Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S et al.. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 141: 467-473

Article (PDF Available)inArchives of Dermatology 141(4):467-73 · April 2005with38 Reads
DOI: 10.1001/archderm.141.4.467 · Source: PubMed
Abstract
To evaluate the efficacy and safety of 5% imiquimod cream compared with vehicle in the treatment of actinic keratosis (AK). Two phase 3 randomized, double-blind, parallel-group, vehicle-controlled studies. Twenty-six ambulatory care offices, including dermatologists in private practice or research centers. Four hundred ninety-two patients, 18 years and older, with 4 to 8 AK lesions in a 25-cm(2) treatment area on the face or the balding scalp were randomized; an additional 162 patients underwent screening but were ineligible. Patients applied 5% imiquimod (Aldara) or vehicle cream to the treatment area once daily, 3 times per week, for 16 weeks, followed by an 8-week posttreatment period. Complete clearance rate (proportion of patients at the 8-week posttreatment visit with no clinically visible AK lesions in the treatment area), partial clearance rate (proportion of patients at the 8-week posttreatment visit with a >/=75% reduction in the number of baseline AK lesions in the treatment area), and frequency and severity of adverse events and local skin reactions were measured. Complete and partial clearance rates for imiquimod-treated patients (48.3% and 64.0%, respectively) were clinically and statistically significantly higher than for vehicle-treated patients (7.2% and 13.6%, respectively). The median percentage reduction of baseline lesions was 86.6% for the imiquimod-treated group and 14.3% for the vehicle-treated group. The 5% imiquimod cream dosed 3 times weekly for 16 weeks is safe and effective for the treatment of AK.
STUDY
Dosing With 5% Imiquimod Cream 3 Times
per Week for the Treatment of Actinic Keratosis
Results of Two Phase 3, Randomized, Double-blind, Parallel-Group,
Vehicle-Controlled Trials
Neil Korman, MD, PhD; Ron Moy, MD; Mark Ling, MD, PhD; Robert Matheson, MD; Stacy Smith, MD;
Scott McKane, MS; James H. Lee, MD, PhD
Objective: To evaluate the efficacy and safety of 5% imi-
quimod cream compared with vehicle in the treatment
of actinic keratosis (AK).
Design: Two phase 3 randomized, double-blind, parallel-
group, vehicle-controlled studies.
Setting: Twenty-six ambulatory care offices, including
dermatologists in private practice or research centers.
Patients: Four hundred ninety-two patients, 18 years
and older, with 4 to 8 AK lesions in a 25-cm
2
treatment
area on the face or the balding scalp were randomized;
an additional 162 patients underwent screening but were
ineligible.
Interventions: Patients applied 5% imiquimod (Al-
dara) or vehicle cream to the treatment area once daily,
3 times per week, for 16 weeks, followed by an 8-week
posttreatment period.
Main Outcome Measurements: Complete clear-
ance rate (proportion of patients at the 8-week posttreat-
ment visit with no clinically visible AK lesions in the treat-
ment area), partial clearance rate (proportion of patients
at the 8-week posttreatment visit with a 75% reduc-
tion in the number of baseline AK lesions in the treat-
ment area), and frequency and severity of adverse events
and local skin reactions were measured.
Results: Complete and partial clearance rates for imi-
quimod-treated patients (48.3% and 64.0%, respectively)
were clinically and statistically significantly higher than for
vehicle-treated patients (7.2% and 13.6%, respectively). The
median percentage reduction of baseline lesions was 86.6%
for the imiquimod-treated group and 14.3% for the vehicle-
treated group.
Conclusion: The 5% imiquimod cream dosed 3 times
weekly for 16 weeks is safe and effective for the treat-
ment of AK.
Arch Dermatol. 2005;141:467-473
A
CTINIC KERATOSES (AKS)
are epidermal lesions con-
sisting of dysplastic kera-
tinocytes that generally
occur in fair-skinned indi-
viduals with long-term exposure to UV ra-
diation.
