A Clinical Trial for Chlorhexidine as Treatment for Vulvovaginal Candidiasis

The study is a 6 months clinical Phase II trial to compare if 1% chlorhexidine gluconate vaginal cream (Hibitane®) is at least as effective and safe as fluconazole (reference treatment) for culture-verified recurrent vulvovaginal candidiasis. The study is a randomized open non-inferiority trial with parallel treatment groups. The trial is not possible to blind for neither participants nor investigators due to the differences between study treatments. There is low risk of bias since the primary outcome variable is objective (negative vaginal culture for Candida albicans).

The participants will be randomization to;

• Investigational medication with Hibitane® vaginal cream 8 ml every night for a week and then prophylactic treatment with 8 ml/week for another 11 weeks or
• Reference treatment with Fluconazole® 150 mg (oral capsule) every 3 days for the first 3 doses, then prophylactic treatment with 150 mg/week for another 11 weeks.

The randomization ratio between the treatment groups will be 1:1. A computer generated block randomization of 15 participants will be performed by the research midwife. Allocation to the study medications will be carried out via opening of opaque sealed envelopes in consecutive order. All women will be identified through a patient log with name and Swedish personal identification number and the randomization number. The randomization number will be used on all paper and CRFs.

Five research visits are planned:

Visit 1 Screening - oral and written study information, signing of informed consent, vaginal culture for Candida albicans and chlamydia/gonorrhea (PCR test).

Visit 2 Inclusion (baseline), within 1 week after Visit 1. Control for inclusion/exclusion criteria, randomization to study medication after positive culture for Candida albicans and negative chlamydia/gonorrhea (PCR test) - health survey, control of concomitant medications, examination, pregnancy test and control of adequate contraceptive methods to avoid pregnancy throughout the study.

Visit 3 1 week (+2 days) after completed treatment. Control of AE, culture for Candida albicans and examination.

Visit 4 After 12 weeks (+ 1 week) from inclusion when prophylactic treatment is completed. Control of AE and relapses, culture for Candida albicans and examination.

Visit 5 Follow-up 6 months (+ 1-2 weeks) from baseline/inclusion. Control of AE and relapses, culture for Candida albicans and examination. End of study.

A weekly web-based dairy (eCRF (Entermedic)) will be used for follow-up of treatment compliance, efficacy and adverse events. During the prophylactic treatment (Visits 2-3) and during the observational phase of the study (Visit 4-5), the participants are asked to report any suspicious relapses in the dairy and contact the research midwife if needed. They will also receive equipment for vaginal cultures that can be used for self-sampling at home to detect true relapses. In case of positive cultures for Candida albicans, they will be offered the same medication as previously used in the study if the treatment was effective and no adverse events occurred. Otherwise, an individual treatment option will be used.

The end of study is defined as completion of the last visit of the last subject. The sponsor and the investigators reserve the rights to discontinue the study at any time for safety reasons or other reasons jeopardizing the justifications of the study.

Supply, labelling, handling and storage:

Chlorhexidine gluconate (Hibitane®) vaginal cream is commercially available in Sweden and will be prescribed from the hospital pharmacy for each participant. It will be stored and kept according to the instructions of the manufacturer.

• Participants randomized to Hibitane® will receive a bottle (250ml) with the vaginal cream together with 10 ml syringes for vaginal administration. The Hibitane® bottle can be stored in the fridge at home between use. Women will receive specific written information as well as oral information on how to self-administer drug vaginally with the syringe.
• Participants randomized to Fluconazole® will receive 14 oral capsules of 150 mg according to the dosage describe above.

Compliance:

Compliance will be evaluated at the follow up visits and the participants will fill out a dairy how the study medications have been taken.

Data collection and data handling:

Every participant will be given an individual, study specific number (i.e. study identifying code) at the time of inclusion. A code key with each individual personal data connected to the identifying code will be created (i.e. patient identification log) and stored separately at the research department at the department of Obstetrics and Gynecology, Danderyd Hosptial, Stockholm, Sweden.

Data will be recorded on individual printed case report forms (CRFs) after which they will be entered into a computerized database before statistical analyses. The database will contain information on demographic variables, type of treatment and measurements in addition to the variables above.