A randomized controled trial: the effect of a medical grade honey formulation (L-Mesitran®) on clinical symptoms of recurrent vulvovaginal candidiasis

Recurrent vulvovaginal candidiasis (RVVC) is predicted to increase to 158
million cases annually by 2030. Treatment options are limited and in 50% of the
cases relapses occur within 12 months after starting fluconazole therapy, which
is the current standard of care. The pathogenesis of RVVC is multifactorial and
recent studies have demonstrated that the vaginal microenvironment and activity
of the immune system have a major impact on the condition. This calls for a
product that meets these characteristics. Medical grade honey (MGH) has
protective, antimicrobial and immunomodulatory activity and may therefore be a
good alternative treatment. We postulate that MGH will actively fight ongoing
infections and modulate the vaginal microenvironment by its anti-inflammatory,
anti-oxidative and immunomodulatory properties, and subsequently may decrease
the number of relapses when compared to fluconazole. Furthermore, we will
analyze the vaginal microbiota to study the effect of MGH on the vaginal
microenvironment, which may explain the possible differences in efficacy
between the two groups.

The primary objective is to investigate the vaginal culture (positive or
negative) after the application of a Medical Grade Honey formulation
(L-Mesitran ®) in relation to the current standard of care (Fluconazole) 1
month after starting treatment in patients with RVCC. Secondary objectives are
to investigate the effects on symptoms, including redness, irritation, itching,
dysuria, dyspareunia and vaginal discharge. In addition, the vaginal culture
after 6 months maintenance therapy and the number of relapses within 12 months
will be investigated. Moreover, information about side effects, discomfort, and
quality of life will be collected and compared. Furthermore, we will analyze
the vaginal microbiota (by vaginal self-swabs) to study the effect of MGH on
the vaginal microenvironment.

Multi-center randomized controlled trial

Intervention 1: Fluconazole (Diflucan®). Therapy according to manufacturer*s
instructions.
As treatment for active RVVC: each patient will receive 3 capsules (150 mg), 1
capsule on day 1, 1 capsule on day 4 and 1 capsule on day 7 for acute treatment
of RVVC.
As prophylaxis to prevent a new RVVC episode: once a week (150 mg) for 6 months
as prophylaxis.

Intervention 2: Medical Grade Honey Formulation (L-Mesitran®)
As treatment for active RVVC - Single daily application with applicator (5
grams) for 4 weeks.
As prophylaxis to prevent a new RVVC episode: Single weekly application with
applicator (5 grams) for five months.

One extra visit to the hospital, for signing informed consent and visit the
farmacy. Normally, there is no long-term follow up, and patients are asked to
come back when the complaints remain. Because we now want to investigate the
effect on microbiological level after 1 month, 6 months and 12 months after
starting treatment, we have to collect vaginal swabs. To minimize the burden to
the patients, we ask the participants to take a vaginal swab themselves using a
self test. These swabs need to be send by pre-paid mail to the hospital for
analysis. In addition, patients will be asked to fill in a questionnaire at
inclusion and 1, 6, 9, and 12 months after start therapy. The questionnaire
will be sent digitally.
The investigational product L-Mesitran® is registered for the treatment of
wounds and has CE and FDA certifications. No contraindications are known to
date. It is advised not to use the product on patients who are sensitive to the
product or any of its components or patients with allergy to honey (which is
very rare and only very few cases have been reported.(1) Based on previous
studies investigating the therapeutic activity of honey for the treatment of
vaginitis, we do not expect any major health problems following the treatment
with Medical grade honey (MGH). Two clinical studies reported that honey was
safe and side effects were absent.(2, 3) Another study that compared a mixture
of bee-honey and yoghurt with local tioconazole (Gynotrosyd) and reported side
effects to be non-compliance (6.09%), soiling of underclothes (17%), and local
irritation (1.2%).(4) During wound care, in rare occasions (less than 1%) a
short burning sensation can be experienced upon application of L-Mesitran to
the wounds; however, this typically disappears within a minute and may be due
to the antiseptic properties, such as the osmotic activity or the low pH of
MGH.
We do not expect any other side effects or discomfort to the investigational
product.
No additional risks are foreseen for participation to the study. Not providing
the standard care (Fluconazole) will not lead to severe complications.