1,2
Although the exact pathogen-
esis of AK is unknown, long-term UV
radiation is known to produce local and
systemic immunosuppression, mutations in
the p53 tumor suppressor gene, and DNA
pyrimidine covalent dimers, each of which
are believed to contribute to the develop-
ment of AK.
3,4
The most common current
therapies for AK include cryosurgery, cu-
rettage with or without electrosurgery, and
topical fluorouracil. Despite the wide-
spread use of these therapies, most have
limitations such as inconvenience, pain, and
scarring. Furthermore, none of the cur-
rent therapies target a critical component
underlying the disease pathogenesis: the
suppression of the immune response.
The only treatment for AK that works
by enhancing the immune response against
dysplastic cells is 5% imiquimod cream (Al-
dara; 3M Pharmaceuticals, St Paul, Minn).
Imiquimod has been shown to induce the
production of interferon , tumor necro-
sis factor , and interleukin (IL) 12 (IL-
12), with a resulting cytokine cascade that
may induce and/or support a cytotoxic T-
lymphocyte immune response.
5
Ongoing
research has recently shown that imi-
See also pages 447 and 507
CME course available at
www.archdermatol.com
Author Affiliations are listed at
the end of this article.
Financial Disclosure: Drs Moy,
Ling, Matheson, and Smith
received support from 3M
Pharmaceuticals for performing
clinical trials. Drs Smith and
Ling have received funding (eg,
research support and honoraria)
from companies with
competing products.
Drs Korman, Moy, and
Matheson received clinical trial
support and honoraria from 3M
Pharmaceuticals. This research
was conducted with financial
support from 3M
Pharmaceuticals, St Paul, Minn.
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quimod may also act through Toll-like receptor 7 to stimu-
late rapid synthesis and release of cytokines from mono-
cytes, macrophages, and dendritic cells. Toll-like
receptors are receptors that recognize special patterns
on immune cell surfaces and are considered essential
components of the human innate immune response.
6
Since imiquimod works through an immunological
mechanism, regimens with infrequent dosing for an ex-
tended duration have been evaluated to minimize po-
tentially intolerable adverse effects. To date, 5 large ran-
domized, double-blind, parallel-group, vehicle-
controlled studies have been conducted to evaluate the
efficacy and safety of topically applied 5% imiquimod
cream vs vehicle cream for the treatment of AK lesions
on the face and balding scalp. Two of these studies evalu-
ated once-daily dosing 2 times per week for 16 weeks;
the other 3 studies evaluated once-daily dosing 3 times
per week for 16 weeks. The complete and partial clear-
ance rates for both studies that evaluated dosing 2 times
per week and for one of those that evaluated dosing 3
times per week have been reported.
7,8
The efficacy end
point in that previously reported study of dosing 3 times
per week included histological confirmation and clini-
cal lesion assessments. The results of the remaining 2 stud-
ies that evaluated the regimen of dosing 3 times per week
are presented herein.
METHODS
STUDY POPULATION
The study population consisted of otherwise healthy men and
women 18 years or older with a clinical diagnosis of 4 to 8 AK
lesions within a contiguous 25-cm
2
treatment area on the face
or the balding scalp as previously described.
7
STUDY DESIGN
Two independent, randomized, double-blind, parallel-group,
vehicle-controlled studies collectively enrolled patients from
26 US study centers (13 centers per study). The primary and
secondary objectives of these studies were to evaluate the ef-
ficacy and safety of 5% imiquimod cream, respectively, com-
pared with vehicle cream in the treatment of AK lesions on the
face or the balding scalp when the cream was applied once daily
3 times per week for 16 weeks.
The studies consisted of prestudy (2 weeks), treatment
(16 weeks), and posttreatment (8 weeks) periods. Patients un-
derwent assessment during treatment weeks 1, 2, 4, 6, 8, 10,
12, 14, and 16 and posttreatment weeks 4 and 8.
At the treatment initiation visit, enrolled patients were as-
signed the next sequential patient study number and the cor-
responding study cream, which was randomized and labeled,
on the basis of a computer-generated randomization schedule
(stratified by study center). Patients were randomized to imi-
quimod or to vehicle cream in a 1:1 ratio. At the treatment ini-
tiation visit, the treatment area and the location of the 4 to 8
baseline AK lesions were recorded and mapped.
Patients were instructed to apply the study cream (imi-
quimod or vehicle) to the entire treatment area at the same time
of day (just before normal sleeping hours), and the cream was
to remain in place for approximately 8 hours. Rest periods
from study cream were allowed at the discretion of the inves-
tigator, but did not alter the length of the 16-week treatment
period. Patients who discontinued treatment were asked to re-
turn for an assessment of their AK lesions at the 8-week post-
treatment visit.
All study procedures and informed consent documents re-
ceived approval from the respective institutional review boards,
and all enrolled patients signed informed consent forms.
EFFICACY MEASUREMENTS
Actinic keratosis lesions were counted at the 4-, 8-, and 16-week
treatment visits and the 8-week posttreatment visit. No differen-
tiation was made between the baseline and new AK lesions.
The primary variable was the complete clearance rate, de-
fined as the proportion of patients at the 8-week posttreat-
ment visit with no clinically visible AK lesions in the treat-
ment area. The secondary efficacy variable was the partial
clearance rate, defined as the proportion of patients at the 8-week
posttreatment visit with at least a 75% reduction in the num-
ber of baseline AK lesions in the treatment area. An additional
measurement of clearance was the median percentage of re-
duction of baseline AK lesions at the 8-week posttreatment visit.
SAFETY MEASUREMENTS
Safety was monitored by reviewing concomitant medication use
and assessing the incidence and severity of adverse events and
local skin reactions. For the purposes of these studies, local skin
reactions were differentiated and prospectively collected inde-
pendently from adverse events (spontaneously reported). Local
skin reactions in the treatment and surrounding areas were clini-
cally categorized as erythema, edema, erosion/ulceration, scabbing/
crusting, weeping/exudation, vesicles, and flaking/scaling/
dryness. The intensity of an investigator-assessed local skin
reaction was rated, with 0 indicating none; 1, mild; 2, moder-
ate; and 3, severe. Reactions within the treatment area that were
not assessed as local skin reactions were reported as adverse events.
At the treatment initiation and 8-week posttreatment visits, in-
vestigators performed skin quality assessments of the treatment
area. Characteristics assessed included skin surface (roughness/
dryness/scaliness), hyperpigmentation, hypopigmentation,
mottled or irregular pigmentation (hyperpigmentation and hy-
popigmentation), degree of scarring, and degree of atrophy. Af-
ter visual, clinical, and tactile examinations of the treatment area,
the investigator coded the intensity of each characteristic (with
0 indicating none; 1, mild; 2, moderate; and 3, severe).
STATISTICAL ANALYSIS
The primary data set analyzed was the intent-to-treat data set,
which consisted of combined data from the 2 studies and in-
cluded all randomized patients. For each study, 94 patients per
treatment group were required to have at least 90% power to de-
tect a difference in complete clearance rates of 35% for the imi-
quimod group vs 14% for the vehicle group, with a type I error
rate of .05. Assuming a 20% dropout rate, 120 patients per treat-
ment group were required, giving a total of 240 patients per study.
There were no interim analyses or stopping rules.
The Cochran-Mantel-Haenszel test was used to compare the
treatment groups (imiquimod vs vehicle) with respect to com-
plete clearance rate; the test was performed at the .05 level of
significance. The difference in complete clearance rates (imi-
quimod minus vehicle) with an associated 95% confidence in-
terval (CI) was calculated. The same analyses were performed
on partial clearance as described for complete clearance. The
Cochran-Armitage test for trend in proportions (2 sided) ex-
amined relationships between complete clearance and the most
intense local skin reaction experienced by patients.
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Adverse events were compared between treatment groups
using the Fisher exact test. Wilcoxon rank sum tests were used
to compare treatment groups with respect to local skin reac-
tion assessments. For skin quality assessments, Wilcoxon signed
rank tests were used to assess the significance of within-
treatment changes from baseline, and Wilcoxon rank sum tests
were used to assess the significance of between-treatment
changes from baseline.
RESULTS
The combined studies enrolled 492 patients; 242 pa-
tients were randomized to 5% imiquimod cream and 250
patients were randomized to vehicle cream (
Figure 1).
Enrollment for both studies began in August 2001, and
all study procedures were completed by August 2002.
DEMOGRAPHICS
The median age of the patients was 67 years. All were
white; 61 (12.4%) were female; and 431 (87.6%) were
male. The sex distribution observed in this study was con-
sistent with previous epidemiological data.
9
There were
no distribution differences for sex, age, race, or skin type
between treatment groups (
Table 1).
EFFICACY
Complete clearance occurred in 117 (48.3%) of 242 pa-
tients in the imiquimod group and 18 (7.2%) of 250 pa-
tients in the vehicle group (P.001). The difference in
complete clearance rates was 41.1% (95% CI, 34.1%-
48.2%). Partial clearance occurred in 155 (64.0%) of imi-
quimod-treated patients and 34 (13.6%) of vehicle-
treated patients (P.001).
Differences for the complete and partial clearance rates
in the imiquimod groups were observed between the 2 stud-
ies; complete clearance rates were 56.4% vs 40.8% and par-
tial clearance rates were 71.8% vs 56.8%. No differences
in baseline characteristics or demographics of the pa-
tients were noted between the 2 studies (data not shown).
For the imiquimod group, there was a statistically sig-
nificant observed association between complete and par-
tial clearance rates and the intensity of local skin reac-
tions. Specifically, clearance rates tended to increase as
the intensity of erythema increased (
Figure 2).
The number of patients who had an increase in AK
lesion count at any point in the treatment period was
higher in the imiquimod group (103/242 [42.6%]) com-
pared with the vehicle group (55/250 [22.0%]). The com-
plete clearance rate was slightly higher for imiquimod-
treated patients who had an increase in AK lesion count
over baseline (56/103 [54.4%]) compared with imi-
quimod-treated patients who did not have an increase in
lesion count (61/139 [43.9%]).
At the 8-week posttreatment visit, the median percent-
age of reduction in AK lesion count was 86.6% for the imi-
quimod group and 14.3% for the vehicle group. This means
that half of the patients in the imiquimod group had at least
an 86.6% reduction in the number of baseline AK lesions.
492 Patients Randomized
242 Received 5% Imiquimod Cream
250 Received Vehicle Cream
210 Completed Treatment Period
32 Withdrew in Treatment Period
237 Completed Treatment Period
13 Withdrew in Treatment Period
209 Completed 8-wk Posttreatment
Assessments
18 Completed 8-wk Posttreatment
Assessments
234 Completed 8-wk Posttreatment
Assessments
1 Completed 8-wk Posttreatment
Assessments
1 Did Not Complete 8-wk Posttreatment
Assessments
14 Did Not Complete 8-wk Posttreatment
Assessments
3 Did Not Complete 8-wk Posttreatment
Assessments
12 Did Not Complete 8-wk Posttreatment
Assessments
Figure 1. Patient accountability for the combined application studies of dosing 3 times per week.
Table 1. Summary of Patient Demographics*
Variable
Treatment Group
P Value†
5% Imiquimod
Cream
(n = 242)
Vehicle Cream
(n = 250)
Sex
Female 32 (13.2) 29 (11.6)
.59
Male 210 (86.6) 221 (88.4)
Age, y
Mean ± SD 66.7 ± 10.6 65.9 ± 9.9
.82
Range 41-87 41-93
White race 242 (100) 250 (100)
Skin type (Fitzpatrick)
I-II 157 (64.9) 149 (59.6)
.26
III-VI 85 (35.1) 101 (40.4)
*Unless otherwise indicated, data are expressed as number (percentage)
of patients.
P values for sex and skin type are calculated by means of the Fisher exact
test; for age, by means of analysis of variance.
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SAFETY
Adverse Events
Adverse events occurred in both the imiquimod (176/242
[72.7%]) and vehicle (149/250 [59.6%]) treatment groups.
