Bacterial Vaginosis
Conditions
Brief summary
A pilot randomized controlled clinical trial of intermittent use of two different vaginal lactobacilli-containing probiotics, and oral metronidazole, to prevent bacterial vaginosis recurrence.
Detailed description
This is a pilot study to prepare for larger clinical trials. Sixty-eight HIV-negative, non-pregnant, sexually active women aged 18-45 with bacterial vaginosis (BV, by modified Amsel criteria and/or Nugent score) and/or Trichomonas vaginalis (TV, on wet mount or by culture) will be treated using oral metronidazole for 7 days. After successful treatment, and when they are free of vaginal candidiasis, other curable sexually transmitted infections (STIs) and urinary tract infection (UTI)), they will be randomised to 4 different vaginal microbiome (VMB) maintenance interventions (17 per group) within 3 days of completing oral metronidazole treatment: 1) Behavioral 'vaginal practices cessation and safer sex' counselling only (control); 2) Behavioral counselling plus 500mg metronidazole pills twice per week for two months; 3) Behavioral counselling plus Ecologic Femi vaginal capsule, once per day for 5 days immediately after oral metronidazole treatment followed by thrice weekly, for two months; 4) Group 4: Behavioral counselling plus Gynophilus vaginal tablet, once every 4 days for two months. Vaginal probiotic use may be ceased temporarily during menstruation. Participants will be asked to adhere to the interventions for 2 months, and VMB assessments will take place before (screening and enrolment visits), during (Day 7, Month 1 and Month 2 visits), and after the interventions (Month 6 visit).
Interventions
BIOLOGICALVaginal multiple lactobacilli-containing probiotic for prevention of BV recurrence
Vaginal probiotic to restore the vaginal microbiome and prevent BV recurrence after metronidazole treatment for BV or TV
DRUGProphylactic use of metronidazole pills (500 mg)
Prophylactic use of metronidazole pills to prevent BV recurrence after metronidazole treatment for BV or TV
BIOLOGICALVaginal Lcr35-containing probiotic for prevention of BV recurrence
Vaginal probiotic to restore the vaginal microbiome and prevent BV recurrence after metronidazole treatment for BV or TV
Sponsors
Rinda Ubuzima, Rwanda
Janneke van de Wijgert
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Sexually active, defined as having had sex at least twice in the two weeks prior to screening * At high risk of HIV/STIs/BV, defined as having had more than one sexual partner in the last 12 months OR having been treated for an STI and/or BV in the last 12 months * Successfully treated for BV (modified Amsel criteria) or TV (wet mount), and free of STIs, symptomatic vaginal candidiasis and UTI at enrollment * Currently in good physical and mental health as judged by a study physician * Willing and able to adhere to study procedures and provide written informed consent.
Exclusion criteria
* Pregnant * HIV positive * Clinician-observed genital ulcers, condylomata, or other genital abnormalities at screening or enrollment * Underwent a gynaecological surgery/invasive procedure in the 3 months prior to screening * History of significant urogenital prolapse, undiagnosed vaginal bleeding, urine or faecal incontinence, or blood clotting disorders * Allergic to metronidazole or any other components of the study drugs * Not willing to stop use of other oral or vaginal probiotics from the screening visit until the end of study participation * Participating in another health intervention study * For any other reason potentially interfering with participant safety or protocol adherence as judged by the Principal Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria | 2 months (intervention period) | Modified Amsel criteria positive is at least 2 of 3 of the following positive: clue cells, vaginal pH, whiff test. Modified intent-to-treat (ITT) analyses (women with Nugent 7-10 at enrollment excluded), using person-years (PY) at risk as denominator of each incidence rate. |
| Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10) | 2 months (intervention period) | The Nugent score is a scale from 0-10 based on visualisation of three different bacterial morphotypes on a Gram stained slide, but in the incidence rates, the variable was used as a binary variable: BV present (Nugent score 7-10) or absent (Nugent score 0-6). Modified intent-to-treat (ITT) analyses (women with Nugent 7-10 at enrollment excluded), using person-years (PY) at risk as the denominator for each incidence rate. |
| Trichomonas Vaginalis (TV) Incidence by Culture | 2 months (intervention period) | A swab was inoculated into an InPouch culture pouch, specifically designed for TV growth. The pouch was checked daily for five days to detect growth. The results was positive when growth detected and negative when no growth detected on the fifth day. Intent-to-treat (ITT) analyses, using person-years (PY) at risk as the denominator for each incidence rate. |
| Vaginal Candidiasis Incidence by Wet Mount Microscopy | 6 months: 2 months intervention period plus 4 months after intervention cessation | A wet mount is a smear of vaginal fluid on a microscopy slide, which is examined under a microscope. Yeasts are visible without staining. The definition of vaginal candidiasis was any yeast visible on the wet mount. Symptomatic vaginal candidiasis was considered a safety outcome because treatment of bacterial vaginosis often results in vaginal candidiasis. Intent-to-treat (ITT) analysis with person-years (PY) at risk as the denominator of all incidence rates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration | 2 months (intervention period) | The vaginal microbiota sequencing results are exploratory and full data can be found in a manuscript on the BioRxiv preprint server. The most important outcome is the concentration of Lactobacillus genus in vaginal samples taken at the end of the intervention period (M2 visit). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | 2 months (intervention period) | Full results have been submitted for publication. Adherence was measured at D7, M1, and M2 visits, and a summary measure over the entire period was calculated (available for women using oral metronidazole, Ecologic Femi+, or Gynophilus LP). After the 2-month intervention period, women using vaginal probiotics (Ecologic Femi+ or Gynophilus LP) were asked structured questions about their experiences with product use. |
Participant flow
Recruitment details
The target population was women at high risk of urogenital infections living in Kigali, Rwanda. Recruitment activities were implemented by study staff with the help of Community Mobilizers, who were selected due to their strong connections with high-risk women in Kigali. They helped staff organize recruitment meetings in relevant communities.
