Phase 3 Randomized Controlled Trial of Non-inferiority of Topical Imiquimod vs. LEEP for Women With Carcinoma In-situ of the Cervix

A randomized controlled trial of patients with CIN 2-3 to receive either surgical excision with LEEP or CKC versus medical therapy with Imiquimod once weekly inserted vaginally for 16 weeks. Inclusion criteria are women age 21 years or older with confirmed histological diagnosis of CIN 2-3 with a normal endocervical curettage (ECC) if obtained and satisfactory colposcopy (the transformation zone of the cervix was completely visualized.) Exclusion criteria include positive CIN2-3 on ECC, presence of cancer, pregnancy or lactation, immune deficiency, hepatitis, or hypersensitivity to Imiquimod. Patients will be randomized to receive excision with LEEP/CKC or Imiquimod 250 mg (5%) cream (12.5 mg of active ingredient) inserted vaginally once a week for 16 weeks.

The primary outcome will be histological regression to CIN 1 or less. Secondary outcomes will be complete histological regression, high-risk Human Papilloma Virus (HPV) clearance, Clearance of HPV 16, 18/45, and patient tolerance of Imiquimod regimen. Follow up with repeat pap, HPV typing to include 16 and 18/45 subtyping, and colposcopy with directed cervical biopsy will be performed at 6 months post initiation of treatment. Patients unable to complete at least 8 treatments and miss two treatments consecutively will be considered failures and offered immediate LEEP. Those patients that complete 8 treatments of Imiquimod will be reevaluated 6 months from initiating treatment. Demographic information will be obtained to include age, gravidity and parity, smoking history, and contraceptive use.

Descriptive statistics will include numbers and rates of occurrence with confidence intervals of regression, pre, and post-treatment HPV including HPV 16 and 18/45 typing, and adverse effects. The assumed regression rate for the LEEP arm varies within studies. We are choosing a conservative estimate of 85% regression rate from CIN2+ to CIN1 or less. More recently in a 2014 publication in the Journal of Virology (Author Antonio Frega, Journal of Clinical Virology 60 (2014) 39-43) 13% of the LEEP patients out of 475 had residual disease after LEEP. In this study they excluded the 10% of patients that had had positive margins on their LEEP specimen. We are not excluding them as this is intent to treat study. For Imiquimod the Grimm study found a 73.3% regression rate with those treated with the active ingredient. A non-inferiority-type design for two proportions using differences is used in which the difference between treatments is defined as medical treatment being preferable if the regression rate is not more than 15% below that of the excisional treatment. Comparison of the regression rates of the two treatments will be made by a non-inferiority Fisher's exact test.

Required sample size was assessed using the PASS software of the NCSS statistical package. Using power = 0.80 and alpha = 0.05, a power analysis predicts the need for 68 patients per arm for 136. Post-treatment HPV rates will be compared similarly. We will recruit 75 patients to each arm to buffer for a dropout rate.