ARTICLE
Auteur(s) :, M Alirezaï1, B
Gerlach2, A Horvath3, D Forsea4, P
Briantais5, M
Guyomar5,*
1Montpellier, France
2Berlin, Germany
3Budapest, Hungary
4Bucarest, Roumania
5Galderma R&D, 635 Route des Lucioles 06902 Sophia
Antipolis, FranceFax: (+33) 4 92 95 20 74.
accepté le 1 Avril 2005
Many agents are available today to treat acne vulgaris. These
include oral and topical antibiotics, topical benzoyl peroxide,
topical retinoids, oral isotretinoin, oral anti-androgens, and zinc
salts [1].Topical antibiotics are known for their anti bacterial
properties and their capacity to inhibit inflammation caused by
bacteria [2, 3]. Current clinical practice for mild to moderate
inflammatory acne involves the combination of a topical retinoid
and a topical antimicrobial such as clindamycin [4]. Topical
clindamycin, a lincosamide antibiotic, is available in the United
States and several European countries for the topical treatment of
acne vulgaris. Existing formulations include lotions, topical
solutions and gels which all have to be applied twice-daily and may
contain alcohol, an agent known for its irritation potential.Many
clinical trials have been conducted to evaluate the efficacy and
safety of these formulations administered in monotherapy, in
combination with the antimicrobial benzoyl peroxide, or with
retinoids such as tretinoin and adapalene, and confirmed the good
efficacy and tolerability profile of clindamycin [5-17].Clindamycin
1% gel as a once-daily water based formulation
(Clindagel®, Galderma Laboratories, Fort Worth, TX,
United States) was developed to improve tolerability and increase
treatment adherence when used alone or in combination with
antimicrobials or retinoids.The aim of the present study was to
demonstrate that a once-daily water based formulation of
clindamycin 1% is as efficacious as its twice daily solution.
Methods
This was a multi centre, investigator-blinded, randomised, active
and placebo-controlled, parallel group evaluation.
The study was conducted in accordance with the ethical
principles originating from the Declaration of Helsinki and Good
Clinical Practices and in compliance with local regulatory
requirements. The study was approved by the ethics committee
appropriate to each participating centre before any subjects were
enrolled. All subjects provided written informed consent prior to
entering the study.
Male and female subjects with acne vulgaris on the face were
enrolled at 45 study centres in Europe. Subjects were at least 12
years of age and had to present with an acne severity grade of 2 to
5 on the Leeds revised scale [18]. Individuals had to have 15-50
inflammatory facial lesions (including papules, pustules and not
more than three nodules) and 30-200 non-inflammatory facial lesions
(including open and closed comedones). Subjects taking certain
topical and systemic treatments were required to undergo washout
periods specific to each type of treatment: 2 weeks for topical
treatments and up to 6 months for systemic treatments (e.g.
systemic retinoids (including isotretinoin) or ciproterone acetate
alone or in combination) before they could enter the study.
Subjects were excluded from the study if they had acne conglobata,
acne fulminans, chloracne, or drug induced acne. Women were
excluded if they were pregnant, planning a pregnancy or nursing;
men were not selected for this study if they had beards that were
likely to cause interference with study assessments.
Subjects were randomised into the study in a 4:4:1 ratio. Those
randomised to clindamycin 1% gel (hereafter clindamycin gel or
active gel), or clindamycin gel vehicle (hereafter vehicle), were
asked to apply the treatment once-daily in the evening; clindamycin
1% topical solution (Dalacin T® Topic, Pharmacia, St
Quentin en Yvelines, France, hereafter clindamycin topical
solution) was to be applied twice-daily in the morning and in the
evening. All products were to be used topically for a 12-week
period. All subjects received verbal and written instructions as to
the proper dosing and study drug application techniques. Subjects
were instructed not to discuss the study treatment regimen or
product packaging with the Investigator in order to maintain the
blind.
Subjects attended the clinic for screening, including
demographics, medical history, entry criteria, and baseline
assessments. A pregnancy test was conducted in women of
childbearing potential. Baseline efficacy and safety assessments
were recorded for eligible subjects and study medication was
dispensed. Subjects could withdraw from the study at any time.
Where possible, subjects who did not complete the study attended
the clinic for a final evaluation.
Efficacy and safety assessments
The inflammatory lesion reduction was the primary efficacy criteria
for this study for both the non-inferiority analysis of data for
clindamycin gel vs clindamycin solution and the superiority
analysis of data for clindamycin gel vs its vehicle. Furthermore,
Global Assessment of Improvement was also a primary efficacy
assessment for the superiority of clindamycin gel over its vehicle.