Pre-assignment details
At the end of the screening process, women were either ineligible or diagnosed with bacterial vaginosis (by modified Amsel criteria and/or Nugent score) and/or trichomoniasis (by culture or wet mount) and treated with 500 mg oral metronidazole 2x/day for 7 days. An enrollment visit was scheduled within three days after treatment completion.
Participants by arm
| Arm | Count |
|---|---|
| Control Behavioral counseling only | 17 |
| Oral Metronidazole Oral metronidazole 2-month intermittent use plus counseling | 17 |
| Ecologic Femi+ Ecologic Femi+ vaginal probiotic capsule 2-month intermittent use plus counseling | 17 |
| Gynophilus LP Gynophilus LP vaginal probiotic tablet 2-month intermittent use plus counseling | 17 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Control | Oral Metronidazole | Ecologic Femi+ | Gynophilus LP |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 17 Participants | 17 Participants | 17 Participants | 17 Participants |
| Age, Continuous | 31 years | 29 years | 30 years | 33 years | 31 years |
| Exchanged sex for money/goods in past month | 63 Participants | 17 Participants | 14 Participants | 15 Participants | 17 Participants |
| Race/Ethnicity, Customized African (Rwandan) | 68 Participants | 17 Participants | 17 Participants | 17 Participants | 17 Participants |
| Region of Enrollment Rwanda | 68 Participants | 17 Participants | 17 Participants | 17 Participants | 17 Participants |
| Sex: Female, Male Female | 68 Participants | 17 Participants | 17 Participants | 17 Participants | 17 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex partners in the past month | 5 sex partners | 5 sex partners | 5 sex partners | 3 sex partners | 3 sex partners |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 2 / 17 | 2 / 17 | 2 / 17 | 3 / 17 |
| serious Total, serious adverse events | 0 / 17 | 1 / 17 | 1 / 17 | 0 / 17 |
Outcome results
Primary
Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria
Modified Amsel criteria positive is at least 2 of 3 of the following positive: clue cells, vaginal pH, whiff test. Modified intent-to-treat (ITT) analyses (women with Nugent 7-10 at enrollment excluded), using person-years (PY) at risk as denominator of each incidence rate.
Time frame: 2 months (intervention period)
Population: Modified ITT population: all randomized women except women with Nugent 7-10 at enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria | 7.53 Incidence: events per PY at risk |
| Oral Metronidazole | Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria | 2.04 Incidence: events per PY at risk |
| Ecologic Femi+ | Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria | 3.36 Incidence: events per PY at risk |
| Gynophilus LP | Bacterial Vaginosis (BV) Incidence by Modified Amsel Criteria | 3.35 Incidence: events per PY at risk |
Primary
Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10)
The Nugent score is a scale from 0-10 based on visualisation of three different bacterial morphotypes on a Gram stained slide, but in the incidence rates, the variable was used as a binary variable: BV present (Nugent score 7-10) or absent (Nugent score 0-6). Modified intent-to-treat (ITT) analyses (women with Nugent 7-10 at enrollment excluded), using person-years (PY) at risk as the denominator for each incidence rate.
Time frame: 2 months (intervention period)
Population: Modified ITT population: All randomized women except women with Nugent 7-10 at enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10) | 10.18 Incidence: events per PY at risk |
| Oral Metronidazole | Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10) | 1.41 Incidence: events per PY at risk |
| Ecologic Femi+ | Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10) | 3.58 Incidence: events per PY at risk |
| Gynophilus LP | Bacterial Vaginosis (BV) Incidence by Nugent Scoring (Nugent 7-10) | 5.36 Incidence: events per PY at risk |
Primary
Trichomonas Vaginalis (TV) Incidence by Culture
A swab was inoculated into an InPouch culture pouch, specifically designed for TV growth. The pouch was checked daily for five days to detect growth. The results was positive when growth detected and negative when no growth detected on the fifth day. Intent-to-treat (ITT) analyses, using person-years (PY) at risk as the denominator for each incidence rate.
