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

Overview

The goal of this clinical trial is to evaluate whether a Coriolus versicolor-based vaginal gel promotes regression of CIN1/CIN2 and facilitates HPV clearance in women aged 30-50 years diagnosed with CIN1 or CIN2 and HPV. In addition, the study will assess patient satisfaction, treatment compliance and characterize the vaginal microbiome. The primary outcomes therefore is: * the regression of the cervical dysplasia from baseline to the follow-up (6 months), which will be assessed through either liquid-based cytology and/or histopathology (biopsy). * HPV 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.

Background Cervical cancer causes approximately 600,000 new cases and 340,000 deaths annually worldwide. It is caused by persistent infections with HPV, a widespread sexually transmitted virus. Over 80% of all sexually active women acquire an HPV infection during their lifetime and some may even be infected more than once. Some HPV infections remain persistent and may cause cervical dysplasia - cervical intraepithelial neoplasia (CIN) - classified as mild (CIN1), moderate (CIN2), or severe (CIN3), including carcinoma in-situ. If left untreated, within two years approximately 50% of CIN2 lesions will regress, 32% persist, and 18% progress. Despite significant efforts to prevent HPV-induced cervical cancer through vaccination and optimized HPV-based screening, HPV infections and CIN remains a substantial global health burden - even in countries with well-organized healthcare systems. In Denmark 30,000 women are yearly diagnosed with HPV and abnormal cervical changes. This leads to further diagnostic follow-up procedures with colposcopy, due to the risk of progression to cancer. Colposcopy is a procedure that allows close visualization of the cervix to identify suspicious lesions and obtain cervical biopsies for histopathological grading. The histopathological classification of CIN1-3 determines the recommended treatment strategy. Surgical excision (cone biopsy) is considered for CIN2, depending on the woman's desire to preserve fertility, and is recommended in all cases of CIN3 or worse (CIN3+). However, this procedure carries risks, including late spontaneous abortion, preterm birth, infection, irregular bleeding and cervical stenosis. Consequently, for women with CIN2 who wish to preserve fertility, a conservative "watchful waiting" approach may be offered. Similarly, the standard management for women with HPV infection and ≤CIN1 also consists of observation without immediate intervention. This "watchful waiting" strategy involves follow-up examination with colposcopy every six months, including HPV testing, cytology test and cervical biopsies. This places a considerable burden on healthcare resources. Furthermore, this follow-up strategy, with its associated risk of disease progression, entails significant negative psychological consequences, including anxiety, stress, and reduced quality of life, as well as an increased long-term risk of developing cancer. Effective non-invasive treatments for HPV-related cervical dysplasia remain an unmet need in current research. Recently, a vaginal gel containing Coriolus versicolor (CV) has been introduced as a potential treatment for HPV infection and cervical dysplasia. The gel, Papilocare, is a non-prescription medicine, which combines the ingredients from CV with moisturizing agent (Hyaluronic acid), tissue reparative agents (NEEM, Aloe vera, Centella Asiatica) and microbiota-balancing properties (BIOECOCIA). The gel is hormone-free and contains a combination of natural ingredients aimed at supporting epithelial regeneration and restoring the vaginal microbiota. Three observational studies and one randomized controlled trial with study populations ranging between 21 to 192 women (aged 18 to 65 years) have recently shown promising results of CV vaginal gel on clearance of HPV (40-87%) and regression of cervical dysplasia (65-85%) compared to a control group. However, these studies are subject to several limitations, including the lack of randomization and their geographical concentration. In addition, comparability across studies is restricted due to heterogeneity in inclusion criteria and study populations, particularly in terms of age. Overall, the limited number of studies also constrains the generalizability of findings, highlighting the need for further high-quality research in this area. Therefore, there is an urgent need to discover this non-invasive and effective treatment options for women diagnosed with HPV infection and non-treatment-requiring cervical abnormalities. If HPV infection can be effectively treated, it may prevent the development of cervical dysplasia and thereby reduce the cervical cancer incidence. Design: This study is designed as a randomized single-blinded controlled multicenter trial. Study population and recruitment: Recruitment will take place at the Departments of Gynecology in Randers and Horsens, with an expected start in January 2026 and continuing until August 2026. The women will be scheduled for colposcopy as part of routine care. Women with the following criteria will be included: * Aged 30-50 years * Positive HPV test * Underwent colposcopy with subsequent histopathological findings of CIN1 or CIN2 * Allocated to a 'watchful waiting' management strategy. * Understand Danish, written and orally. Exclusion criteria will be: * Pregnancy or breastfeeding * Unexplained bleeding * Immunosuppressive/modulatory diseases or treatment * Cancer or cancer related diseases After obtained consent, 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. Age and histopathological result will be considered in the randomisation process to achieve comparable group allocation. The follow-up examination at 6 month - including the tissue samples to be collected - will follow standard procedures regardless of whether the woman participates in the study or not. For each group follow-up will be conducted with colposcopy using cervical cytology and cervix biopsies. Perspective: Cervical cancer represents a societal economic burden that is expected to increase in line with the rising average life expectancy. It also accounts for a relatively higher loss of life-years compared to other major cancer types and unfortunately demographic models predict a rising incidence of cervical cancer over the next 20 years. The results obtained from this study could significantly contribute to offering a new management of treatment strategy for women with HPV infections and cervical dysplasia. A safe and nonsurgical innovative treatment such as CV-based Vaginal Gel can help repair cervical lesions and enhance HPV clearance, significantly reduce the psychological burden on the affected women and the overall healthcare costs associated with cervical dysplasia and cervical cancer. If HPV infection can be effectively treated, it may prevent the development of cervical dysplasia and thereby contribute to a reduction in cervical cancer incidence. 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.