Title: A randomised controlled trial to assess the clinical and cost effectiveness of topical lactic acid gel for treating second and subsequent episodes of bacterial vaginosis
Funder: Department of Health and Social Care

Abstract: Target Population Women with symptoms of bacterial vaginosis (BV) and at least one similar episode which responded to BV treatment within the previous 2 years. Health Technologies The health technology is intravaginal lactic acid gel. Previous small studies have reported inconsistent results - efficacy of 18-100%. The regimen used most commonly in previous trials is once daily application for one week and increased dosing did not affect the response rate (efficacy 23-93% for once/day cf. 18-100% for twice/day). To permit comparison with previous trials, maximise participant acceptability and because the effectiveness of this regimen remains unconfirmed we propose using lactic acid gel inserted intravaginally once a day for 7 days. The control group will receive a 7 day course of twice daily oral metronidazole. This has been chosen as the comparator because it is active against anaerobic bacteria associated with BV, commonly used in clinical practice, supported by evidence from randomised controlled trials and recommended as first line therapy in the UK treatment guideline for BV. Measurement of Costs and Outcomes The primary outcome measure is resolution of bacterial vaginosis based on participant reported symptoms at 2 weeks. Secondary outcome measures are the time to first recurrence of BV (recorded in a participant diary), frequency of BV symptoms over 26 weeks (recorded in participant diary), frequency of BV treatment over 26 weeks (recorded in participant diary), microbiological resolution of BV on microscopy (using Hay Ison assessment criteria), adverse events (assessed via participant reporting), tolerability of treatment (using a visual analogue scale measure and participant interview), adherence to treatment (using reporting of missed doses and participant interview), quality of life (using SF-12 questionnaire), cost effectiveness (cost per case successfully treated and cost per QALY) and concurrent sexually transmitted infections (laboratory testing for chlamydia, gonorrhoea and trichomonas). Sample size The trial is powered to detect an absolute risk difference of 6% in the treatment response between the two groups. 1710 participants (855 in each group) will provide 90% power with a two sided alpha of 5%, assuming resolution of symptoms for 80% of participants allocated to oral metronidazole (based on published trials and cohorts). To allow for non-collection of the primary outcome of up to 10%, a total of 1900 participants will be recruited. Project timetable Month: 0-6: Set Up 7-33: Recruitment - projected recruitment is 78 participants per month (average 4/month for each sexual health clinic and 0.7/month (8-9/year) for each primary care centre). Recruitment will be for 27 months including an allowance for the phased initiation of sites before recruitment reaches full capacity. This estimate is based on a retrospective case record review at both sexual health clinics and primary care centres, and our previous experience. It assumes that 30% of eligible participants give consent. 13: Feasibility Assessment – based on number of participants completing their Week 2 assessment and adherence to lactic acid gel against pre-defined targets. 34-40: Follow Up 41-45: Analysis and Reporting Expertise The team have experience in delivering clinical trials in primary and secondary care, laboratory evaluation, clinical management of BV, qualitative assessment, statistics and economic evaluation

Lay abstract: Bacterial vaginosis (BV) is a common condition in women which causes a discharge from the vagina, often with an unpleasant fishy smell. This is embarrassing and often distressing. It is also associated with developing more generalised pelvic infection, the occurrence of complications in pregnancy (including miscarriage and premature delivery) and an increased risk of catching and passing on HIV. It affects 30-50% of women at some time in their lives and although it can often be treated with antibiotics, it comes back again within a few months in about a third of women who then require repeated courses of antibiotic treatment. The exact cause of BV is not known but it is associated with a change in the type of bacteria in the vagina with a reduction in ‘lactobacilli’ and an increase in ‘anaerobic bacteria’. In women without BV, lactobacilli make lactic acid which prevents the growth of anaerobic bacteria but in BV (when the lactobacilli numbers decrease) the vagina is less acid than usual. The increased number of anaerobic bacteria produce various chemicals which cause inflammation and an unpleasant smell. The aim of this trial is to see if using lactic acid gel in the vagina to ‘replace’ the vaginal acidity can treat BV. Some previous studies have suggested that this approach could be successful but they are not conclusive and current guidelines highlight a need for more information before recommending the use of intravaginal lactic acid gel. The study will be undertaken in women presenting with symptoms of BV and who also have a history of at least one previously treated episode of BV in the past 2 years. Women will be randomly allocated to put lactic acid gel into the vagina every day for a week or to take metronidazole tablets twice daily for a week. This will allow a direct comparison of the two treatments. The main outcome of the trial is whether the BV symptoms get better a week after finishing therapy. Other outcomes that will be measured are how long until the next episode of BV occurs, how frequently BV recurs over the next 6 months, any side effects of the treatment, whether BV resolves using a microscope test, how much the treatment costs, whether it is taken correctly, whether any sexually transmitted infections are present, and overall quality of life. We will also interview some of the women to ask how easy they found using the treatments. The study will be large enough to detect a difference of 6% in the cure rate between lactic acid gel and metronidazole tablets (based on an estimated 80% of women responding to oral metronidazole). To allow for up to 10% of women being lost to follow up, a total of 1900 women will be recruited. The study will take 45 months to complete, including set up, recruitment of patients, follow up, data analysis and writing the final report. It will include a formal assessment of recruitment after the first 6 months to ensure that it is on target and likely to achieve its objectives, with the option to add further recruitment sites if necessary. The research team has expertise in running clinical studies and in managing women with recurrent BV. Two patient members will join an independent steering committee to provide input into the management of the study. The results of the trial will be reported at medical conferences, sent to BV guideline writing groups and sent to participants who take part in the trial.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION