Safety and Effectiveness Study of Actinic Keratosis Treatment Following Cryosurgery

A Phase 3b Randomized, Double-blinded, Placebo-controlled, Multicenter, Efficacy and Safety Study of Imiquimod Cream Following Cryosurgery for the Treatment of Actinic Keratoses

The objective of this study is to evaluate the efficacy and safety of imiquimod cream versus placebo cream when used after cryosurgery in the treatment of actinic keratoses (AKs).

In this multicenter, randomized, double-blind, placebo-controlled study, the efficacy and safety of imiquimod 3.75% cream following cryosurgery to treat clinically typical visible or palpable AK lesions on the face was compared with that of placebo cream. Based on a 1:1 randomization, approximately 120 subjects applied imiquimod 3.75% cream daily (up to 500 mg cream daily [18.75 mg imiquimod]) and approximately 120 subjects applied placebo cream daily during two 2-week periods (Cycle 1 and Cycle 2) separated by 2 weeks of no treatment. Subjects visited the clinic 9 times-1 screening/cryosurgery visit (additional visits might be needed during the screening period to assess healing from the cryosurgery), 4 treatment visits(treatment initiation at Weeks 0 and 4 and treatment follow-up at the end of Weeks 2 and 6), and 4 posttreatment visits (4, 8, 14, and 20 weeks after the last administration of study treatment at the end of Week 6). The total study duration for a subject, including a 2-week screening period, was up to 28 weeks. Prior to cryosurgery, subjects had to have ≥10 clinically typical visible or palpable AK lesions in an area that exceeded 25 cm^2 on the face to be eligible for participation in the study. At screening, a minimum of 5 visible lesions were not treated with cryosurgery, and 5 to 14 visible lesions were treated with cryosurgery. Subjects had to have at least 5 AK lesions after the skin healed sufficiently from the cryosurgery to be eligible for randomization to either imiquimod 3.75% or placebo cream. Subjects applied up to 2 packets of study cream (500 mg total) as a thin layer to the entire face, avoiding the periocular areas, lips, and nares; ears were excluded from both assessment and treatment. Study cream was applied prior to normal sleeping hours and removed approximately 8 hours later with mild soap and water. Rest periods from daily treatment could be approved by the investigator as needed, with treatment resumption at the investigator's discretion.

Imiquimod 3.75% cream (250 mg/packet) up to 2 packets applied daily Two 2-week treatment periods (Cycle 1 and Cycle 2) separated by a 2-week no-treatment period

cream applied once daily for two 2-week treatment periods (Cycle 1 and Cycle 2) separated by a 2-week no-treatment period

The primary efficacy endpoint was a comparison between the active and placebo treatment groups of percent change from baseline in the total AK lesion count at Week 26. All AK lesions on the face were included in the analysis-treated and untreated AK lesions at baseline (defined as the AK lesion count just prior to cryosurgery) and new lesions that appeared post-baseline.

Proportion of subjects who achieved complete clearance of all AK lesions, cryosurgery-treated AK lesions, and non cryosurgery-treated AK lesions from baseline to Week 26/EOS in the ITT population.

LSRs were assessed independently from AEs. The frequency and percentage of subjects, as well as the mean (SD) and median score for severity (none=0, mild=1, moderate=2, and severe=3), were summarized by treatment group and by visit for the following LSRs: erythema, edema, weeping/exudates, flaking/ scaling/dryness, and scabbing/crusting. Erosion and ulceration were also evaluated (none=0, erosion=1, and ulceration=2). A score of greater than 0 for the specified LSR was considered a "treatment site reaction".

Inclusion Criteria: In good general health Negative urine pregnancy test (for women of child-bearing potential) and agree to use an approved method of birth control while enrolled in the study. Prior to cryosurgery, have ≥ 10 clinically typical (visible or palpable) AKs in an area that exceeds 25 cm2 on the face. Must have had cryosurgery on 5 to 14 AKs on the face after giving informed consent and prior to receiving study medication. Lesions previously treated with cryosurgery must be healed sufficiently prior to randomization to study cream. Following cryosurgery, have ≥ 5 clinically typical (visible or palpable) AKs in an area that exceeds 25 cm2 on the face that are suitable for treatment with the study cream. Exclusion Criteria: Women who are pregnant, lactating, or planning to become pregnant during the study Had a medical event within 90 days of the visit (e.g., stroke, heart attack, etc.). Have any skin condition in the treatment area that may be made worse by treatment with imiquimod (e.g., rosacea, psoriasis, atopic dermatitis, eczema). Have received specific treatments/medications in the treatment area within the designated time period prior to study treatment initiation