At least 1 adverse event considered by the investigator as
possibly or probably related to the study drug was re-
ported by 104 (43.0%) of imiquimod-treated patients and
22 (8.8%) of vehicle-treated patients (P.001). The most
frequently reported adverse event was application site re-
action, with “itching at target site” reported most often. Ap-
plication site reactions were reported by 94 (38.8%) of imi-
quimod-treated patients and 18 (7.2%) of vehicle-treated
patients (P.001). The most frequently reported applica-
tion site reactions that were considered possibly or prob-
ably related to study cream are listed by type in
Table 2.
Other adverse events showing statistically significant
differences between the imiquimod and vehicle groups
were fever (7 patients [2.9%] vs 1 patient [0.4%]; P=.04)
and postoperative pain (9 patients [3.7%] vs 2 patients
[0.8%]; P=.03). The adverse events of postoperative pain
reported by patients included references to dental pro-
cedures (5 patients), unspecified operation (2 sub-
jects), and squamous cell carcinoma removal from the
ear of a subject randomized to the treatment of the scalp,
hammer toe surgery, arthroscopic knee surgery, and kid-
ney surgery (1 patient each). None of the adverse events
of postoperative pain were considered by the investiga-
tor to be related to study drug.
Forty-two serious adverse events were reported by 20
patients (12 imiquimod- and 8 vehicle-treated pa-
tients); none of the serious adverse events were consid-
ered by the investigator to be related to study drug. No
deaths occurred in these studies.
Local Skin Reactions
Local skin reactions were common and occurred in both
treatment groups. Both imiquimod- and vehicle-treated
patients experienced severe local skin reactions; the rate
of severe local skin reactions was higher in the imi-
quimod group.
Table 3 includes the most intense
70
60
50
40
30
20
10
0
None
(n
=
4)
Mild
(n
=
36)
Moderate
(n
=
121)
Severe
(n
=
80)
Erythema Intensity
Complete Clearance Rate, %
0%
25%
46%
65%
Figure 2. Complete clearance by most intense erythema in the 5%
imiquimod cream–treated subjects. Cochran-Armitage test for trend P.001
(2 sided). There was a trend for complete clearance to increase as the
intensity of erythema increased.
Table 2. Application Site Reactions Possibly or Probably
Related to Study Drug Reported by at Least 1% of Patients
Application Site
Reaction†
Treatment Group, No. (%)*
P Value‡
5% Imiquimod
Cream
(n = 242)
Vehicle Cream
(n = 250)
Itching at target site 70 (28.9) 10 (4.0) .001
Burning at target site 18 (7.4) 2 (0.8) .001
Itching at remote site 17 (7.0) 3 (1.2) .001
Pain at target site 9 (3.7) 0 .002
Tenderness at target site 5 (2.1) 2 (0.8) .28
Infection at target site 4 (1.7) 0 .06
Burning at remote site 4 (1.7) 0 .06
Stinging at target site 3 (1.2) 1 (0.4) .37
Swollen at remote site 3 (1.2) 0 .12
Tenderness at remote site 3 (1.2) 0 .12
*Both study treatments were applied 3 times per week.
†Target site refers to the treatment area; remote site refers to the area
surrounding the treatment area and beyond.
‡Calculated by means of the Fisher exact test.
Table 3. Three Most Frequent Investigator-Assessed Local Skin Reactions
Summary by Intensity
Skin Reactions, No. (%)*
Erythema Flaking/Scaling/Dryness Scabbing/Crusting
Imiquimod Vehicle Imiquimod Vehicle Imiquimod Vehicle
Most intense during the study
None 4/241 (1.7) 29/250 (11.6) 13/241 (5.4) 41/250 (16.4) 32/241 (13.3) 140/250 (56.0)
Mild 36/241 (14.9) 158/250 (63.2) 88/241 (36.5) 152/250 (60.8) 60/241 (24.9) 95/250 (38.0)
Moderate 121/241 (50.2) 63/250 (25.2) 119/241 (49.4) 56/250 (22.4) 83/241 (34.4) 15/250 (6.0)
Severe 80/241 (33.2) 0/250 21/241 (8.7) 1/250 (0.4) 66/241 (27.4) 0/250
Any during study (mild, moderate, or severe) 237/241 (98.3) 221/250 (88.4) 228/241 (94.6) 209/250 (83.6) 209/241 (86.7) 110/250 (44.0)
Baseline score (none) 73/242 (30.2) 76/249 (30.5) 71/242 (29.3) 78/249 (31.3) 210/242 (86.8) 217/248 (87.5)
8-wk Posttreatment visit score (none) 130/226 (57.5) 101/235 (43.0) 165/226 (73.0) 94/235 (40.0) 224/226 (99.1) 208/235 (88.5)
*Imiquimod administered as 5% imiquimod cream. One imiquimod-treated patient did not undergo an assessment of local skin reactions after treatment
initiation, so the denominator for the imiquimod group is 241 rather than 242. Baseline data were missing (not collected) for 1 vehicle-treated patient for
flaking/scaling/dryness, and for 2 vehicle-treated patients for scabbing/crusting.
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investigator-assessed local skin reactions in the treat-
ment area during the course of the study (excluding the
treatment initiation visit), the percentage of patients with
any reaction at any time after treatment initiation, the
number of patients with no reaction at treatment initia-
tion, and the number of patients with no reaction at the
8-week posttreatment visit. Overall, local skin reactions
were well tolerated and generally resolved or dimin-
ished in intensity after cessation of treatment (
Figure 3).
Discontinuations From Study
Patients could have discontinued (withdrawn) from the
treatment period, the posttreatment period, or both. Pa-
tients who withdrew from the treatment period did not
restart treatment, but were asked to return for posttreat-
ment procedures. During the treatment period, 32 (13.2%)
of 242 imiquimod-treated patients and 13 (5.2%) of 250
vehicle-treated patients discontinued from the study. Fif-
teen imiquimod-treated patients and 15 vehicle-treated
patients discontinued during the posttreatment period.
Table 4 summarizes the patients who discontinued dur-
ing the treatment and posttreatment periods, stratified
by reason for the discontinuation.
Rest Periods
Rest periods were taken by 99 (40.9%) of 242 imiquimod-
treated patients and 2 (0.8%) of 250 vehicle-treated pa-
tients. Of the patients taking rest periods, 86 (86.9%) of
the 99 imiquimod-treated patients and 2 (100%) of the
2 vehicle-treated patients resumed treatment after their
last rest period.
Skin Quality Assessment
In general, the 8-week posttreatment assessments for each
skin quality category indicated more patients with less
intense scores than those with more intense scores after
treatment with imiquimod.
Scores for scarring and skin surface categories showed
statistically significant within-treatment shifts from base-
line to 8 weeks after treatment for the imiquimod group.
Statistical significance was also found when scores for skin
surface were compared between imiquimod and vehicle
groups. Each significant shift was due to imiquimod-
treated patients having less intense scores at 8 weeks af-
ter treatment than at baseline. Of the 226 imiquimod-
treated patients with both initiation and 8-week
posttreatment skin surface assessments, 9 (4.0%) had an
increase and 115 (50.9%) had a decrease in intensity at
the 8-week posttreatment assessment compared with base-
line. Because of inconsistencies in the investigators’ in-
terpretation of hyperpigmentation, hypopigmentation, and
mottled pigmentation, these data are not presented.
COMMENT
The results from these large clinical studies and previ-
ously published studies confirm that 5% imiquimod cream
is a safe and effective treatment option for AK. Unlike
other treatments for AK, imiquimod is an immune-
based therapy. Imiquimod has been shown to stimulate
the immune system by activating antigen-presenting cells
such as monocytes/macrophages and dendritic cells to
produce interferon and other cytokines and chemo-
kines. Imiquimod appears to mediate these cellular ef-
fects through a Toll-like receptor, leading to the activa-
tion of transcription factor nuclear factor B, which then
culminates in the transcription of a number of cyto-
kines including tumor necrosis factor , IL-1, IL-6, IL-8,
and IL-12.
