Effectiveness of a Vaginal Gel on CIN1/2 Regression and HPV Clearance.

Effectiveness of Coriolus Versicolor-based Vaginal Gel on HPV Clearance and Regression of Cervical Intraepithelial Neoplasia: a Multicenter Randomized Controlled Trial

The goal of this clinical trial is to evaluate whether a Coriolus versicolor-based vaginal gel facilitates HPV clearance in women aged 30-50 years diagnosed with HPV and CIN1 or CIN2. In addition, the study will investigate whether the gel promotes regression of CIN1/CIN2, assessment of patient satisfaction, treatment compliance and characterize the vaginal microbiome.

The primary outcomes therefore is:

• hrHPV clearance from baseline to follow-up (6 months)

In this randomized controlled study, eligible participants will be randomized 1:1 into two groups:

1. Intervention group: Women (n=35) will apply a CV-based vaginal gel (Papilocare®) daily for 21 days for 3 months. Afterward, the gel should be used every other day for an additional 3 months. Every month includes a 7-day break due to menstruation (28 days cycle).
2. Control group; Women (n=35) will follow the conventional "wait and see" approach.

Persistent high-risk Human Papillomavirus (hrHPV) infections and Cervical Intraepithelial Neoplasia (CIN) represent significant public health and clinical concern. Currently, no established treatment is available to promote HPV clearance, and cervical excision remains the standard treatment for moderate- to high-grade CIN lesions despite its procedural risks. Management of women with mild to moderate lesions often involves "watchful waiting" with repeated controls, which may impose a considerable psychological burden. Therefore, there is a clinical need for effective, non-invasive treatment options for this patient population. To address this need, the primary aim of this study is to evaluate the effectiveness of a vaginal gel (Papilocare®) containing Coriolus Versicolor (CV) extract and other natural ingredients, in promoting hrHPV clearance. Secondary aims include evaluation of histological CIN regression, changes in vaginal microbiome composition, levels of stress and anxiety, patient satisfaction and treatment compliance.

This study is a multicenter, parallel-group, randomized controlled trial including women aged 30 to 50 years with both known hrHPV and histologically confirmed CIN1 or CIN2 (n = 70). Outcome assessors will be blinded to treatment allocation.

Participants will be randomized 1:1 to either six months of treatment with Papilocare® Vaginal gel (n = 35), or six months of conventional "watchful waiting" strategy (n = 35). Both groups will have a follow-up examination after 6 months, including colposcopy, cervical biopsies and two self-collected vaginal swabs for hrHPV genotyping and microbiome assessment. Participants will complete digital questionnaires before and after the intervention period, including the State-Trait Anxiety Inventory (STAI-20) and the Perceived Stress Scale (PSS-10). Additionally, the intervention group will complete questionnaires evaluating treatment compliance and satisfaction at 3 and 6 months.

This study will provide important evidence on effectiveness of a CV-based vaginal gel in women with hrHPV infection and CIN lesions. The inclusion of histopathological evaluation and comparison of vaginal microbiome composition will provide novel insight into biological factors associated with hrHPV clearance and CIN regression. If proven clinically effective, this intervention could offer a new, safe and non-surgical treatment option for women with hrHPV-related cervical lesions, addressing an unmet need where no approved therapeutic treatment currently exists.

Both positive, negative, and inconclusive results from the project will be published in international peer-reviewed scientific journals and presented at national as well as international conferences.

Inclusion criteria:

• Aged 30-50 years
• A positive hrHPV test with histopathological confirmed CIN1 or CIN2
• Managed under a 'watchful waiting' strategy as part of standard management
• Understand Danish, both written and orally

Exclusion criteria:

• Pregnancy or breastfeeding
• Unexplained vaginal bleeding
• Immunosuppressive or immunomodulatory conditions or treatment
• Diabetes mellitus
• Prior hysterectomy
• Any ongoing cancer diagnosis, prior CIN3 or a history of malignancy in the genital/anal region within 5 years (excl. non-melanoma skin cancer)