Rwanda Vaginal Microbiota Restoration Study (VMB)

Preparing for a Clinical Trial of Interventions to Maintain Normal Vaginal Microbiota for Preventing Adverse Reproductive Health Outcomes in Africa

A pilot randomized controlled clinical trial of intermittent use of two different vaginal lactobacilli-containing probiotics, and oral metronidazole, to prevent bacterial vaginosis recurrence.

Study Overview

• Status: Completed
• Conditions: Bacterial Vaginosis
• Intervention / Treatment: Drug: Prophylactic use of metronidazole pills (500 mg); Biological: Vaginal multiple lactobacilli-containing probiotic for prevention of BV recurrence; Biological: Vaginal Lcr35-containing probiotic for prevention of BV 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).

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Group 1; Negative control group: After initial treatment for BV/TV, no intervention.
Other: Group 2; Positive control group: After initial treatment for BV/TV, metronidazole pills (500 mg) twice per week for 2 months.	Drug: Prophylactic use of metronidazole pills (500 mg); Prophylactic use of metronidazole pills to prevent BV recurrence after metronidazole treatment for BV or TV; Other Names: Tricozole
Active Comparator: Group 3; 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.	Biological: Vaginal 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; Other Names: Ecologic Femi+ vaginal capsule
Active Comparator: Group 4; After initial treatment for BV/TV, Gynophilus LP vaginal tablet (a vaginal probiotic) once every 4 days for two months.	Biological: Vaginal 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; Other Names: Gynophilus LP vaginal tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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)

Other Outcome Measures

Outcome Measure	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.	2 months (intervention period)

Collaborators and Investigators

• Sponsor: Janneke van de Wijgert
• Collaborators: Rinda Ubuzima, Rwanda
• Investigators: Study Chair: Janneke H van de Wijgert, PhD, University of Liverpool

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2015
• Primary Completion (Actual): February 23, 2016
• Study Completion (Actual): August 6, 2018

Study Registration Dates

• First Submitted: May 21, 2015
• First Submitted That Met QC Criteria: May 28, 2015
• First Posted (Estimate): June 2, 2015

Study Record Updates

• Last Update Posted (Actual): July 16, 2019
• Last Update Submitted That Met QC Criteria: June 21, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Vaginal Diseases; Vaginitis; Vaginosis, Bacterial; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: RETH000828