Hexaminolevulinate Photodynamic Therapy (HAL-PDT) With Deferred Surgery Versus Surgery for High-grade Squamous Intraepithelial Lesions (HSIL)

High-grade squamous intraepithelial lesions (HSIL), encompassing cervical intraepithelial neoplasia grade 2 (CIN2) with p16 positivity and grade 3 (CIN3), are well-established precursors to invasive cervical cancer. Immediate excisional procedures such as loop electrosurgical excision procedure (LEEP) or cold knife conization remain the standard of care; however, they are associated with significant long-term morbidities, including cervical stenosis, cervical incompetence, and adverse obstetric outcomes in women of childbearing age. Hexaminolevulinate photodynamic therapy (HAL-PDT) is a non-invasive, tissue-preserving modality that offers a potential alternative.

This Phase II trial is designed to test the hypothesis that HAL-PDT (HAL-PDT Q2W×6 ) with deferred surgery achieves a 12-month pathological regression rate non-inferior to that of immediate surgery, while providing a favorable safety and quality-of-life profile.

A total of 230 subjects are planned for enrollment, with 115 allocated to each treatment arm. The primary efficacy analysis will be performed on both the Intention-to-Treat (ITT) and Per-Protocol (PP) populations to test the non-inferiority margin, which is pre-specified based on clinically acceptable thresholds. Safety analyses will be conducted on the Safety Set (SS).

• Loop Electrosurgical Excision Procedure (LEEP) or Cold Knife Conization (CKC) (Procedure): Subjects undergo immediate surgical excision of the cervical lesion via either Loop Electrosurgical Excision Procedure (LEEP) or Cold Knife Conization (CKC), as determined by the investigator based on the subject's individual lesion characteristics, size, and clinical presentation, following standard institutional surgical protocols.
• HAL 5% with illumination (Combination product): HAL-PDT is a drug-device combination product. The drug is hexaminolevulinate hydrochloride (HAL) 5% ointment. The device is a single-use cervical light delivery device (CL7) with integrated red LEDs. The ointment is applied into the device cup, placed against the cervix for 5 hours of drug absorption, then automatically delivers 125 J/cm² photodynamic therapy for 4 hours and 36 minutes. Total in-situ time is 11-24 hours. Patients remove the device themselves. Treatment regimen: one session every 2 weeks for a total of 6 sessions (Q2W × 6).

Primary outcomes

• Histopathological regression rate at 12 months [12 months after the first treatment]: Proportion of participants with pathological remission on colposcopy-directed cervical biopsy at 12 months after the first treatment. Pathological remission is defined as histopathological finding of normal tissue or low-grade squamous intraepithelial lesion (LSIL)

Secondary outcomes

• Human Papillomavirus (HPV) baseline clearance rate at 6 months [6 months after the first treatment]: Proportion of participants with clearance of baseline high-risk Human Papillomavirus (HPV) subtypes at 6 months after the first treatment. HPV clearance is defined as undetectable of the same high-risk HPV subtype(s) that were present at baseline.
• Pathological remission rate at 6 months [6 months after the first treatment]: Proportion of participants with pathological remission on colposcopy-directed cervical biopsy at 6 months after the first treatment. Pathological remission is defined as histopathological finding of normal tissue or low-grade squamous intraepithelial lesion (LSIL).
• HPV baseline clearance rate at 12 months [12 months after the first treatment]: Proportion of participants with clearance of baseline high-risk HPV subtypes at 12 months after the first treatment. HPV clearance is defined as undetectable of the same high-risk HPV subtype(s) that were present at baseline.
• Quality of life assessed by EORTC QLQ-CX24 [12 months after the first treatment]: Quality of life assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Cervical Cancer Module (EORTC QLQ-CX24). Scores for each domain are linearly transformed to a 0-100 scale. For global health status and functional domains, a higher score indicates a better outcome (better quality of life/function). For symptom scales, a higher score indicates a worse outcome (more severe symptoms).
• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [From informed consent through 12 months after the first treatment]: Incidence, type, severity (mild, moderate, severe), duration, and relatedness to photodynamic therapy and/or surgical treatment of adverse events (AEs) and serious adverse events (SAEs) occurring from signing of informed consent through the end of study follow-up.
• Incidence of cervical cancer at 12 months [12 months after the first treatment]: Proportion of participants with histologically confirmed cervical cancer (any stage) diagnosed within 12 months after the first treatment.

Sex: Female, ages: 18 Days to any

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.
* Subject age ≥18 years.
* Presence of High-Grade Squamous Intraepithelial Lesion (HSIL) (CIN2 P16 positive/CIN3), specifically: HSIL with histopathological diagnosis of grade II/III (CIN2 P16 positive/CIN3) within 3 months prior to the first treatment.
* Adequate colposcopy, including: (a) Complete visibility of the cervical transformation zone, including the squamocolumnar junction; (b) Complete visibility of lesion margins.
* The investigator determines that non-surgical treatment is acceptable for the participant.
* The investigator determines that the cervical size is suitable for placement of the HAL-PDT device.
* Meets the following conditions: Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result prior to the start of treatment. 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. WOCBP is defined as a female who has experienced menarche, has not undergone hysterectomy or bilateral oophorectomy, and has not reached natural menopause (i.e., no menstruation at all for the past 24 consecutive months).

Exclusion Criteria:

* Cervical adenocarcinoma in situ or other glandular lesions, invasive cervical cancer, or suspected malignant lesions.
* CIN2 with P16 negative.
* Lesions extending to the vaginal wall, cervical canal, or vaginal fornix, or lesions located on the vulva.
* Prior physical or surgical treatment to the cervix resulting in incomplete cervical structure (e.g., cold knife conization), or receipt of physical or surgical therapy for CIN2 or CIN3 after the current histopathological diagnosis.
* The first study treatment day falls within 7 half-lives of the last antiviral medication.
* 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 the study drug, 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 study treatment.
* Poor compliance or judged by the investigator to be unsuitable for participation in this clinical study.