Bioequivalence of Generic Imiquimod Cream, 5% When Compared to Aldara™ (Imiquimod) Cream, 5% in the Treatment of Actinic Keratosis

A Multicenter, Double-Blind, Randomized, Parallel Group, Vehicle-Controlled Study to Determine the Clinical Equivalence of a Generic Imiquimod Cream, 5% and Aldara™ Cream in Subjects With Actinic Keratosis

At the end of the study, safety and efficacy outcome measures will be compared to determine a) if dosing with Generic Imiquimod cream, 5% is therapeutically equivalent to the currently marketed Aldara (imiquimod) cream, 5% and b) if both imiquimod 5% creams are superior in comparison to the Vehicle cream.

A nationwide, multicenter, double-blind, vehicle-controlled parallel group comparison study of a Generic Imiquimod cream, 5% (Actavis Mid-Atlantic LLC) and currently marketed Aldara (imiquimod) cream, 5% (distributed by Graceway Pharmaceuticals, LLC) was conducted in subjects with actinic keratoses (AKs) on the face and/or anterior scalp in order to evaluate the therapeutic equivalence of these two active treatments and to establish superiority of the efficacy of these two products over a Vehicle cream. Subjects were randomized to one of three treatment groups on a 2:2:1 basis as follows: (1) Generic Imiquimod cream, 5%, (2) Aldara (imiquimod) cream, 5%, and (3) Vehicle cream. The duration of treatment was 16 weeks (± 7 days).

The primary efficacy endpoint was the proportion of subjects in each treatment group with Complete Clearance (having no clinically visible actinic keratosis lesions in the 25 cm2 contiguous treatment area at the 8-week post-treatment visit) of AK lesions. The secondary efficacy endpoints were the Partial Clearance rates, defined as the proportion of subjects with at least a 75% reduction in the number of AK lesions counted at Baseline at the end-of-treatment visit (Week 16, EOT) and at the 8 weeks post-treatment visit/test-of-cure (Week 24, TOC), and the proportion of subjects with Complete Clearance of AK lesions at the end-of-treatment (Week 16, EOT) visit.

A 90% Wald's confidence interval with Yate's continuity correction was constructed around the difference between the proportions of subjects with Complete Clearance of AK lesions in the active treatments (Generic Imiquimod minus Aldara) to evaluate therapeutic equivalence in the primary efficacy analyses. Two-sided, continuity-corrected statistics were used to evaluate the superiority of each active treatment's Complete Clearance rate over that of the Vehicle treatment. The therapeutic comparability evaluations in the per-protocol (PP) population were considered primary while those in the intent-to-treat (ITT) population were considered supportive. The superiority comparisons in the ITT population were considered primary while those in the PP population were considered supportive. If the 90% confidence interval (CI) around the difference between the Generic Imiquimod and Aldara Complete Clearance rates in the PP population were contained within the interval 0.20 to +0.20, and each of these rates was greater than, and statistically different (p<0.05) from, the Vehicle rate in the ITT population, then Generic Imiquimod and Aldara were considered to be therapeutically equivalent.

Secondary efficacy analyses were conducted on the proportion of subjects in each treatment group with Complete Clearance of AK lesions at the Week 16, EOT visit as well as evaluation of the Partial Clearance of AK lesions at both the EOT and TOC visits. The results at both the EOT visit (Week 16) and those at 8 weeks post-treatment (Week 24, TOC) were statistically analyzed by the same methods described for the primary efficacy variable.

Both EOT and TOC analyses were conducted in the ITT population. The TOC analysis was conducted in the PP population and the EOT analysis was conducted in the EOT PP population.

Inclusion Criteria:

• Subjects were male or non-pregnant females, 18 years of age or older, in generally good health. Females who were post-menopausal, surgically sterile or using a medically acceptable form of birth control with a negative urine pregnancy test at the Baseline visit.
• Subjects provided written and verbal informed consent.
• Subjects presented to the clinic with at least 4 but no more than 12 visible, discrete nonhyperkeratotic, nonhypertrophic actinic keratosis lesions within a 25 cm2 Treatment Area on the face and/or anterior scalp.
• Subjects were willing and able to comply with study instructions and return to the clinic for required visits.

Exclusion Criteria:

• Subjects who were lactating, or planning to become pregnant during the study.
• Subjects had hyperkeratotic, hypertrophic or large mat-like AKs within the 25 cm2 Treatment Area.
• Subjects who had the need or were planning to be exposed to artificial tanning devices or excessive sunlight during the trial.
• Subjects who were immunosuppressed (e.g., HIV, systemic malignancy, graft vs. host disease, etc.).
• Subjects who experienced an unsuccessful outcome from previous imiquimod therapy.
• Subjects with known hypersensitivity or previous allergic reaction to any of the active or inactive components of the study drugs.
• Within 2 months: Facial and/or Anterior Scalp: laser resurfacing, photodynamic therapy, chemical peels, dermabrasion, topical application of 5-FU, imiquimod, diclofenac sodium or other treatments for AK or photodamage.
• Subjects who used the following systemic, oral or topical therapies for the periods specified prior to entry into the study:

Within 2 days: Topicals of any kind to the selected Treatment Area. Within 2 weeks: Facial topical medications: corticosteroids, alpha- hydroxyacids (e.g., glycolic acid, lactic acid, etc. greater than 5%), beta-hydroxyacid (salicylic acid greater than 2%), urea - greater than 5% or prescription retinoids (e.g., tazarotene, adapalene, tretinoin) to the face and/or anterior scalp.

Within 2 weeks: Cryotherapy to lesions adjacent to or within the 25 cm2 Treatment Area.

Within 4 weeks: Systemic steroid therapy: chemotherapeutic agents, psoralens, immunotherapy, or retinoids.