited Adverse Events (AEs) Through the Final Visit | over 64 days | 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. |
| Number of Participants Willing to Use This Type of Product in the Future | over 36 days | 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) |
Countries
South Africa
Participant flow
Pre-assignment details
45 were randomized to study product. 8 became then ineligible for randomization for the following reasons: * Not completing metronidazole course (n=1) * Acute UTI, STD, or vaginal infection besides BV (n=2) * Any condition requiring use of systemic antibiotics during the trial (n=2) * floods impacting on site access (n=2) * site disruption because of social unrest (n=1)
Participants by arm
| Arm | Count |
|---|---|
| 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.
LACTIN-V: administered vaginally | 32 |
| 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.
Placebo: administered vaginally | 13 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | LACTIN-V | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 13 Participants | 45 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 13 Participants | 45 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 32 participants | 13 participants | 45 participants |
| Sex: Female, Male Female | 32 Participants | 13 Participants | 45 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Vaginal Gram Stain with Nugent Score 4-10 | 32 participants | 13 participants | 45 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 13 |
| other Total, other adverse events | 26 / 32 | 9 / 13 |
| serious Total, serious adverse events | 0 / 32 | 0 / 13 |
Outcome results
Primary
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.
Time frame: over 64 days
Population: All 45 participants are included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LACTIN-V | Number of Participants Reporting Any Solicited Adverse Events (AEs) Through the Final Visit | 26 Participants |
| Placebo | Number of Participants Reporting Any Solicited Adverse Events (AEs) Through the Final Visit | 9 Participants |
Primary
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)
Time frame: over 36 days
Population: Available acceptability data at Day 36: LACTIN-V n=30, Placebo n=13. Missing data from two participants in the LACTIN-V group.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LACTIN-V | Number of Participants Willing to Use This Type of Product in the Future | agree | 11 Participants |
| LACTIN-V | Number of Participants Willing to Use This Type of Product in the Future | disagree | 2 Participants |
| LACTIN-V | Number of Participants Willing to Use This Type of Product in the Future | strongly agree | 11 Participants |
| LACTIN-V | Number of Participants Willing to Use This Type of Product in the Future | strongly disagree | 1 Participants |
| LACTIN-V | Number of Participants Willing to Use This Type of Product in the Future | neutral | 5 Participants |
| Placebo | Number of Participants Willing to Use This Type of Product in the Future | strongly disagree | 0 Participants |
| Placebo | Number of Participants Willing to Use This Type of Product in the Future | agree | 7 Participants |
| Placebo | Number of Participants Willing to Use This Type of Product in the Future | neutral | 3 Participants |
| Placebo | Number of Participants Willing to Use This Type of Product in the Future | disagree | 0 Participants |
| Placebo | Number of Participants Willing to Use This Type of Product in the Future | strongly agree | 3 Participants |
Primary
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.
Time frame: over 64 days
Population: Available samples at baseline and Day 64: LACTIN-V n=30, Placebo n=11. The comparison of the LACTIN-V vs. placebo arms was performed on a modified Intent to Treat (mITT) population, excluding one placebo participant who was erroneously dispensed two doses of LACTIN-V.~Additionally, missing samples at Day 64 from two participants in the LACTIN-V group and one participant in the placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LACTIN-V | Number of Participants With Genital Tract Inflammation | 3 Participants |
| Placebo | Number of Participants With Genital Tract Inflammation | 2 Participants |
Primary
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).
Time frame: over 64 days
Population: The comparison of the LACTIN-V vs. placebo arms was performed on a modified Intent to Treat (mITT) population, excluding one placebo participant who was erroneously dispensed two doses of LACTIN-V.~Available samples at Day 36: LACTIN-V n=32, Placebo n=12. Available samples at Day 64: LACTIN-V n=31, Placebo n=11.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LACTIN-V | Number of Participants With Lactobacillus-dominant Vaginal Microbiota | L. crispatus dominant vaginal bacterial community (> 50% relative abundance) on Day 36 | 13 Participants |
| LACTIN-V | Number of Participants With Lactobacillus-dominant Vaginal Microbiota | L. crispatus dominant vaginal bacterial community (> 50% relative abundance) on Day 64 | 8 Participants |
| Placebo | Number of Participants With Lactobacillus-dominant Vaginal Microbiota | L. crispatus dominant vaginal bacterial community (> 50% relative abundance) on Day 36 | 0 Participants |
| Placebo | Number of Participants With Lactobacillus-dominant Vaginal Microbiota | L. crispatus dominant vaginal bacterial community (> 50% relative abundance) on Day 64 | 1 Participants |
Primary
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).
Time frame: over 64 days
Population: The comparison of the LACTIN-V vs. placebo arms was performed on a modified Intent to Treat (mITT) population, excluding one placebo participant who was erroneously dispensed two doses of LACTIN-V.~Additionally, at Day 64 a missing sample from one participant in the placebo group.~Available samples at Day 36: LACTIN-V n=32, Placebo n=12. Available samples at Day 64: LACTIN-V n=32, Placebo n=11.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LACTIN-V | Number of Participants With Vaginal Colonization of L. Crispatus CTV-05 | Detection of L. crispatus CTV-05 at Day 36 | 22 Participants |
| LACTIN-V | Number of Participants With Vaginal Colonization of L. Crispatus CTV-05 | Detection of L. crispatus CTV-05 at Day 64 | 15 Participants |
| Placebo | Number of Participants With Vaginal Colonization of L. Crispatus CTV-05 | Detection of L. crispatus CTV-05 at Day 36 | 1 Participants |
| Placebo | Number of Participants With Vaginal Colonization of L. Crispatus CTV-05 | Detection of L. crispatus CTV-05 at Day 64 | 1 Participants |
Primary
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.
Time frame: over 64 days
Population: The comparison of the LACTIN-V vs. placebo arms was performed on a modified Intent to Treat (mITT) population, excluding one placebo participant who was erroneously dispensed two doses of LACTIN-V.~Additionally, at Day 36 a missing sample from one participant in the LACTIN-V group.~Available samples at Day 36: LACTIN-V n=31, Placebo n=12. Available samples at Day 64: LACTIN-V n=32, Placebo n=12.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LACTIN-V | Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain | Nugent Score 4-10 on Vaginal Gram Stain at Day 36 | 12 Participants |
| LACTIN-V | Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain | Nugent Score 4-10 on Vaginal Gram Stain at Day 64 | 15 Participants |
| Placebo | Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain | Nugent Score 4-10 on Vaginal Gram Stain at Day 36 | 6 Participants |
| Placebo | Number of Participants With Vaginal Dysbiosis Indicated by a Nugent Score 4-10 on Vaginal Gram Stain | Nugent Score 4-10 on Vaginal Gram Stain at Day 64 | 6 Participants |