Secondary endpoints included results of total lesion reduction
(inflammatory + non-inflammatory), Global Severity Grade and Global
Assessment of Improvement relative to those obtained with
clindamycin topical solution. At each visit, the investigator
counted the number of inflammatory (sum of papules and pustules
only) and non-inflammatory (sum of open and closed comedones) acne
lesions on the face. The numbers of all types of lesions were
counted separately.
The acne Global Severity Grade (GSG) was assessed prior to
counting lesions. All investigators were provided with a colour
copy of the grading system in order to assist the assessment of the
subject’s acne. Only the facial grading was used to classify the
subject. The Global Assessment of Improvement was evaluated, by the
investigator, at week 12 by comparing the acne condition of each
subject to the baseline photograph by using a 7-point scale ranging
from – 1 = worse, to 5 = clear. Adverse events were reported
by questioning the subjects.
Evaluations after baseline took place at weeks 4, 8, and 12.
Statistical analyses
The non-inferiority of the gel formulation versus the topical
solution of clindamycin 1% was demonstrated by showing that the
lower limit of the 95% CI of the difference between the 2 active
treatments was not below – 10% in terms of percent reduction
from baseline in inflammatory lesions counts after a 12-week
treatment (PP analysis) and at endpoint (ITT analysis). Non
parametrical 95% CI of the difference between the 2 active
treatments was calculated using the Cochran-Mantel-Haenszel (CMH)
procedure stratified by pseudo centre.
The superiority of the active gel over its vehicle was
demonstrated by showing a significant difference between these 2
groups for percent reduction in inflammatory lesions counts at
endpoint and Global Assessment of Improvement at the final
visit.
The superiority was calculated via a CMH test stratified by
pseudo-centre and using the ridit transformation for percent
reduction in inflammatory lesions and for global assessment of
improvement. The row mean score statistic was used, tests were
2-sided and significance was declared at a 5% threshold.
Total lesion reductions and GSS were submitted to a CMH test
stratified by pseudo-center and using the ridit transformation.
Global Assessment of Improvement as a secondary criterion was
submitted to a CMH test stratified by pseudo-center and using the
ridit transformation.
The per-protocol (PP) population included all randomized
subjects who did not have any major deviation from the protocol
that may have a possible impact on the outcome. The intent-to-treat
(ITT) population, consisting of the entire population enrolled and
randomized, was used to demonstrate superiority.
Assuming a 20% rate of subjects excluded from the PP analysis, a
total of 594 subjects needed to be enrolled (264 in each active
treatment group, 66 in the vehicle group).
Results
Disposition of subjects
A total of 592 subjects were included in the study; 530 subjects
completed the study: 233 subjects in the clindamycin gel group, 240
in the clindamycin solution group and 57 in the clindamycin vehicle
group.
Discontinuation from the study was reported for 62 subjects
(10.5%): 32 subjects in the clindamycin gel group, 21 subjects in
the clindamycin solution group and 9 subjects in the vehicle group.
Two (0.3%) subjects discontinued the study due to AEs: 1 case of
eczema in the clindamycin gel group and 1 case of sunburn in the
clindamycin solution group. Both adverse events were related to
study treatment.
Demographic and baseline characteristics
Of the 592 included subjects, 41.7% were male and 58.3% were
female. The total mean age was 20.5 ± 5.1 years and most of
subjects in each group were white/Caucasoid. All treatment groups
were comparable in terms of gender, age, and racial distribution.
Further demographics and baseline information are shown in table 1(
Table 1 ).
