Safety, Tolerability and Efficacy of Vaginal Suppository WO3191 in the Post-treatment of Bacterial Vaginosis

Study Overview
=================
Brief Summary
-----------------
Bacterial Vaginosis (BV) is a common infectious disorder and is characterized by a disturbance in the vaginal microbiological milieu. Anaerobic bacteria, such as Gardnerella vaginalis and Atopobium vaginae overgrow the physiologic vaginal flora which is dominated by Lactobacilli. BV can arise and remit spontaneously but often presents as a recurrent disease. New findings indicate that the presence of an adherent bacterial biofilm on the vaginal mucosa seems to be the reason for the recurrence of BV as well as the overgrowth condition by anaerobic bacteria. Biofilms are defined as a structured consortium of bacteria embedded in a matrix of extracellular polymeric substances (EPS). The purpose of this study is to achieve substantial results with respect to tolerability and safety, and to gain further knowledge on the clinical efficacy of Vaginal suppository WO3191, the investigation will be performed in a parallel-design, double-blind, randomised, controlled manner.

Detailed Description
-----------------
This investigation is a multicentre, parallel-group, double-blind, controlled trial with an open Follow-up Phase of 12 weeks. It is conducted to gain clinical experience and further knowledge about the certified medical device Vaginal suppository WO3191 in women with bacterial vaginosis. In this investigation the Investigational Medical Device (IMD) will be used as post-treatment following standard therapy with oral metronidazole for BV. IMD will be applied 2 times a week for 3 weeks. The primary purpose is the evaluation of the safety and local tolerability of WO3191, therefore all adverse events (AEs) and adverse device effects (ADEs) will be documented. Furthermore, patients will be asked for possibly arising subjective vaginal symptoms (burning, itching, bleeding, pain, dryness) and will be examined for possibly arising objective vaginal findings (redness, petechial bleeding, dryness, swelling). The secondary purpose of this investigation is to gain clinical experience and further knowledge about Vaginal suppository WO3191 with respect to the efficacy in the post-treatment of bacterial vaginosis. In addition pH-values and microbiological data shall be examined. Furthermore, the difference between Vaginal suppository WO3191 (Group A) and the comparator (Vagisan® Lactic Acid, group B) with respect to the safety, tolerability and the efficacy in the post-treatment of bacterial vaginosis shall be evaluated exploratively. Patients who have completed all regular visits (Visit 1 - 4; Visit 1 - Screening, Visit 2 - Randomization, Start of application of IMD; Visit 3 - one week after Visit 2; Visit 4 - two weeks after Visit 3, End of application of IMD) of the investigation shall attend an observational Follow-up Phase of 12 weeks with a final Visit 5. At Visit 5 recurrences of BV as well as the sustainability of the efficacy of Vaginal suppository WO3191 will be evaluated.

Official Title
-----------------
A Prospective Parallel-design, Double-blind, Randomised, Controlled Investigation to Gain Clinical Experience and Further Knowledge About the Certified Medical Device Vaginal Suppository WO 3191 With Respect to Safety, Tolerability and Efficacy in the Post-Treatment of Bacterial Vaginosis