10-12
These cytokines stimulate several other as-
pects of the innate immune response and are important
for directing the adaptive immune response. The en-
hancement of the immune response is an ideal therapeu-
B
A
C
Figure 3. Resolution of actinic keratosis (AK) lesions after treatment with
5% imiquimod cream. A, Baseline count of 5 AK lesions in treatment area.
B, At treatment week 8, 6 AK lesions, mild edema, erosion/ulceration,
flaking/scaling/dryness, scabbing/crusting, and moderate erythema are seen.
C, At 8 weeks after treatment, complete clearance (0 lesions) and no local
skin reactions are seen.
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tic approach for AK. The pathogenesis of AK involves sup-
pression of the immune response against the abnormal
cells that can be caused by long-term UV light expo-
sure. Imiquimod treatment can reverse this immunosup-
pression, which potentially could reduce the rate of re-
currences and the possibility of malignant transformation.
The complete and partial clearance rates for the imi-
quimod-treated patients were 48.3% and 64.0%, respec-
tively. The clinical response with imiquimod dosing 3 times
per week was higher than the response seen with dosing 2
times per weekg
7
; however, the magnitude of the increase
was not as large as expected for a dosing regimen that was
50% higher. The modest difference in the clinical re-
sponse between the 2 dosing regimens may be partly re-
lated to the low complete clearance seen in one of the stud-
ies evaluating dosing 3 times per week (40.8% vs 56.4%).
No methodological explanation for this difference was ap-
parent. The difference was most likely the result of ran-
dom variation seen with clinical studies. However, the com-
plete clearance rate from the third study that also evaluated
dosing 3 times per week was 57.1%.
8
These data suggest
that the 56% clearance rate is more likely the true efficacy
for this dosing regimen. If the actual efficacy rate for dos-
ing 3 times per week is closer to the 56%, the incremental
benefit of higher doses of imiquimod may be clinically jus-
tified in some patients.
The end point of complete clearance was a rigorous study
end point that underestimated the clinical effectiveness of
this treatment. For example, patients who experienced reso-
lution of 7 of 8 lesions were still considered treatment fail-
ures because they did not achieve complete clearance. A
more clinically useful measurement of the benefit is the
median percentage of reduction in the number of lesions
counted at baseline for each patient. The median percent-
age of reduction in baseline lesions was greater than 86%
in the studies of dosing 3 times per week. This compares
favorably with reported lesion clearance rates of pharma-
cological and nonpharmacological treatments for AK.
13
More frequent dosing (3 vs 2 times per week) was as-
sociated with more local skin and application site reac-
tions, more rest periods, and more subjects who discon-
tinued treatment owing to local skin reactions (10/242 [4%]
for imiquimod 3 times per week).
7
However, the reac-
tions were generally well tolerated and either resolved or
diminished in intensity after cessation of treatment. This
pharmacodynamic response is consistent with the im-
mune mechanism of imiquimod. Futhermore, complete and
partial clearance rates tended to increase as the intensity
level of erythema increased. Therefore, based on the ap-
pearance of local skin reactions and their association with
clearance, local skin reactions can be considered an exten-
sion of the pharmacological effects of imiquimod cream.
This pharmacological response contributed to one of
the limitations of this study. Although the study design
was double blind, the pharmacodynamic effect of imi-
quimod treatment may have biased the investigators’ as-
sessments; however, when there is an evident pharma-
codynamic response, bias is inherent in the study.
An additional benefit from imiquimod treatment ap-
pears to be improved skin quality compared with vehicle
treatment. Although this phenomenon has been observed
with nonspecific treatments that induce inflammation, the
cytokines observed after imiquimod treatment have been
reported to mediate wound healing and tissue remodel-
ing.
14-16
Therefore, an improved cosmetic outcome may be
another potential benefit of imiquimod treatment.
Because imiquimod works by enhancing the innate and
adaptive immune responses, individual patient re-
sponses will vary depending on many intrinsic and ex-
trinsic factors, such as the number and responsiveness of
Langerhans cells and extent of solar damage. Although it
is not known which factors will predict a patient’s re-
sponse to imiquimod, it is reassuring to clinicians that many
different dosing regimens appear to be safe and effective.
