ARTICLE Tretinoin
is available in a range of strengths and formulations for the topical treatment
of acne, including liquids, gels and creams. All of these formulations may
cause some degree of skin irritation but this is thought to be least with
the cream formulations and most problematic with tretinoin liquid [1, 2].
Adapalene is a naphthoic acid derivative with retinoid-like activity that
has demonstrated greater selectivity for certain retinoic acid receptors
than tretinoin [3]. Topical therapy with tretinoin may have to be initiated
at a low dose level because of skin irritation and then titrated up to higher
doses [4] but, in contrast, treatment with adapalene can be started with
the maximum strength formulation (gel 0.1%). Consequently, in one clinical
trial, patients treated with adapalene gel 0.1% have experienced a more
rapid onset of reduction of acne lesions than those treated with tretinoin
gel in comparative studies.[5]. Clinical trials have also shown a more favourable
skin tolerability profile than that seen with tretinoin gel [5-7].
Adapalene gel 0.1% has also been shown to produce less skin irritation
than tretinoin 0.025% cream, and was preferred by patients, in a previous
4-week bilateral study [8]. The aim of the current study was to investigate
the efficacy and tolerability of adapalene gel 0.1% compared with a high
strength tretinoin cream (0.05%) in patients with acne vulgaris during
10 week trial.
Materials and methods
Study design
This 10-week, large-scale, multicentre, randomised, investigator-masked,
active-controlled, parallel group study included 409 consenting male and
non-pregnant female patients with acne vulgaris. Patients had to be between
12 and 25 years of age with mild or moderate acne vulgaris (global facial
grades 1-5), with non-inflammatory lesion (open and closed comedones)
counts between 30 and 125 inclusive and inflammatory lesion counts (papules
and pustules) between 10 and 40 inclusive. All patients underwent washout
of topical anti-acne treatments (2 weeks), systemic antibiotics (4 weeks)
and systemic retinoid treatments (6 months) prior to study entry.
Patients with acne conglobata, acne fulminans, secondary acne or with
an underlying disease or some other dermatological condition that required
the use of interfering topical or systemic therapy were excluded from
the study as were patients receiving treatment with Diane®/Dianette®.
In addition, patients who were known to be allergic to any of the study
preparations; those who had a beard which could interfere with study assessments;
who were pregnant and/or nursing; who had received topical anti-inflammatory
treatment on the face within 2 weeks prior to study entry; or who had
participated in another clinical study within the previous 30 days were
also not eligible for inclusion.
Patients were assigned to treatment with adapalene gel 0.1% (Galderma
Laboratories, Inc.) (n = 204) or tretinoin cream 0.05% (Ortho Pharmaceutical
Corporation) (n = 205) using a randomisation procedure generated
by the RANUNI routine of SAS (SAS Institute, Cary, NC, USA) in blocks
of 10 patients for each investigator. Each patient enrolled was assigned
a unique number, corresponding to the chronological order of study entry
within each centre, which also corresponded to the patient number indicated
on the test material label. The test materials were packaged in 45 g tubes
with identical blinded labelling and secondary packaging. The study was
investigator masked because of the differing external appearance of the
test materials; adapalene gel is a translucent gel material, whereas tretinoin
cream is yellowish-white. The tubes containing the test materials were
not identical, so patients were instructed to keep all test material containers
out of view from the investigators or evaluators at study visits. In addition,
the investigator was not responsible for handing out the study medication
to patients, thus masking which patients received which particular medication.
Patients were instructed verbally and in writing to apply a thin layer
of adapalene gel 0.1% or tretinoin cream 0.05% to the entire facial area
once daily at bedtime for 10 weeks. No time intervals were specified between
application and meals or any other activity. Cetaphil Cleanser and Cetaphil
Moisturiser (Galderma, Fort Worth, TX, USA) were provided to patients
in an attempt to standardise washing and moisturising procedures, respectively.
Patients were scheduled for five visits (baseline and weeks 1, 3, 6
and 10) and at each visit the investigators assessed patients' response
to treatment and tolerability parameters. Each patient received a new
container of study medication at baseline and as needed at weeks 3 and
6. Patients were instructed on the importance of returning their study
medications at each visit and an account was made of the dates and amounts
of study medication dispensed and returned. Treatment compliance was assessed
by collection and examination of test material containers at all visits.
Efficacy parameters assessed included: global improvement, comedo counts,
inflammatory lesion counts and acne severity (baseline and week 10 only).
