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[ORIGINAL RESEARCH]

Efficacy and Safety of Clindamycin

Phosphate 1.2% and Tretinoin 0.025% Gel
for the Treatment of Acne and Acne-induced
Post-inflammatory Hyperpigmentation in
Patients with Skin of Color
VALERIE D. CALLENDER, MD; CHERIE M. YOUNG, MD;
CHESAHNA KINDRED, MD, MBA; SUSAN C. TAYLOR, MD
Callender Center for Clinical Research, Glenn Dale, Maryland; Society Hill Dermatology, Philadelphia, Pennsylvania

ABSTRACT
Objective: To assess the efficacy and safety of a topical gel containing clindamycin 1.2% and tretinoin 0.025% for the
treatment of acne and acne-induced postinflammatory hyperpigmentation (PIH) in darker skinned patients. Design:
Randomized, double-blind, placebo-controlled study. Setting: Two United States clinical sites. Participants: Thirty-three
patients 12 years of age or older with skin types IV to VI, mild-to-moderate facial acne, and PIH were enrolled.
Measurements: Patients applied clindamycin phosphate/tretinoin gel or a nonmedicated vehicle each evening and a sun
protection factor 30 sunscreen daily. Changes in skin erythema and hyperpigmentation were measured using a
chromameter and photographic images. Efficacy was assessed using the Evaluators Global Acne Severity Scale, lesion
counts, Post-inflammatory Hyperpigmentation Severity Scales and Patient’s Global Assessment Scale. Safety and
tolerability were assessed by adverse event reports and a Safety Assessment Scale. Results: The mean (SD) baseline
inflammatory lesion count was 11.9 (11.1) in clindamycin/tretinoin-treated patients, decreasing by 5.5 (6.56) after 12
weeks while the mean baseline inflammatory lesion count was 13.6 (11.15) in placebo-treated patients, decreasing by 4.1
(11.36) (p=0.05 for change from baseline, clindamycin/tretinoin vs. placebo). Clindamycin/tretinoin-treated patients
generally demonstrated superior efficacy versus placebo treatment. The clindamycin/tretinoin topical gel was well
tolerated, causing little or no irritation, although one patient withdrew due to periorbital edema of moderate severity
possibly related to clindamycin/tretinoin gel. Conclusion: Although limited by small sample size, the results of this pilot
study suggest clindamycin phosphate 1.2% and tretinoin 0.025% topical gel is a safe and effective option for treating mild-
to-moderate acne in patients with skin of color. (J Clin Aesthet Dermatol. 2012;5(7):25–32.)

A
cne is a chronic disorder of the pilosebaceous unit affects people without regard to race or ethnicity and is
characterized by inflammatory papules, pustules, therefore one of the most common conditions treated by
open and closed comedones, cysts and nodules dermatologists.3
affecting both adolescents and adults. The pathophysiology Of special concern among darker skinned patients with
of acne is complex, but includes increased sebum acne is the occurrence of postinflammatory hyper-
production, follicular hyperkeratosis, proliferation of pigmentation (PIH).4–7 Inflammatory acne lesions disrupt the
Propionibacterium acnes, and reactive inflammation.1,2 It epidermal basal layer causing melanocytes to increase

DISCLOSURE: Dr. Callender is a consultant, speaker, and investigator for Medicis; Dr. Taylor is an investigator for Medicis; Drs. Young and Kindred
report no relevant conflicts of interest. Financial support for this study was provided by Medicis Pharmaceutical Corporation.
ADDRESS CORRESPONDENCE TO: Valerie D. Callender, MD, Callender Center for Clinical Research, 12200 Annapolis Road, Suite 315, Glenn Dale,
MD 20769; E-mail: [email protected]

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TABLE 1. Evaluator’s global acne severity scale

GRADE VALUE DEFINITION

Clear 0 Normal, clear skin with no evidence of acne vulgaris

Rare noninflammatory lesions present, with rare noninflamed papules (papules must be
Almost clear 1
resolving and may be hyperpigmented, though not pink-red)

Some noninflammatory lesions are present, with few inflammatory lesions (papules/pustules
Mild 2
only, no nodulocystic lesions)

Noninflammatory lesions predominate, with multiple inflammatory lesions evident; several to

Moderate 3
many comedones and papules/pustules; there may or may not be one small nodulocystic lesion

Inflammatory lesions are more apparent, many comedones and papules/pustules, there may
Severe 4
or may not be a few nodulocystic lesions