CONCLUSIONS
Dosing with 5% imiquimod cream 3 times per week for
16 weeks was a safe and effective regimen for the treat-
Table 4. Patients Discontinued From the Treatment and Posttreatment Periods for Any Reason*
Primary Reason
for Discontinuation
Treatment Group,† No. (%)
Treatment Period Posttreatment Period
Imiquimod
(n = 242)
Vehicle
(n = 250)
Imiquimod
(n = 242)
Vehicle
(n = 250)
Adverse event 10 (4.1) 6 (2.4) 2 (0.8) 4 (1.6)
Lost to follow-up‡ 2 (0.8) 3 (1.2) 2 (0.8) 4 (1.6)
Decreased 0 0 0 0
Personal 8 (3.3) 4 (1.6) 8 (3.3) 6 (2.4)
Noncompliance 1 (0.4) 0 0 0
Other 0 0 1 (0.4)§ 1 (0.4)§
Local skin reaction 10 (4.1) 0 1 (0.4) 0
Entry criteria violated 1 (0.4) 0 1 (0.4) 0
Total 32 (13.2) 13 (5.2) 15 (6.2) 15 (6.0)
*Patients could have been discontinued from the treatment period, the posttreatment period, or both.
†Imiquimod administered as 5% imiquimod cream.
‡Of the 6 patients lost to follow-up, 1 moved out of state, 4 did not respond after repeated telephone calls and letters, and 1 was coded as unknown reason.
§Other was specified for 1 imiquimod-treated patient for use of exclusionary drugs and treatment with liquid nitrogen and for 1 vehicle-treated patient for
treatment of actinic keratosis during the posttreatment period.
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ment of AK. The overall efficacy was higher for dosing 3
times per week than for 2 times per week; however, the
rate of local skin reactions was also higher. These re-
sults, in addition to results from previously published
studies, suggest that many different dosing regimens are
effective and that dosing could be tailored to minimize
drug exposure and adverse effects.
Accepted for Publication: April 27, 2004.
Author Affiliations: Department of Dermatology, Uni-
versity Hospitals of Cleveland, Case Western Reserve Uni-
versity, Cleveland, Ohio (Dr Korman); Skin Cancer and
Dermatologic Surgery Medical Group and Westwood Am-
bulatory Center, Los Angeles, Calif (Dr Moy); MedaPhase,
Inc, Newnan, Ga (Dr Ling); Oregon Medical Research
Center, Portland (Dr Matheson); Therapeutics Inc, La
Jolla, Calif (Dr Smith); and 3M Pharmaceuticals, St Paul,
Minn (Mr McKane and Dr Lee).
Correspondence: Neil Korman, MD, PhD, Department
of Dermatology, University Hospitals of Cleveland, 11100
Euclid Ave, Cleveland, OH 44106 (njk2@po.cwru
.edu).
Group Information: The Imiquimod AK Investigators in-
clude the following: Neil Korman, MD, PhD (coordinat-
ing investigator); Ron Moy, MD (coordinating investi-
gator); Debra Breneman, MD; Armand Cognetta, MD;
Ponciano Cruz, MD; Frank Dunlap, MD; Ruth Gilboa,
MD; Marc Green, MD; Karen Harkaway, MD; Chris-
topher Huerter, MD; Michael Jarratt, MD; Steven Kem-
pers, MD; Debra Liu, MD; Mark Ling, MD, PhD; Keith
Loven, MD; Robert Matheson, MD; Jennie Muglia, MD;
Keyvan Nouri, MD; Charles Phillips, MD; Tania Phill-
ips, MD; Elyse Rafal, MD; Paul Ratner, MD; Toivo Rist,
MD; Michael Scannon, MD; Stacy Smith, MD; and James
Swinehart, MD.
Acknowledgment: We thank Nanda Gosala, MD, for
medical monitoring; Mary Owens, MD, for editorial con-
tributions; Terry L. Fox, MS, for statistical analyses sup-
port; and Amy Brown for manuscript preparation.
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