Table 1 Subject disposition and baseline data (ITT
population)
|
- Clindamycin 1% gel
- (N = 265)
|
- Clindamycin 1% topical solution
- (N = 261)
|
|
|
|
Gender
|
|
|
|
|
|
|
Male
|
N (%)
|
111 (41.9)
|
109 (41.8)
|
27 (40.9)
|
247 (41.7)
|
|
Female
|
N (%)
|
154 (58.1)
|
152 (58.2)
|
39 (59.1)
|
345 (58.3)
|
|
Age
|
Mean ± SD
|
20.4 ± 5.0
|
20.6 ± 5.3
|
20.5 ± 4.4
|
20.5 ± 5.1
|
|
Min
|
12.0
|
12.0
|
12.0
|
12.0
|
|
Max
|
35.0
|
35.0
|
34.0
|
35.0
|
|
Race
|
|
|
|
|
|
|
White/Caucasoid
|
N (%)
|
259 (97.7)
|
256 (98.1)
|
65 (98.5)
|
580 (98.0)
|
|
Black/Negroid
|
N (%)
|
3 (1.1)
|
3 (1.1)
|
1 (1.5)
|
7 (1.2)
|
|
Yellow/Mongoloid
|
N (%)
|
1 (0.4)
|
2 (0.8)
|
0
|
3 (0.5)
|
|
Other/Mixed
|
N (%)
|
2 (0.8)
|
0
|
0
|
2 (0.3)
|
|
Total lesion counts
|
Mean ± SD
|
98.1 ± 36.0
|
97.9 ± 37.5
|
106.2 ± 40.7
|
99.0 ± 37.3
|
|
Inflammatory lesion counts
|
Mean ± SD
|
29.3 ± 10.4
|
28.6 ± 9.9
|
29.9 ± 12.0
|
29.0 ± 10.3
|
|
Non-Inflammatory lesion counts
|
Mean ± SD
|
68.9 ± 33.0
|
69.4 ± 34.0
|
76.3 ± 37.0
|
69.6 ± 33.9
|
|
Global Severity Grade
|
Mean ± SD
|
3.0 ± 0.9
|
3.1 ± 0.9
|
3.1 ± 1.0
|
3.1 ± 0.9
|
Efficacy evaluation
Results of the percent reduction from baseline in inflammatory
lesions at week 12 (PP population) were 65.6% in the gel group and
65.6% in the topical solution group. The lower limit of the 95% CI
of the difference between the gel and the topical solution at week
12 was with – 4.20%, above the pre-specified inferiority
margin of – 10%. The results, confirmed by those in the ITT
population, demonstrated that the efficacy of clindamycin gel is
similar to that of clindamycin topical solution.
Results of the percentage reduction from baseline in
inflammatory lesions at week 12-LOCF (ITT population) were 62.2% in
the active gel and 50.6% in the vehicle group, demonstrating that
clindamycin gel was significantly superior to its vehicle (p =
0.006). Results in PP population showed consistency with the ITT
results.
( Figure 1 )
details the mean percentage reduction in the inflammatory lesion
count throughout the study.
The analysis of Global Assessment of Improvement (ITT
population) after 12 weeks of treatment demonstrated that acne had
markedly improved, almost cleared, or cleared in 56.6% of subjects
treated with clindamycin gel, in 64.6% of the subjects treated with
clindamycin topical solution and in 41.0% of the subjects treated
with gel vehicle. The distribution of global improvement was
significantly different between the active gel and its vehicle (p =
0.001); there was no significant difference between the 2 active
formulations (( figure
2 )). Results were confirmed by those in the PP
population.
Results for the percent reduction from baseline in total lesion
count and for the GSG at endpoint showed no statistical difference
between the active gel and the topical solution and confirmed the
superiority of the active gel versus its vehicle (p = 0.009 for the
percentage reduction of total lesions and p = 0.003 for the GSG;
figures 3 and 4, respectively). The PP analyses confirmed the
results from the ITT population.
Safety evaluation
Forty-eight (8.1%) subjects experienced a total of 59 adverse
events (AEs): 22 (8.3%) subjects in the clindamycin gel group, 22
(8.4%) in the clindamycin topical solution group, and 4 (6.1%) in
the vehicle group. All active treatments were well tolerated: a
total of only 16 (2.7%) study subjects reported AEs related to
study treatment: 6 (2.3%) subjects in the active gel group, 9
(3.4%) in the topical solution group, and 1 (1.5%) in the vehicle
gel group).
A total of 21 (3.5%) subjects experienced dermatological AEs: 9
(3.4%) subjects in the clindamycin gel group and 12 (4.6%) in the
clindamycin topical solution group. Five of these (2 subjects
reported dry skin, 2 a burning sensation and 1 eczema) in the gel
group and 8 (three presenting with dry skin, 2 with irritation, 2
with worsening of the disorder and 1 reported sun-burning) in the
topical solution group reported dermatological AEs related to study
treatment. Four subjects experienced non-dermatological, treatment
related AEs (2 in the active gel group: 1 with pharyngitis and 1
with cystitis, and 2 in the topical solution group: 1 case of
cystitis and 1 with kidney pain). No dermatological AEs were
reported for the vehicle group and no treatment related serious AEs
occurred during the course of the study.