Photographs were taken at baseline and provided to the investigators to
use as a reference when grading global improvement at each visit on a
scale of: - 1 (worsening acne), 0 (no change) to 5 (clear of acne). Acne
severity was evaluated according to the Burke and Cunliffe [9] photographic
acne grades. Local tolerability parameters (erythema, dryness, desquamation
and stinging/burning) were measured according to the scale: none = 0,
mild = 1-3, moderate = 4-6, and severe = 7-9. Spontaneously reported adverse
events were recorded and safety was assessed by evaluation of the incidence
of adverse events. Systemic haematology and biochemistry variables were
not assessed during this study. Furthermore, prognostic variables such
as, age, sex, sites of acne and evaluation of less active acne lesions
were not monitored.
Statistical methods
This large-scale multicentre study was conducted at 10 centres in the
USA, two centres in Canada and at one centre each in the UK and France.
The estimated sample size for this study of 120 patients per treatment
group was based on the skin safety parameters of erythema and dryness
at weeks 1 and 3, using a two-sided t-test with alpha = 0.05 and
80% power.
The entire population of patients enrolled and randomised was included
in the intent-to-treat (ITT) efficacy analysis. All patients who received
at least one dose of study medication were included in the safety analysis.
Statistical analyses of lesion counts were made at each visit using analysis
of covariance (ANCOVA). The model included treatment, investigator, treatment-by-investigator
interaction and baseline lesion count. A square-root transformation was
used in order to meet the assumptions of homogeneity of variance and normality.
The percent reduction from baseline at each visit was compared for significant
treatment differences using the Cochran-Mantel-Haenszel (CMH) row means
score test statistic. The ridit transformation was used and the investigator
formed the strata. All skin safety evaluations were tested for significant
treatment differences at each visit using the same methodology. Patient
characteristics were compared using Fisher's Exact test or t-test and
the percentage of patients using a moisturiser was compared between treatments
using the Fisher's Exact test. The time to moisturisation use was tested
using survival analysis with the log-rank statistic and the severity of
treatment-related dry skin adverse events was compared using the Mantel-Haenszel
chi-square statistic.
Results
Study population
A total of 409 patients were included in the study. The majority of
patients were of Caucasian ethnic origin, with skin phototypes II and
III and grade 1-2 acne severity at baseline. All patients had acne vulgaris
as opposed to other acne-related conditions. The results from the study
were not evaluated or broken down by the prognostic variables of age,
sex, or acne severity. No significant protocol deviations occurred during
the study. Only one patient in the adapalene gel 0.1% group and two patients
in the tretinoin cream 0.05% group withdrew from the study for medical
reasons and 365 patients (89%) were evaluable for efficacy at week 10.
Overall, there were no statistically significant differences in patient
characteristics at baseline between the two treatment groups. Patient
demographic characteristics at baseline and patient flow in the study
are summarised in Table I.
Sample size calculations were based on skin safety parameters (erythema
and dryness). The estimated sample size for erythema and dryness at weeks
1 and 3 required 107 patients to be included in each treatment group.
It was estimated that approximately 10% of patients would not be evaluable
at week 1 or 3, and therefore 120 patients per treatment group were to
be enrolled. This sample size was sufficient to detect a mean difference
of approximately 0.25 (scale 0-3) between the treatments in terms of mean
scores with 80% power, either for erythema or dryness at weeks 1 or 3.
In addition, the sample size also enabled a difference of 15% between
the treatments in terms of percentage reduction in lesion counts with
80% power. The target sample size of 120 patients per group was exceeded
(adapalene, n = 204; tretinoin, n = 205) due to the inclusion of patients
recruited at centres outside the USA.
Although the primary outcome variable was tolerability, we have presented
the data in a more standard format with the efficacy data reported before
the tolerability data.
Efficacy
Median inflammatory lesion counts in the adapalene gel 0.1%-treated
group and the tretinoin cream 0.05%-treated group at baseline were 20.5
and 21.0, respectively (P = NS), and were reduced to 13.0 and 14.0,
respectively, at week 10. At week 3 the median percent changes in the
inflammatory lesion count were - 20.0% for adapalene gel 0.1% and - 14.3%
for tretinoin cream 0.05%, although the between-treatment difference lessened
as the study progressed and by week 10 the median percent changes were
similar (Fig. 1) with
no statistically significant differences observed between treatments.
