This is a prospective, multicenter real-world study evaluating the effectiveness and safety of hexaminolevulinate photodynamic therapy (HAL-PDT) in patients with cervical intraepithelial neoplasia grade 2 (CIN2). Treatment is guided by colposcopic response: patients receive 2, 3, or 4 sessions of HAL-PDT based on lesion persistence at Day 60 and Day 90 assessments. The primary endpoint is histopathological regression rate at 6 months after first treatment. Secondary endpoints include histopathological regression at 12 months, HPV clearance at 6 and 12 months, and safety. A total of 500 patients will be enrolled.
BACKGROUND: Cervical intraepithelial neoplasia grade 2 (CIN2) is a high-grade precancerous lesion with a variable natural history. Current management options include active surveillance or local ablation/excision, but there is interest in minimally invasive treatments that preserve cervical integrity. Hexaminolevulinate photodynamic therapy (HAL-PDT) uses a photosensitizer that accumulates in dysplastic cells and, upon activation by red light, induces targeted cell death while potentially stimulating local anti-HPV immunity. STUDY DESIGN RATIONALE: This prospective, multicenter real-world study is designed to assess the effectiveness and safety of HAL-PDT in routine clinical practice. Unlike a traditional randomized controlled trial, this study uses an adaptive treatment regimen guided by colposcopic response at predefined time points. Participants receive an initial two PDT sessions, and additional sessions (up to a total of four) are given if lesions persist on colposcopy. This response-adaptive approach mirrors clinical decision-making and allows evaluation of a tailored treatment strategy. DETAILED PROCEDURES: * Index date: Day 1 (first PDT). * PDT sessions: Day 1, Day 30-37 (mandatory for all). Additional PDT at Day 60-67 (if lesions present at D60 colposcopy) and/or at Day 90-97 (if lesions persist after third PDT). * Colposcopy with biopsy for histopathology is performed at baseline (within 3 months pre-enrollment), at Month 6 (±7 days), and at Month 12 (±7 days). HPV genotyping and TCT are performed at screening, Month 3 (only for those receiving additional PDT), Month 6, and Month 12. * Adverse events are collected from informed consent through the 12-month follow-up. STATISTICAL METHODS: The primary analysis will estimate the histopathological regression rate at 6 months with a two-sided 95% confidence interval using the exact binomial method. Secondary endpoints (regression at 12 months, HPV clearance at 6 and 12 months) will be analyzed similarly. Subgroup analyses by number of PDT sessions (2, 3, or 4) are exploratory. No formal hypothesis testing against an external control is planned. Safety data will be summarized descriptively. SAMPLE SIZE CONSIDERATIONS: A total of 500 participants will be enrolled.
Study Type
OBSERVATIONAL
Enrollment
500
Histopathological regression rate at 6 months
Proportion of participants with histopathological downgrading from cervical intraepithelial neoplasia grade 2 (CIN2) to normal or low-grade squamous intraepithelial lesion (LSIL/CIN1) on colposcopy-directed cervical biopsy, assessed at 6 months after the first HAL-PDT treatment.
Time frame: 6 months after the first HAL-PDT session
Histopathological regression rate at 12 months
Proportion of participants with histopathological downgrading from cervical intraepithelial neoplasia grade 2 (CIN2) to normal or low-grade squamous intraepithelial lesion (LSIL/CIN1) on colposcopy-directed cervical biopsy, assessed at 12 months after the first HAL-PDT treatment.
Time frame: 12 months after the first HAL-PDT session
HPV clearance rate at 6 months
Proportion of participants with clearance of high-risk human papillomavirus (HPV) subtypes (including but not limited to HPV 16, 18, 52, 58) assessed at 6 months after the first HAL-PDT treatment. HPV clearance is defined as undetectable of the same high-risk HPV subtype that was present at baseline.
Time frame: 6 months after the first HAL-PDT session
HPV clearance rate at 12 months
Proportion of participants with clearance of high-risk human papillomavirus (HPV) subtypes (including but not limited to HPV 16, 18, 52, 58) assessed at 12 months after the first HAL-PDT treatment. HPV clearance is defined as undetectable of the same high-risk HPV subtype that was present at baseline.
Time frame: 12 months after the first HAL-PDT session
Safety and tolerability of HAL-PDT
Incidence, type, severity (mild, moderate, severe), duration, and relatedness to study treatment of adverse events (AEs) and serious adverse events (SAEs) occurring from signing of informed consent through the end of study follow-up.
Time frame: From informed consent through 12 months after first HAL-PDT session (approximately up to 12 months)
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