The LISA (Lactoferrin InStead of Antibiotics/Antifungals) Feasibility Study (LISA)

Is the Naturally Occurring Prebiotic Lactoferrin an Acceptable Alternative to Antibiotic/Antifungal Tablets for Women With Bacterial Vaginosis or Thrush?

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 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.

Methods The investigators will recruit a total of 57 women with BV and 57 with thrush from two sexual health clinics and a general practice. Women will be asked 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/antifungal tablets. All women will be asked to provide repeat vaginal samples at home and text us about any symptoms to 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.

Outcome measures:

• 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 who report their symptoms have resolved after a week
• How quickly infections clear or recur - from analysis of samples

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Bacterial Vaginosis; Candida Vaginal
• Intervention / Treatment: Other: Vaginal lactoferrin; Drug: Usual care

Detailed Description

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: a sexual health clinic 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
• Percentage of participants who complete twice weekly symptom questionnaires and provide self-taken vaginal samples at home which are suitable for microbiological analyses. These findings will inform the design of a future definitive trial.

Masking

This is an open label trial and there will be no blinding to treatment allocation of the participants or researchers. However, the analysis of samples (Gram stain and microbiome analysis) will be done blind to treatment allocation [1].

Sample size calculations and analysis

We will recruit 114 women in order to achieve a final sample of 90 followed-up women at 12-weeks (30 with BV given lactoferrin, 30 with candida given lactoferrin, and 30 controls (15 with BV, 15 candida) given oral antibiotics/antifungals. This allows for 24 women (21%) either lost to follow up (12%), recruited in general practice but not BV/thrush on Gram stain (4%) or given antibiotics for an STI (3%) an unrelated reason (2%, eg dental abscess) as antibiotics may affect both symptoms and the vaginal microbiome. Sixty intervention women and 30 controls is consistent with numbers recommended by Teare et al for feasibility studies and will provide an acceptable level of precision around the study's key feasibility outcomes [32].

For example, a recruitment rate of 50% (114/228) will have a 95% confidence interval of 43.5% to 56.5%; and a follow-up rate of 80% (91 /114) will have a 95% confidence interval of 72.5% to 87.2%.

Each week the sexual health specialist investigator sees an average of six eligible women in his recurrent vaginitis clinic and the general practitioner investigator sees one or two in general practice. PPI work and our previous trials suggest ≥50% of eligible women will agree to participate [26, 27]. If we recruit an average of 3 women a week (two in clinic, one in GP) we should complete recruitment of 114 women within 38 weeks. We will allow 12 months.

Analysis of quantitative study outcomes will be descriptive. Numbers and percentages will be presented, along with 95% confidence intervals. Weekly pessary/tablet counts will be presented as mean (SD) or median (IQR) as appropriate. Numbers of adverse events and number of women with adverse events will be summarised. The flow of participants through the study will be presented in a CONSORT diagram.

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 ≥70% of women, recruitment rate≥50%, follow-up ≥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.

• Study Type: Interventional
• Enrollment (Anticipated): 114
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pippa Oakeshott, MD; Phone Number: 020 8725 0153; Email: oakeshot@sgul.ac.uk
• Study Contact Backup: Name: Fiona Reid, MSc; Email: fiona.reid@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, se1 7eh
    • St Thomas' NHS Trust
    • Contact: Phillip Hay, FRCP; Email: phillip.Hay@gstt.nhs.uk
  • London, United Kingdom, SW17 ORE
    • St George's, University of London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Aged 16-49 years

  • Having periods (apart from women with a Mirena IUCD or polycystic ovary syndrome)
  • Ability to consent
  • Clinical diagnosis of BV or thrush confirmed on Gram stain
  • Willing to be randomised to vaginal lactoferrin pessaries or oral antibiotics/antifungals
  • Agrees to provide vaginal samples at home and post/deliver them back to the research team.
  • Agrees to avoid douching during the study (as this can flush out lactobacilli needed for a healthy microbiome).

Exclusion Criteria:

• Pregnant or breast feeding
• Currently has chlamydia, gonorrhoea or trichomonas (as treatment for these would affect the results).
• Known allergy to metronidazole or azoles
• Post-menopausal (because of diagnostic confusion between atrophic vaginitis and bacterial vaginosis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lactoferrin intervention group; Women will be given bovine lactoferrin 300mg vaginal pessaries to insert every evening for the first 21 days of the study [25].	Other: Vaginal lactoferrin; Lactoferrin vaginal pessaries to insert nightly for seven nights; Other Names: Difesan vaginal pessaries
Active Comparator: Usual care control - standard oral antibiotics/antifungals; Control women with BV will be given oral metronidazole 400mg twice daily for five days (and routine advice about avoiding alcohol). Control women with candida will be given a fluconazole 150mg capsule to take orally the same day.	Drug: Usual care; Women with bacterial vaginosis will be given oral metronidazole and women with vaginal candida will be given oral fluconazole; Other Names: Oral metronidazole or fluconazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The acceptability of vaginal lactoferrin treatment	This will be assessed from interviews with 15-20 participants	4-16 weeks after recruitment
Adherence to treatment	This will be assessed from participants' weekly count of remaining pessaries/tablets from questionnaires at 1, 2, 3 and 4 weeks	During the first 4 weeks of the study
Recruitment rate	Investigators will record the percentage of eligible women who agree to take part	Up to 15 months
Follow-up rate	Investigators will record the percentage of randomised women who are followed up after 12 weeks	Up to 20 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of study procedures, and whether participants think other women would be willing to take part in a future randomised trial of lactoferrin versus oral antibiotics.	Investigators will conduct telephone interviews between 4 and 16 weeks after recruitment with 15-20 participants	4-16 weeks after recruitment
Adverse events such as nausea, vomiting, vaginal irritation, abdominal pain, rashes, diarrhoea	Investigators will ask about adverse events during weekly text questionnaires during the first four weeks and on the final questionnaire at 12 weeks follow up	Between recruitment and 12 week follow up
Recurrence or persistence of infection by 12 weeks	Investigators will ask about symptoms of infection on the final 12 week questionnaire and assess infection status by analysis of self-taken vaginal samples	At 12 week follow up
Feasibility of obtaining data on healthcare use	This will be assessed by comparing reported healthcare use in final 12 week questionnaires with a medical record search in 30 participants	Last 6 months of study
Percentage of participants who complete twice weekly symptom questionnaires for the first four weeks after recruitment.	This will be assessed from analysis of questionnaires.	During the 12 weeks after recruitment
Percent of self-taken samples suitable for microbiological analysis	This will be assessed from microbiological analysis of self-taken vaginal samples	During the 12 weeks after recruitment

Collaborators and Investigators

• Sponsor: St George's, University of London
• Collaborators: King's College London; Statens Serum Institut
• Investigators: Principal Investigator: Pippa Oakeshott, MD, St George's, University of London

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: May 27, 2022
• First Submitted That Met QC Criteria: June 21, 2022
• First Posted (Actual): June 27, 2022

Study Record Updates

• Last Update Posted (Actual): October 13, 2022
• Last Update Submitted That Met QC Criteria: October 11, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: prebiotic; lactoferrin
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Vaginitis; Vaginal Diseases; Vaginosis, Bacterial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Metronidazole; Fluconazole; Lactoferrin
• Other Study ID Numbers: 2021.0268

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No