Time frame: 2 months (intervention period)
Population: All randomized women except one woman in the Gynophilus LP group who withdrew immediately after enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Trichomonas Vaginalis (TV) Incidence by Culture | 1.10 Incidence: events per PY at risk |
| Oral Metronidazole | Trichomonas Vaginalis (TV) Incidence by Culture | 0 Incidence: events per PY at risk |
| Ecologic Femi+ | Trichomonas Vaginalis (TV) Incidence by Culture | 0 Incidence: events per PY at risk |
| Gynophilus LP | Trichomonas Vaginalis (TV) Incidence by Culture | 0 Incidence: events per PY at risk |
Primary
Vaginal Candidiasis Incidence by Wet Mount Microscopy
A wet mount is a smear of vaginal fluid on a microscopy slide, which is examined under a microscope. Yeasts are visible without staining. The definition of vaginal candidiasis was any yeast visible on the wet mount. Symptomatic vaginal candidiasis was considered a safety outcome because treatment of bacterial vaginosis often results in vaginal candidiasis. Intent-to-treat (ITT) analysis with person-years (PY) at risk as the denominator of all incidence rates.
Time frame: 6 months: 2 months intervention period plus 4 months after intervention cessation
Population: All randomized women except one woman in the Gynophilus LP group who withdrew immediately after enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Vaginal Candidiasis Incidence by Wet Mount Microscopy | 0 Incidence: events per PY at risk |
| Oral Metronidazole | Vaginal Candidiasis Incidence by Wet Mount Microscopy | 0 Incidence: events per PY at risk |
| Ecologic Femi+ | Vaginal Candidiasis Incidence by Wet Mount Microscopy | 0 Incidence: events per PY at risk |
| Gynophilus LP | Vaginal Candidiasis Incidence by Wet Mount Microscopy | 0 Incidence: events per PY at risk |
Secondary
Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration
The vaginal microbiota sequencing results are exploratory and full data can be found in a manuscript on the BioRxiv preprint server. The most important outcome is the concentration of Lactobacillus genus in vaginal samples taken at the end of the intervention period (M2 visit).
Time frame: 2 months (intervention period)
Population: All randomized women except for one woman in Gynophilus LP who withdrew immediately after enrollment, using lactobacillus concentration in log10 copies per microliter at the M2 visit (at the time of intervention cessation).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration | 3.86 Lactobacillus log10 copies/microliter |
| Oral Metronidazole | Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration | 5.21 Lactobacillus log10 copies/microliter |
| Ecologic Femi+ | Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration | 5.30 Lactobacillus log10 copies/microliter |
| Gynophilus LP | Vaginal Microbiota Composition by Illumina HiSeq Sequencing: Lactobacillus Genus Concentration | 4.68 Lactobacillus log10 copies/microliter |
Other Pre-specified
Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview
Full results have been submitted for publication. Adherence was measured at D7, M1, and M2 visits, and a summary measure over the entire period was calculated (available for women using oral metronidazole, Ecologic Femi+, or Gynophilus LP). After the 2-month intervention period, women using vaginal probiotics (Ecologic Femi+ or Gynophilus LP) were asked structured questions about their experiences with product use.
Time frame: 2 months (intervention period)
Population: Adherence data are available for all randomized women except one woman in the Gynophilus LP group who withdrew immediately after enrollment. Acceptability data are available for all women randomized to the two vaginal probiotics groups except two women in the Gynophilus LP group (another woman withdrew prior to the Month 2 visit).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Perfect (100%) overall adherence | 12 Participants |
| Control | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥90% | 14 Participants |
| Control | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥80% | 15 Participants |
| Oral Metronidazole | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥90% | 15 Participants |
| Oral Metronidazole | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Probiotic insertion as very comfortable | 17 Participants |
| Oral Metronidazole | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥80% | 17 Participants |
| Oral Metronidazole | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Perfect (100%) overall adherence | 10 Participants |
| Oral Metronidazole | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Probiotic insertion became easier over time | 17 Participants |
| Ecologic Femi+ | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Perfect (100%) overall adherence | 8 Participants |
| Ecologic Femi+ | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥90% | 11 Participants |
| Ecologic Femi+ | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Probiotic insertion became easier over time | 15 Participants |
| Ecologic Femi+ | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Overall adherence ≥80% | 13 Participants |
| Ecologic Femi+ | Feasibility/Acceptability of Vaginal Probiotic Use by Structured Face-to-face Interview | Probiotic insertion as very comfortable | 15 Participants |