ProF-001_Phase IIa

Study Overview
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Brief Summary
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This is a multi-center, randomized, prospective, active-controlled, double-blind, dose-escalation study comparing dose response of clinical efficacy, safety, local tolerability of three different doses of ProF-001/Candiplus® (Candiplus® 0.2%, Candiplus® with 0.3%, Candiplus® with 0.4%) to 1% clotrimazole vaginal cream. Patients with acute episode of vulvovaginal candidiasis (VVC) will be randomized to receive a daily dose of either 5 ml (intravaginal) of Candiplus® at three different doses for the first 3 days and 2.5 ml for the remaining 3 days or 5 ml (intravaginal) application of 1% clotrimazole cream over the first 3 days and 2.5 ml for the remaining 3 days according to the following scheme (with each application 2 cm of cream will be applied to the vulvar region): Cohort 1: Candiplus® 0.2% versus clotrimazole mono Cohort 2: Candiplus® 0.3% versus clotrimazole mono Cohort 3: Candiplus® 0.4% versus clotrimazole mono Randomization into the cohorts will occur consecutively from the lowest dose to the highest dose, i.e. patients will be randomized first in cohort 1 and finally in cohort 3. The proposed study is - after a pilot study to assess critical pharmacokinetic data - the second study within a clinical trial program with the objective to develop a new combination therapy for the treatment of vulvovaginal candidiasis. The new combination consists of two registered drug substances.

Official Title
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A Phase IIa Randomized, Active-controlled, Double-blind, Dose-escalation Study in Patients With Vulvovaginal Candidiasis to Evaluate Dose Response Relationship of Clinical Efficacy, Safety and Tolerability of Topically Administered ProF-001

Conditions
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Vulvovaginal Candidiasis (VVC)

Intervention / Treatment
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* Drug: Candiplus
* Drug: Clotrimazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal female patients ≥ 18 years old Patients suffering from an acute episode of vulvovaginal candidiasis, characterized by: Positive vaginal smear (native, KOH) for budding yeasts and/or fungal (pseudo-) hyphae, normal or intermediate flora (G I and G II) Positive clinical symptoms (itching, burning, irritation, edema, erythema, excoriations), with a subjective symptom score of at least 3 (0=absent, 1=mild, 2=moderate, and 3=severe), with score being at least moderate for at least 1 subjective symptom and itching being present, and a total sign and symptom score of at least 4 Readiness for sexual abstinence from start of treatment until test of cure (TOC) - visit Sufficient knowledge of German language to understand trial instructions and rating scales, and ability to comply with treatment Written informed consent prior to enrolment Exclusion Criteria: Known hypersensitivity to any ingredient of the investigational medicinal product Pregnancy or breast feeding at time of screening Menstrual bleeding (spotting is not an exclusion criterion) during the first three days of treatment Acute cystitis Patients with clinical signs of other infectious causes of vulvovaginitis: bacterial vaginosis (GIII), trichomonas vaginalis, herpes simplex genitalis Treatment with antimycotics (systemic or vaginal) within 7 days of randomization Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) Patients with other clinical gynecological abnormalities, such as infections of the upper urogenital tract (pelvic inflammatory disease, adnexitis) Subjects with another vaginal or vulvar condition that would confound the interpretation of clinical response (e.g. Lichen sclerosus, neuropathic pain) Subjects who will be under treatment or surgery for gynecological pathologies during the study period, i.e, cervical intraepithelial neoplasia, cervical carcinoma, other neoplasms Known alcohol, drug or medication abuse Any clinically relevant concomitant condition that could compromise the objectives of this study and/ or the patient's compliance (eg. known immune deficiency syndrome with clinical relevance at time of screening) Participation in another interventional clinical trial within the last 30 days Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub-investigators, or study nurse) or relationship to the sponsor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0,2% Candiplus<br>Candiplus® 0.2% | Drug: Candiplus<br>* Administration of Candiplus<br>|
| Experimental: 0,3% Candiplus<br>Candiplus® 0.3% | Drug: Candiplus<br>* Administration of Candiplus<br>|
| Experimental: 0,4% Candiplus<br>Candiplus® 0.4% | Drug: Candiplus<br>* Administration of Candiplus<br>|
| Active Comparator: Clotri mono<br>Clotrimazole mono | Drug: Clotrimazole<br>* Administration of Clotrimazole<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined outcome measure of: Symptom relief within the first 60 minutes (after application of investigational product or active control) and clinical cure at day 7 (± 3 days). | As the primary outcome symptom relief within the first 60 minutes will be documented. A reduction of the subjective symptom score ≥ 2 is expected. Furthermore clinical cure at day 7 will be documented. Clinical cure is defined as absence of signs and symptoms of VVC. | within 60 minutes after application and at day 7 (± 3 days) after drug application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with local adverse events and serious adverse events (SAEs) with causal relationship to study medication | All local adverse events and serious adverse events with causal relationship to study medication (drug reaction) will be documented in a descriptive manner. | overall study period (max. 65 days) | 
| Symptom relief within the first 60 minutes (after application of investigational product or active control, reduction of the subjective symptom score ≥ 2) | Symptom relief within the first 60 minutes will be documented. A reduction of the subjective symptom score ≥ 2 is expected. | within 60 minutes after drug application | 
| Clinical cure (absence of signs and symptoms of VVC) at the TOC visit (=day 7/ accepted time window ±3days) | Clinical cure at day 7 will be documented. Clinical cure is defined as absence of signs and symptoms of VVC. | day 7 ±3 days after drug application | 
| Mycological outcome: Vaginal swab culture negative for growth of Candida albicans and/or Candida species at the TOC visit (day 7 / ±3days) | A vaginal swab culture will be taken on day 7 / ±3days. The test result is expected to be negative for growth of Candida albicans and/or Candida species.visit (day 7 / ±3days) | day 7 ±3 days after drug application | 
| Responder outcome: absence of signs and symptoms plus vaginal swab culture negative for growth of Candida albicans and/or Candida species at the TOC visit (day 7 / ±3days) | Presence or absence of signs and symptoms will be documented. Vaginal swab culture is expected to be negative for growth of Candida albicans and/or Candida species at the TOC visit. | day 7 ±3 days after drug application | 
| Time to improvement of symptoms after first intervention | The time to improvement of symptoms after the first intervention will be documented. | overall study period (max. 65 days) | 
| Time to termination of clinical symptoms | The time to termination of clinical symptoms will be documented. | overall study period (max. 65 days) | 
| Clinical relapse of VVC during follow-up period | Every clinical relapse of VVC during the follow-up period will be documented. | follow-up period (from day 8 to day 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Candiplus, Vulvovaginal candidiasis, Clotrimazole, Safety, Tolerability, Clinical efficacy