Only 2 (0.3%) subjects discontinued the study due to drug
related AEs: 1 in the active gel group had eczema and 1 in the
topical solution group reported sunburn.
An overview of all adverse events which occurred during the
course of the study is provided in table 2( Table 2 ).
All AEs were classified by the investigators as being of either
mild or moderate severity.
Table 2 Overview of adverse events occurred during the
study
|
- Clindamycin 1% gel
- N = 265
|
- Clindamycin 1% topical solution
- N = 261
|
|
|
|
Events1
|
|
Events1
|
|
Events1
|
N (%) Subjects
|
Events1
|
N (%) Subjects
|
|
All AEs
|
28
|
22 (8.3%)
|
27
|
22 (8.4%)
|
4
|
4 (6.1%)
|
59
|
48 (8.1%)
|
|
Related AEs
|
7
|
6 (2.3%)
|
9
|
9 (3.4%)
|
1
|
1 (1.5%)
|
17
|
16 (2.7%)
|
|
All dermatologic AEs
|
9
|
9 (3.4%)
|
12
|
12 (4.6%)
|
0
|
0 (0.0%)
|
21
|
21 (3.5%)
|
|
Related dermatologic AEs
|
5
|
5 (1.9%)
|
8
|
8 (3.1%)
|
0
|
0 (0.0%)
|
13
|
13 (2.2%)
|
|
AEs leading to withdrawal
|
1
|
1 (0.4%)
|
1
|
1 (0.4%)
|
0
|
0 (0%)
|
2
|
2 (0.3%)
|
Discussion
Acne vulgaris is a complex skin disorder involving multiple
abnormalities of the pilosebaceous unit including
hyperkeratinisation, sebum production, bacterial proliferation, and
inflammation [19, 20]. If not treated properly, acne may be
physically and emotionally scarring, causing those afflicted by the
disease to have significant psychosocial morbidity and reduced
self-esteem [21, 22].
With bacterial resistance being a general health concern, a
rapid and successful onset of efficacy is of greatest importance.
Hence limitation to patients with inflamed lesions, close
monitoring of efficacy and short time treatments in combination or
in alternation with benzoyl peroxide and compliance-enhancing
therapies with topical antibiotics are key elements to a successful
treatment with topical antibiotics [22-27].
The present multicentre study aimed to confirm the similar
efficacy and safety of a water-based topical gel formulation with a
once-a-day application compared to the currently available twice
daily and alcohol solution of clindamycin 1%, allowing for an
improved patient compliance. Further aims of this newly developed
formulation were to propose to the users a fluid gel, easy to apply
on the skin, well adapted to patients with sensitive and irritated
skin, providing appropriate cosmetic properties.
Overall the efficacy evaluation confirmed the superiority (p =
0.006) of clindamycin gel compared to its vehicle and demonstrated
similar efficacy to clindamycin topical solution. Inflammatory
lesion counts decreased after a 12-week treatment by 65.6% for both
active treatments and by less than 60% with the vehicle.
Further efficacy assessments confirmed that both active
formulations of clindamycin significantly improved the total lesion
reduction, the Global Assessment of Improvement, and the GSG. In
addition, the superiority of clindamycin gel relative to its
vehicle was confirmed with a statistical significance (p = 0.009
for total lesion reduction, p = 0.001 for the Global Assessment of
Improvement and p = 0.002 for the GSG).
Both clindamycin 1% gel and clindamycin 1% topical solution were
well tolerated. Only 16 subjects presented with related
dermatological side effects.
The present study results paralleled observations made by Rizer
et al. in 2001 [5]: the water based formulation gel is equivalent
in efficacy and safety to a currently available alcohol base
formulation of clindamycin 1% [5].
In addition, this new formulation may increase, with its once a
day application in combination with topical retinoids, the
patient’s adherence to the prescribed acne treatment.
In conclusion, with no significant difference, neither in
efficacy nor in safety, the new, water-based, once-a-day
clindamycin 1% gel applied alone, or in combination with retinoids
or with benzoyl peroxide preparations, is an effective, safe, and
convenient alternative to the twice-a-day topical alcohol solution
in the treatment of acne vulgaris.
Acknowledgements
The authors would like to thank the members of the
Clindagel® study team for their participation in the
study and Patrick Göritz, Galderma R&D, Sophia Antipolis,
France for editorial assistance.
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