HAL-PDT for Cervical Intraepithelial Neoplasia Grade 2

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.

Inclusion criteria

• Voluntarily participate in this clinical study, fully understand the study content, procedures, and potential adverse reactions, and be able to sign the written informed consent form.
• Able to complete the study in accordance with the study protocol.
• Female aged ≥18 years and ≤50 years.
• Newly diagnosed High-Grade Squamous Intraepithelial Lesion (HSIL), cervical intraepithelial neoplasia grade 2 (CIN2) within 3 months, specifically: CIN2 confirmed by tissue biopsy within 3 months prior to the first treatment.

Note: Histopathological diagnosis will be assessed by the pathology department of the participating hospital for enrollment.

• Adequate colposcopy, including:

• Complete visibility of the cervical transformation zone, including the squamocolumnar junction;
• Complete visibility of lesion margins;
• No lesion extension into the cervical canal.
• Cervical size deemed suitable for placement of the HAL-PDT device as assessed by the investigator according to the HAL-PDT package insert.
• Meets the following conditions: negative pregnancy test; no plan for pregnancy during the study period; no sexual activity or use of effective and reliable contraception from the end of the last menstrual period to the start of the study, and agreement to use condoms for barrier contraception during the study period.

Exclusion criteria

Subjects who meet any of the following criteria will be excluded from this study:

• Cervical adenocarcinoma in situ or other glandular lesions, invasive cervical cancer, or suspected malignant lesions.
• Lesions extending to the vaginal wall, cervical canal, or vaginal fornix, or lesions located on the vulva.
• Prior treatment (surgical or physical therapy) for the condition, or receipt of physical or surgical therapy within 3 months after the current histopathological diagnosis of CIN2.
• The date of the first HAL-PDT treatment falls within 7 half-lives of the last antiviral medication.
• History of toxic shock syndrome.
• Severe pelvic inflammatory disease, severe cervicitis, or other severe gynecological infectious diseases found on colposcopic or clinical examination.
• Investigator judges that vaginal bleeding during treatment may affect treatment outcomes.
• Receipt of any inactivated vaccine within 2 weeks prior to the first treatment, or any live vaccine within 4 weeks prior to the first treatment.
• Previous severe cardiovascular, cerebrovascular, neurological, psychiatric, endocrine, or hematopoietic disease that has not been cured; known severely compromised immune function, or need for long-term use of corticosteroids or immunosuppressants; history of malignancy within 5 years.
• History of clinically significant immunosuppression or confirmed autoimmune disease; or primary immunodeficiency.
• Known or newly identified active sexually transmitted diseases (STDs), including but not limited to HIV, syphilis, genital herpes, unless adequately treated and tested negative before study treatment.
• Presence of a cardiac pacemaker.
• Suspected or known porphyria, or known allergy to hexaminolevulinate, its chemically similar compounds, or photosensitizers.
• Allergy to silicone.
• Pregnant or breastfeeding women.
• Delivery or miscarriage within 6 weeks prior to enrollment.
• Participation in any other clinical trial within 30 days prior to HAL-PDT treatment.
• Poor compliance or judged by the investigator to be unsuitable for participation in this clinical study.