Imiquimod 2.5% and 3.75% for the Treatment of Actinic Keratoses: Two Phase 3,Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies
February 2014 | Volume 13 | Issue 2 | Original Article | 166 | Copyright © February 2014
Neil Swanson MD,a Christina Cognata Smith PharmD,b Mandeep Kaur MD,b and Gary Goldenberg MDc
aDepartment of Dermatology, Oregon Health and Science University, Portland, OR
bFormerly with Medicis (A division of Valeant Pharmaceuticals) Scottsdale, AZ
cDepartment of Dermatology, Mount Sinai School of Medicine, New York, NY
Abstract
BACKGROUND: Imiquimod 3.75% and 2.5% creams were studied for the treatment of actinic keratosis (AK) of the full face or balding
scalp, to determine comparable efficacy and tolerability to imiquimod 5% cream.
METHODS: In two identical multicenter, randomized, double-blind, placebo controlled studies. Adult subjects with 5 to 20 visible lesions,
or palpable AKs in an area that exceeded 25cm2 on either the face or balding scalp were randomized to imiquimod 3.75%, 2.5% or
vehicle cream (1:1:1) applied once daily for two 2-week treatment cycles, with a 2-week, no-treatment interval between cycles. Efficacy
was assessed 8 weeks posttreatment (End of Study Visit [EOS]). Primary efficacy was rate of complete clearance of AK lesions. Secondary
efficacy endpoints were rate of partial clearance at EOS (≥ 75% reduction in number of AK lesions compared to baseline) and
median percent decrease from baseline lesion count. Safety assessments included visual assessment of local skin reactions (LSRs),
number and duration of study treatment rest periods required due to intolerant LSRs, adverse events (AEs) and clinical laboratory tests.
RESULTS: Overall 479 patients were randomized to imiquimod 3.75%, 2.5%, or vehicle. Complete clearance rates were 35.6%, 30.6%,
and 6.3% respectively (both P<.001 versus vehicle). The difference in complete clearance rates (imiquimod minus vehicle) was 29.3%
and 24.3%, respectively. Partial clearance rates were 59.4%, 48.1%, and 22.6% respectively (both P<.001 versus vehicle). Median %
reductions in AK lesions were 81.8%, 71.8%, and 25.0% respectively (P<.001 versus vehicle). All primary and secondary efficacy endpoints
were greater in Study 1. Photodamage in the treatment area was 'much improved' with imiquimod 3.75%. Both active creams
were well tolerated with few treatment-related discontinuations.
CONCLUSIONS: In two well-controlled Phase 3 studies, both imiquimod 3.75% and 2.5% creams were more effective than vehicle and
well tolerated when administered daily as a 2-week on/off/on regimen to treat AK. Reduction in AK lesions was comparable to that
reported with imiquimod 5% with fewer local AEs.
J Drugs Dermatol. 2014;13(2):166-169.
INTRODUCTION
Actinic keratosis (AK) is one of the most common skin conditions
seen in dermatological practice.1 From 2000 to 2003,
there were an estimated 5.2 million physician visits annually
in the United States, and the incidence of AK and associated
physician visits appear to be rising.2,3 AKs are typically found on
sun-exposed skin, such as the face, balding scalp, and back of the
hand, especially in fair-skinned individuals (Fitzpatrick skin types
I-III) of advanced age.4 One study found that head, neck, and forearms
comprised 75% of all reported AK lesions;5 multiple lesions
are commonly observed,6 and they are more prevalent in men.7
Most AKs are diagnosed clinically (red, scaly papules or
plaques, 2–5 mm in diameter, occurring in sun-exposed sites
such as face, ears, neck, forearms, hands, and balding scalp)
and rarely confirmed histologically. Although AKs can spontaneously
regress untreated;8 effective treatment combined with
routine surveillance is important, especially in patients with
multiple AKs due to the possibility of malignant transformation
into squamous cell carcinoma (SCC),9 something that increases
with increased duration of presence of an AK.10
The Food and Drug Administration (FDA) approved Imiquimod
5% cream for treatment of AK in 2004. A systematic review and
meta-analysis of five randomized double-blind studies in 1293
patients demonstrated its safe and effective use in the short-term
treatment of AK.11 Complete clearance occurred in 50% of patients
treated with imiquimod 5% cream, compared to 5% treated with
vehicle, and the number needed to treat (NNT) for one patient to
have their AKs completely cleared after 12–16 weeks was 2.2.11
Although treatment adherence was good in these studies, the
long duration and frequent dosing with imiquimod 5% cream
(applied continuously for 16 weeks or as two 4-week cycles) may
be considered inconvenient by some patients and adherence in
real-life dermatology practice could suffer.12 A shorter treatment
duration with daily imiquimod 5% cream was not well tolerated,
with greater than 30% of patients discontinuing treatment.13
To investigate whether a lower concentration of imiquimod
might be efficacious in the treatment of AK on a larger surface
area, with reduced adverse reactions, two placebo-controlled
