Title: Is the naturally occurring prebiotic Lactoferrin an acceptable alternative to antibiotic tablets for women with bacterial vaginosis or thrush? The LISA (Lactoferrin InStead of Antibiotics) randomised feasibility trial
Funder: Department of Health and Social Care

Abstract: Research Question: Is it feasible to conduct a future trial to investigate if Lactoferrin is an acceptable alternative to oral antibiotics/antifungals for women with bacterial vaginosis or thrush? Background Over 200,000 women are affected by bacterial vaginosis (BV) or vaginal candida/thrush each year in England. A million women suffer recurrent infections which many find distressing. The infections may also be associated with HIV infection and adverse pregnancy outcomes. Although BV and candida can be treated with oral antibiotics/antifungals, these can have side effects and encourage the development of antimicrobial resistance, a major global health problem. Lactoferrin is a naturally occurring prebiotic protein present in the vagina where it helps to prevent infections and normalise the vaginal microbiome. It has been used to treat refractory BV and may also be effective against candida, but more evidence is needed. Objective To see if it is feasible to conduct a future, definitive trial in women with BV or candida to investigate if vaginal lactoferrin pessaries are as effective as oral antibiotics in resolving symptoms, preventing recurrent infection and producing a healthy lactobacilli-dominated vaginal microbiome. Design: open label randomised feasibility study over 12 weeks with qualitative, economic and microbiological evaluations. Setting: two sexual health clinics and a general practice Population 114 women with genitourinary symptoms and BV (n=57) or candida (n=57) confirmed on vaginal Gram stain. After completing questionnaires and providing self-taken vaginal samples women will be randomly allocated 2:1 into intervention or control groups. All women will be followed up with repeat samples and text/online questionnaires after 1,2,3,4 and 12 weeks. Intervention 38 women with BV and 38 women with candida will be given vaginal 300mg lactoferrin pessaries to insert nightly for 21 nights Comparator 19 women with BV will be given metronidazole 400mg twice daily for 5-days, and 19 women with candida will be given a fluconazole 150mg capsule. Outcomes Acceptability of vaginal lactoferrin - from questionnaires, and interviews Adherence to treatment (from participants weekly count of remaining pessaries/tablets) Recruitment rate and willingness of women to be randomised Follow-up rate Acceptability of study procedures such as providing vaginal samples and responding to texts about symptoms. Adverse events Estimate of the cost of lactoferrin and the feasibility of obtaining data on healthcare use Rate of resolution of symptoms and/or restoration of a healthy lactobacilli-dominated vaginal microbiome (from questionnaires and microbiological analyses) to inform the design of a future definitive trial. Timetable (months) 1-2 set-up 3-14 recruit 114 women and randomise 2:1 to lactoferrin/standard treatment 6-19 12-week follow-up in clinic 11-20 qualitative evaluation 13-20 statistical/cost/microbiome analyses 18-23 reports/dissemination Impact/Dissemination Study findings will be published in high impact journals and widely publicised. If progression criteria are met, (lactoferrin is acceptable to &ge;70% of women, recruitment rate&ge;50%, follow-up &ge;70%,) this could lead to a definitive trial which confirms that treating BV/candida with lactoferrin is an acceptable, effective, safe and cost-effective alternative to antibiotics. This could benefit women by reducing their use of antibiotics, preventing recurrent infections and decreasing the spread of antimicrobial resistance.

Lay abstract: Three-quarters of women have bacterial vaginosis (BV) or vaginal thrush/candida yeast infection at least once during their lifetime. Symptoms can include abnormal vaginal discharge, soreness, itching and an unpleasant smell. BV during pregnancy can make the baby come too early. In the UK over a million women suffer recurrent vaginal infections. These can affect their sexual relationships and quality of life, and may need repeated courses of treatment. But some women prefer not to keep taking antibiotics which can have side effects and encourage the growth of resistant superbugs. Lactoferrin is a harmless prebiotic protein derived from cow s milk. Women also have naturally occurring lactoferrin in their vagina where it helps to prevent infections and encourage the growth of healthy bacteria. Recent research suggests lactoferrin may be an effective treatment for BV and thrush, but this needs to be confirmed. Aim To see if it is feasible to conduct a future trial to prove whether lactoferrin vaginal pessaries are an acceptable, effective and cost-effective alternative to antibiotic tablets for women with BV or thrush. What we will do We will recruit a total of 57 women with BV and 57 with thrush from two sexual health clinics and a general practice. We will ask women to provide self-taken vaginal samples with a cotton bud, and to complete a confidential sexual-health questionnaire. Then the women will be divided into two groups. One group will be given lactoferrin vaginal pessaries to use every night for 3-weeks. The other group will be given antibiotic tablets. All women will be asked to provide repeat vaginal samples at home and text us about any symptoms so we can see if the treatment works, if the infection comes back and if they would like antibiotics. After 12-weeks all women will be invited back for a final check-up and given &pound;30. We will measure: Acceptability and use of vaginal lactoferrin - from questionnaires, and interviews with 15-20 women Recruitment and follow-up rates Cost of lactoferrin treatment The percentage of women in each group who report their symptoms have resolved after a week How quickly infections clear or recur - from analysis of samples Patient involvement Eight women with BV/thrush helped design the study. They said vaginal infections can be distressing and spoil your sex life. They thought many women would prefer to try a natural treatment instead of antibiotics. One has agreed to be co-applicant. She will also help publicise results. Patient benefit If this study leads to a trial showing vaginal lactoferrin is an acceptable and effective alternative to antibiotics, this could help relieve symptoms, prevent antimicrobial resistance and save NHS costs. Future research might show if lactoferrin could also reduce infection-related preterm birth.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION