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| Name | Class |
|---|---|
| Rinda Ubuzima, Rwanda | UNKNOWN |
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A pilot randomized controlled clinical trial of intermittent use of two different vaginal lactobacilli-containing probiotics, and oral metronidazole, to prevent bacterial vaginosis recurrence.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 | No Intervention | Negative control group: After initial treatment for BV/TV, no intervention. | |
| Group 2 | Other | Positive control group: After initial treatment for BV/TV, metronidazole pills (500 mg) twice per week for 2 months. |
|
| Group 3 | Active Comparator | After initial treatment for BV/TV, Ecologic Femi+ vaginal capsule (a vaginal probiotic) once per day for 5 days immediately after the initial treatment followed by thrice weekly for two months. |
|
| Group 4 | Active Comparator | After initial treatment for BV/TV, Gynophilus LP vaginal tablet (a vaginal probiotic) once every 4 days for two months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vaginal multiple lactobacilli-containing probiotic for prevention of BV recurrence | Biological | Vaginal probiotic to restore the vaginal microbiome and prevent BV recurrence after metronidazole treatment for BV or TV |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 2 months (intervention period) |
| 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. | 2 months (intervention period) |
| 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. | 2 months (intervention period) |
| 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. | 6 months: 2 months intervention period plus 4 months after intervention cessation |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 2 months (intervention period) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Janneke H van de Wijgert, PhD | University of Liverpool | Study Chair |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33514681 | Derived | Verwijs MC, Agaba S, Umulisa MM, van de Wijgert JHHM. Feasibility and acceptability of frequent vaginal self-sampling at home by Rwandan women at high risk of urogenital tract infections. Sex Transm Infect. 2022 Feb;98(1):58-61. doi: 10.1136/sextrans-2020-054816. Epub 2021 Jan 29. | |
| 32434932 | Derived | Verwijs MC, Agaba S, Umulisa MM, Uwineza M, Nivoliez A, Lievens E, van de Wijgert JHHM. Vaginal probiotic adherence and acceptability in Rwandan women with high sexual risk participating in a pilot randomised controlled trial: a mixed-methods approach. BMJ Open. 2020 May 19;10(5):e031819. doi: 10.1136/bmjopen-2019-031819. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Control | Behavioral counseling only |
| FG001 | Oral Metronidazole | Oral metronidazole 2-month intermittent use plus counseling |
| FG002 | Ecologic Femi+ | Ecologic Femi+ vaginal probiotic capsule 2-month intermittent use plus counseling |
| FG003 | Gynophilus LP | Gynophilus LP vaginal probiotic tablet 2-month intermittent use plus counseling |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Control | Behavioral counseling only |
| BG001 | Oral Metronidazole | Oral metronidazole 2-month intermittent use plus counseling |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Modified ITT population: all randomized women except women with Nugent 7-10 at enrollment. | Posted | Number | 95% Confidence Interval | Incidence: events per PY at risk | 2 months (intervention period) |
|
6 months: during the 2-month intervention period and up to 4 months after intervention cessation
The definition of adverse events does not differ from the clinicaltrials.gov definitions.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control | Behavioral counseling only | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Typhoid fever | Infections and infestations | MedDRA | Systematic Assessment | A participant was hospitalized with typhoid fever during the study; this occurred after the intervention period. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Burning when passing urine | Renal and urinary disorders | MedDRA (15.0) | Systematic Assessment |
The two most important limitations were the modest sample size (this trial was funded as a pilot trial) and our inability to exclude women with gonorrhea and/or chlamydia infection at the time of randomization (due to slow testing turn-around).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Janneke van de Wijgert, Chief Investigator | University of Liverpool | +447557195108 | j.vandewijgert@liverpool.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 22, 2015 | May 28, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 16, 2016 | May 28, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D016585 | Vaginosis, Bacterial |
| ID | Term |
|---|---|
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D014627 | Vaginitis |
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|
| Prophylactic use of metronidazole pills (500 mg) | Drug | Prophylactic use of metronidazole pills to prevent BV recurrence after metronidazole treatment for BV or TV |
|
|
| Vaginal Lcr35-containing probiotic for prevention of BV recurrence | Biological | Vaginal probiotic to restore the vaginal microbiome and prevent BV recurrence after metronidazole treatment for BV or TV |
|
|
| 2 months (intervention period) |
| 31404542 | Derived | Verwijs MC, Agaba SK, Darby AC, van de Wijgert JHHM. Impact of oral metronidazole treatment on the vaginal microbiota and correlates of treatment failure. Am J Obstet Gynecol. 2020 Feb;222(2):157.e1-157.e13. doi: 10.1016/j.ajog.2019.08.008. Epub 2019 Aug 9. |
| BG002 | Ecologic Femi+ | Ecologic Femi+ vaginal probiotic capsule 2-month intermittent use plus counseling |
| BG003 | Gynophilus LP | Gynophilus LP vaginal probiotic tablet 2-month intermittent use plus counseling |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Exchanged sex for money/goods in past month | Count of Participants | Participants |
|
| Sex partners in the past month | Median | Inter-Quartile Range | sex partners |
|
| OG002 | Ecologic Femi+ | Ecologic Femi+ vaginal probiotic capsules 2-months intermittent use plus counseling |
| OG003 | Gynophilus LP | Gynophilus LP vaginal probiotic tablets 2-months intermittent use plus counseling |
|
|
| 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. | Modified ITT population: All randomized women except women with Nugent 7-10 at enrollment. | Posted | Number | 95% Confidence Interval | Incidence: events per PY at risk | 2 months (intervention period) |
|
|
|
| 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. | All randomized women except one woman in the Gynophilus LP group who withdrew immediately after enrollment. | Posted | Number | 95% Confidence Interval | Incidence: events per PY at risk | 2 months (intervention period) |
|
|
|
| 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. | All randomized women except one woman in the Gynophilus LP group who withdrew immediately after enrollment. | Posted | Number | 95% Confidence Interval | Incidence: events per PY at risk | 6 months: 2 months intervention period plus 4 months after intervention cessation |
|
|
|
| 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). | 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). | Posted | Mean | 95% Confidence Interval | Lactobacillus log10 copies/microliter | 2 months (intervention period) |
|
|
|
| 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. | 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). | Posted | Count of Participants | Participants | 2 months (intervention period) |
|
|
|
| 17 |
| 0 |
| 17 |
| 2 |
| 17 |
| EG001 | Oral Metronidazole | Oral metronidazole 2-months intermittent use plus counseling | 0 | 17 | 1 | 17 | 2 | 17 |
| EG002 | Ecologic Femi+ | Ecologic Femi+ vaginal probiotic capsules 2-months intermittent use plus counseling | 0 | 17 | 1 | 17 | 2 | 17 |
| EG003 | Gynophilus LP | Gynophilus LP vaginal probiotic tablets 2-months intermittent use plus counseling | 0 | 17 | 0 | 17 | 3 | 17 |
|
| Malaria during pregnancy | Infections and infestations | MedDRA (15.0) | Systematic Assessment | A participant was hospitalized with malaria (while pregnant) during the study; this occurred after the intervention period. |
|
| Genital burning | Reproductive system and breast disorders | MedDRA (15.0) | Systematic Assessment |
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| Genital itching | Reproductive system and breast disorders | MedDRA (15.0) | Systematic Assessment |
|
| Pain during sex | Reproductive system and breast disorders | MedDRA (15.0) | Systematic Assessment |
|
| Lower abdominal pain | General disorders | MedDRA (15.0) | Systematic Assessment |
|
| Unusual vaginal discharge | Reproductive system and breast disorders | MedDRA (15.0) | Systematic Assessment |
|
| Sores in the genital and/or anal area | Reproductive system and breast disorders | MedDRA (15.0) | Systematic Assessment |
|
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| D014623 |
| Vaginal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| Overall adherence ≥90% |
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| Overall adherence ≥80% |
|
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| Probiotic insertion as "very comfortable" |
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| Probiotic insertion became easier over time |
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|