The median non-inflammatory lesion counts in the adapalene gel 0.1%-treated
group and the tretinoin cream 0.05%-treated group at baseline were 49.0
and 50.0, respectively (P = NS), and were reduced to 25.0 in both
groups at the end of the study. At week 10, the median percent changes
in the non-inflammatory lesion count were similar with no statistically
significant difference between treatments (Fig.
2). In addition, the median total lesion counts in both groups were
73.0 at baseline (P = NS) and were reduced to 39.0 at week 10.
Both adapalene gel 0.1% and tretinoin cream 0.05% produced clinically
significant improvements from baseline to study completion, although there
were no statistically or clinically significant differences between the
two treatment groups. The median percent changes in the total lesion count
at week 10 in the adapalene gel 0.1%-treated group and the tretinoin cream
0.05%-treated group were similar with no statistically significant difference
between treatments. Table
II shows the mean lesion counts and the spread of the data around
them.
Similarly, there were no statistically significant differences between
treatments in terms of global improvement with 109 patients (59.6%) and
105 patients (57.7%) in the adapalene gel 0.1%-treated and tretinoin cream
0.05%-treated groups, respectively, showing marked or moderate improvement,
or almost total clearance, of acne at week 10. Thus improvement in acne
lesions was similar with both treatments. Acne severity was also the same
in the adapalene gel 0.1%-treated and tretinoin cream 0.05%-treated groups
at week 10 (facial grade < 1 [45% and 41% of patients, respectively];
facial grade 1-2 [53% and 58%, respectively]; and facial grade 3-5 [2%
in both treatment groups]).
Concomitant medications
The most frequently used concomitant medications in both treatment groups
during the study included: moisturisers; non-steroidal anti-inflammatory
drugs; antihistamines/ decongestants; vitamins/mineral diet supplements;
analgesics; and systemic contraceptives. Moisturisers were allowed as
treatment for irritation and 101 (49.5%) of the adapalene gel 0.1%-treated
patients required the use of a moisturiser in comparison with 127 (62%)
of the tretinoin cream 0.05%-treated patients (P < 0.05 between
treatments). In addition, the time that elapsed between the start of treatment
and the need to use a moisturiser was significantly longer (difference
in median times to utilisation of 25 days) in the adapalene gel 0.1% group
than the tretinoin cream 0.05% group (P < 0.01 between treatments).
Although none of the patients required a moisturiser at baseline, 40%
of the tretinoin cream 0.05%-treated patients were using a moisturiser
by week 1 in comparison with only 25% in the adapalene gel 0.1%-treated
group.
Tolerability
Statistically significant differences in mean tolerability scores for
erythema, dryness and desquamation (P < 0.05) in favour of adapalene
gel 0.1% versus tretinoin cream 0.05% were demonstrated between weeks
1 and 6 (Fig. 3a-c). Although
patients treated with adapalene gel 0.1% had less stinging/burning than
tretinoin cream 0.05%-treated patients during the early portion of the
study, the between treatment difference did not reach statistical significance
(Fig. 3d).
A greater proportion of adapalene gel 0.1%-treated patients showed no
signs of dryness at each week than tretinoin cream 0.05%-treated patients.
Only 20 patients (10%) in the adapalene gel 0.1% group had moderate or
severe dryness compared to 41 patients (20%) in the tretinoin cream 0.05%
group at week 1. None of the adapalene gel 0.1%-treated patients had severe
dryness at week 1 in comparison with four patients who received tretinoin
cream 0.05%. At week 10, 65% of the adapalene gel 0.1%- and 59% of the
tretinoin cream 0.05%-treated patients had no signs of dryness. No desquamation
was present at week 1 in 56% of adapalene gel 0.1%-treated patients versus
34% of tretinoin cream 0.05%-treated patients. In addition, of the patients
treated with adapalene, only 17 had moderate and one had severe desquamation
at week 1, in comparison with 44 and five patients, respectively, treated
with tretinoin. In the subgroup of patients who required the use of a
moisturiser, adapalene gel 0.1% treated patients experienced significantly
less desquamation than tretinoin cream 0.05%-treated patients at week
1 (mean scores were 1.43 and 2.45, respectively; P < 0.05) and
week 6 (mean scores were 0.70 and 1.20, respectively; P < 0.05).
Similarly, among patients who did not use a moisturiser, adapalene gel
0.1%-treated patients experienced significantly less desquamation than
tretinoin cream 0.05%-treated patients at week 1 (0.64 and 0.84, respectively;
P < 0.05) and week 6 (0.54 and 0.59, respectively; P
< 0.05). Overall, patients in both the adapalene gel 0.1% treatment
group and the tretinoin cream 0.05% group used comparable amounts of study
medication (approximately 0.3 g per person per day).
Adverse events
Overall, 83 patients (41%) in the adapalene gel 0.1%-treated group and
101 patients (49%) in the tretinoin cream 0.05%-treated group experienced
139 and 164 dermatological treatment-related adverse events, respectively,
most of which were of mild severity. The most frequently reported treatment-related
adverse events were dry skin (125 events in 105 patients) and skin irritation
(126 events in 125 patients). No serious adverse events were reported
during the study. Only one patient in the adapalene gel 0.1%-treated group
was discontinued due to moderate skin irritation considered related to
treatment and two patients in the tretinoin cream 0.05%-treated group
were discontinued due to mild skin irritation and mild skin discomfort/moderate
skin dryness considered related to treatment.
Discussion
In this group of patients with mild or moderate acne at baseline, efficacy
results at the end of 10 weeks' randomised treatment were comparable between
adapalene gel 0.1% and tretinoin cream 0.05% with similar reductions in
lesion counts and similar degrees of global improvement. This study confirms
the results of previous trials in which adapalene gel 0.1% was shown to
have an equivalent efficacy to tretinoin in acne patients, and a more
favourable tolerability profile [5-7]. In particular, adapalene gel 0.1%
demonstrated better cutaneous tolerability over tretinoin cream 0.025%
in a 4-week bilateral study [8]. This study showed that adapalene gel
0.1% was significantly better tolerated than tretinoin cream 0.05% in
terms of erythema, dryness and desquamation. In addition, it was also
slightly better than tretinoin cream 0.05% for stinging/burning, with
equivalent efficacy against inflammatory lesions, and open and closed
comedones after 10 weeks of treatment. Significantly more of the tretinoin
cream-treated patients than adapalene gel-treated patients required the
use of a moisturiser, and there was also a significantly shorter lead-time
to when patients needed to use a moisturiser in the tretinoin cream-treated
group than in the adapalene gel-treated group. The dosage regimens employed
in this study were in accordance with the products' package inserts and,
overall, adapalene gel 0.1% was well tolerated and produced a significantly
lower incidence of dry skin events related to treatment than tretinoin
cream 0.05%. The investigators responsible for assessing acne were trained
in evaluating acne severity, counting lesions, completing the case report
forms and using the Cunliffe scale of evaluating acne severity and global
improvement in acne. During the study, no attempt was made to quantify
or compare adverse events reported by each investigator.
Observations from the clinic suggest that patients are more likely to
comply with treatments that demonstrate high tolerability over those that
are seen as more irritating. For example, some topical therapies, such
as tretinoin, are perceived to cause troublesome skin irritation and therefore
some patients may have concerns surrounding their administration, which
may in turn mean that they comply less well with therapy. Consequently,
well tolerated therapies are desirable because in the clinic, high patient
compliance with therapy may enhance the treatment outcome.
Additionally, in clinical trials, patients are more likely to use the
recommended amount of study product on a daily basis, whereas in the non-clinical
trial situation individuals may try to conserve administration of the
anti-acne product, due to cost concerns, for example. Ongoing research
in the department of one of the authors (William J Cunliffe) has indicated
that the quantity of anti-acne products used by clinic patients is significantly
less than that used by those in clinical trials (Zaghoul S., Goodfield
M.J., Cunliffe W.J., personal communication).
CONCLUSION
In conclusion, adapalene gel 0.1% showed equivalent efficacy in reduction
of acne lesion counts and global improvement of acne severity, and was
significantly better tolerated than tretinoin cream 0.05%. Thus, in the
clinic there may be patient preference for an equally effective, but less
irritating topical retinoid such as adapalene gel 0.1%.
Acknowledgements
This study was supported by an educational grant from Galderma Laboratories.
Dr. W.J. Cunliffe acknowledges financial support in the form of research
grants and personnel financial support from Galderma Laboratories.
Dr. F. William Danby, Dr. Frank Dunlap and Dr. David Gratton acknowledge
the receipt of research grants from Galderma Laboratories to support the
clinical trial.
Dr. Michael H. Gold acknowledges receiving financial support in the
form of research grants from Galderma Laboratories.
Dr. Alan Greenspan received no financial support from Galderma Laboratories
to perform the clinical trial, however, he has since become a consultant
to Galderma Laboratories.
Article accepted on 11/4/02
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