Conditions
-----------------
Vaginosis, Bacterial

Intervention / Treatment
-----------------
* Other: Medical Device: WO3191
* Other: Medical Device: Vagisan® Lactic Acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed declaration of consent and signed data protection declaration after having been informed about the nature, relevance and the scope of the investigation and about the expected desired and undesired effects of the IMD Premenopause, age 18 to 50 years (incl. patients with Intrauterine device, e.g. Mirena® with amenorrhoea) Acute BV (at least 3 of 4 Amsel's Criteria fulfilled and Nugent Score > 6) Existing bacterial biofilm in the vagina, verified by positive EPS of bacterial biofilm and by microscopy Requirement of oral treatment of metronidazole for BV Exclusion Criteria: Postmenopause (no menses in the last six months prior to enrolment) Positive Herpes simplex infection Positive Candida spp. infection Positive Trichomonas spp. infection Pathologic PAP (III, III D-V) within the last 3 months Chronic immunosuppressive diseases (i.e. HIV) or treatment (i.e. transplantation) Malignant conditions of CIN, VIN or VAIN, currently and / or within the past 6 months Presence or history (within the last 5 years) of any other malignancy Previous chemotherapy (within 6 months before start of this investigation) Current vaginal or systemic treatment with antibiotics or corticosteroids, systemic treatment with NSAIDs (nonsteroidal anti-inflammatory drugs) within the last two weeks prior to start of this investigation (except metronidazole for the treatment of BV: prescription of metronidazole before investigation entry; except NSAIDs taken in a single dose in case of need, e.g. for headache) Use of not permitted contraception or not willing to use contraception (Allowed contraception: oral hormonal contraceptives, intrauterine device, surgical, sexual abstinence; Not permitted contraception: condoms, local spermicides, intravaginal contraceptive measures) Pregnancy or lactation Active Smokers (more than 5 cigarettes per day) Use of any other intravaginal medicinal product or medical device (including all intravaginal contraceptive measures (e.g. NuvaRing®, local spermicides) Known hypersensitivity to one or more of the active and / or inactive ingredients of the antibiotic treatment (metronidazole: mandatory for inclusion) Known hypersensitivity to one or more of the ingredients of the IMD (test product and/or comparator)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Medical Device: WO3191<br>The vaginal suppository is used for the reduction and/or inhibition of vaginal biofilms that were shown to be related to recurrent bacterial vaginosis. | Other: Medical Device: WO3191<br>* application of vaginal suppository WO3191: 2 days per week (with a treatment-free interval of three days or two days, respectively; e.g. Monday and Friday)<br>|
| Active Comparator: Medical Device: Vagisan® Lactic Acid<br>It is used for the maintenance and restoration of a natural pH level in the vagina. The acidification of the vaginal milieu with lactic acid promotes the growth of typical vaginal flora (lactic acid bacteria) and is unfavourable for the growth of pathogens in the vagina. Vagisan® Lactic Acid is used in the post-treatment of bacterial vaginosis. | Other: Medical Device: Vagisan® Lactic Acid<br>* application of Vagisan® Lactic Acid: 2 days per week (with a treatment-free interval of three days or two days, respectively; e.g. Monday and Friday)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local tolerability of IMD defined as a cumulative sum score of solicited local ADE for each Patient | Local tolerability of the IMD will be defined as a cumulative sum score of the solicited local (vaginal) ADE (consisting of subjectively experienced symptoms rated by the patient: burning, itching, bleeding, pain, dryness and objectively documented findings rated by the physician: redness, petechial bleeding, dryness, swelling) for each patient after 1 and 3 weeks of application (Visit 3 and Visit 4, respectively). | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective symptoms (local tolerability) | Each of the subjective symptoms (scored from 0 [none/normal] to 3 [severe]) at Visit 2 (before the first application), Visit 3 (after 1 week of application) and Visit 4 (after 3 weeks of application) | 3 weeks | 
| Objective findings | Each finding (scored from 0 [none/normal] to 3 [severe]) as well as each sum score at Visit 3 (after 1 week of application) and Visit 4 (after 3 weeks of application) will be summarised by the maximum value and the mean value for Visit 3 and Visit 4, respectively | 3 weeks | 
| Global judgement of tolerability | Global judgement of tolerability by investigator and patient at Visit 4 (after 3 weeks of application) | 3 weeks | 
| AE and ADE (Safety) | Unsolicited AEs and ADEs | up to 4 months | 
| Occurrence of AE / SAE / ADE / SADE (Serious Adverse Event) (Safety) | Occurrence of AE / SAE / ADE / SADE | up to 4 months | 
| Characteristics of AE / SAE / ADE / SADE (Safety) | Characteristics of occured AE / SAE / ADE / SADE | up to 4 months | 
| Change in biofilm EPS | Proof of the biofilm EPS at Visit 2 (before the first application), Visit 3 (after 1 week of application), Visit 4 (after 3 weeks of application) and Visit 5 (after Follow-up Phase, i.e.12 weeks after the end of the application Phase (Visit 4)) Combined Parameter: Evaluation of Extracellular Polymeric Substances (EPS) in urine samples and evaluation of existence of bacterial biofilm | up to 4 months | 
| Change in pH-value from vaginal smear | pH-value from vaginal smear at visit 2 (before the first application), Visit 3 (after 1 week of application), Visit 4 (after 3 weeks of application) and Visit 5 (after Follow-up Phase, i.e.12 weeks after the end of the application Phase (Visit 4)) | within 4 months | 
| Change in Nugent-Score | Nugent-Score at Visit 2 (before the first application), Visit 3 (after 1 week of application) and Visit 4 (after 3 weeks of application) | within 3 weeks | 
| Change in Vaginal flora | Vaginal flora (Lactobacillus spp., Atopobium vaginae and Gardnerella vaginalis) at Visit 2 (before the first application), Visit 3 (after 1 week of application) Visit 4 (after 3 weeks of application) and Visit 5 (after Follow-up Phase, i.e.12 weeks after the end of the application Phase (Visit 4)) | within 4 months | 
| Time to recurrence of BV | Time from the end of application (Visit 4) to the first recurrence of BV within the Follow-up Phase of 12 weeks | up to 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bacterial Vaginosis, BV