A double-blind randomized placebo-controlled trial of hexaminolevulinate (HAL) photodynamic therapy in patients with cervical intraepithelial neoplasia (CIN) 1&2

Objective: Current treatments for clinically relevant CIN are generally extirpative procedures or cryotherapy. These procedures have known long term morbidities including risk for preterm birth. This study investigated the optimal dose and optimal treatment population with respect to safety and efficacy of a novel, potentially tissue preserving treatment for CIN and persistent HPV infection. Methods: Two hundred sixty patients with local biopsy confirmed CIN1 (138 patients) or CIN2 (122 patients) were enrolled at 23 clinical sites in the United States and Europe. Response evaluation was based on adjudicated central pathology review. Patients were randomized to hexylaminolevulinate (HAL) 0.2%, 1%, 5% or placebo ointment combined with an office-placed single-use intravaginal drug delivery device providing red light photoactivation. The drug/ device was applied by the provider and removed by the patients after 10 hours. Patients were offered one re-treatment at 3 months if there was not a complete response. All patients were followed for 9 months after initial treatment. Study endpoints included lesion response by colposcopically-directed biopsy with HPV DNA resolution as well as safety monitoring. Results: One hundred three patients with CIN I and 87 patients with CIN2 were included in the response analyses. The mean age was 29 (range 18-60). 136 (52%) received a second treatment. After 3 months, patients with CIN2 showed a statistically significant and dose-dependent histologic regression in 95% (18/19 pts) (p= 0.01) compared to 57% (12/21 pts) in the placebo arm. Notably, HAL 5% showed oncogenic HPV regression in 62% (8/13 pts) (p= 0.08) compared to 28% (5/18 pts) in the placebo arm, and cleared 83% (5/6 pts) of HPV16/18 infections compared to no clearance (0/6 pts) in the placebo arm. In the total CIN1/2 patient population, HAL 5% showed a lesion response of 66% (33/50 pts) and HPV16/18 clearance in 54% (7/13 pts) compared to 11% (1/9 pts) in the placebo arm. There were no drug related serious adverse events and the treatment was well tolerated. Conclusions: This is a novel non-surgical outpatient treatment with a high provider and patient acceptance that holds promise as an effective and well-tolerated alternative for the treatment of women with CIN2 as well as for patients with oncogenic HPV infections, notably 16/18. Further phase 3 development is ongoing.