Highly inflammatory lesions predominate, variable number of comedones, many papules/

Very severe 5
pustules, and many nodulocystic lesions

From: Schlessinger J, Menter A, Gold M, et al. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate
and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol. 2007;6: 607–615.11

melanin production.8 PIH is common in patients with skin of 0.025% gel for the treatment of mild-to-moderate acne and
color and can persist for months or years. The psychological acne-induced PIH.
and emotional distress caused by dyschromias, such as PIH,
can have a significant impact on the health-related quality of METHODS
life of affected individuals.8,9 While PIH may respond to Study subjects. Patients were eligible for enrollment if
treatments, such as chemical peels and laser therapy,7 the they were 12 years of age or older with skin types IV to VI and
preferred approach is to prevent or minimize the occurrence exhibited mild-to-moderate facial acne and mild-to-moderate
of PIH. PIH. Patients were excluded from participation if they had
Several treatments are currently available alone or in seborrheic dermatitis, PIH of solely dermal origin, acne
combination for the treatment of acne including benzoyl vulgaris known to be resistant to oral antibiotics or had a
peroxide, topical or oral antibiotics, and topical retinoids. history of Crohn’s disease, regional enteritis, or ulcerative or
Some of these combinations may be more beneficial for the antibiotic-related colitis. Patients taking erythromycin,
treatment of acne and PIH than others. For example, a trial neuromuscular blocking agents, hormone replacement or
comparing different topical therapeutic regimens in patients oral/transdermal contraceptive therapy, hydroquinone or
of color with acne treated with a clindamycin 1% + benzoyl other depigmenting medication within 14 days of the study,
peroxide 5% topical gel in combination with tretinoin 0.04% tetracycline or any other photosensitizing medication within
topical gel showed greater resolution of hyperpigmentation 30 days of the study, isotretinoin, chemical peels,
than patients treated with the same clindamycin/benzoyl microdermabrasion or laser treatment within six months of
peroxide topical gel in combination with tretinoin 0.01% or the study, and patients with a known allergy or sensitivity to
adapalene 0.1% topical gels.10 the study medication or its components were also excluded.
Combined therapy with a topical retinoid and clindamycin Women who were pregnant or breastfeeding were not
has been shown to be more effective than monotherapy in allowed to participate in the study. Women of childbearing
addressing all the pathogenic factors of acne11 and the safety age agreed to use a reliable form of contraception other than
and efficacy of this combination has become well oral contraceptives for the duration of the study and were
established.12–17 A commercially available product containing required to provide a negative pregnancy test before starting
clindamycin phosphate 1.2% combined with tretinoin 0.025% the study.
gel is approved for the treatment of acne vulgaris in patients Study drugs. The active treatment contained
12 years of age and older. The primary objective of the clindamycin phosphate 1.2% and tretinoin 0.025% in an
following placebo-controlled, double-blind study was to aqueous base of purified water, glycerin, carbomer 981,
assess the efficacy and safety of clindamycin 1.2%/tretinoin methylparaben, polysorbate 80, edetate sodium, citric acid,

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TABLE 2. Postinflammatory hyperpigmentation severity scale

OVERALL PIGMENTARY INTENSITY ERYTHEMA,
AREA OF HYPERPIGMENTED DEGREE OF
GRADE DISEASE OF HYPERPIGMENTED BURNING, PEELING,
LESIONS (% FACIAL AREA) HYPOPIGMENTATION
SEVERITY LESIONS DRYNESS

0 Normal None None None None

Present, but
1 Trace (mild and localized) Trace (1–10%) Trace (slight and localized) Trace
<mild

Mild (slightly
2 Mild (mild and diffuse) Mild (1–25%) Mild (slight and diffuse) Mild
noticeable)

Between mild Moderate (moderate and Moderate (noticeable and

3 Moderate (26–40% ) Moderate
and moderate diffuse) diffuse)

Moderate Marked (moderate and Marked (noticeable and

4 Marked (41–50% ) Marked
(noticeable) dense) dense)

Between
Severe (prominent and Severe (complete lack of
5 moderate and Severe (>50% ) Severe
dense) melanin pigmentation)
marked

Marked
6 — — — —
(distinctive)

Between marked
7 — — — —
and severe

—
Severe — —
8 —
(very distinctive)

propylparaben, butylated hydroxytoluene and tromethamine

TABLE 3. Patient’s Global Assessment Scale
(Ziana® Gel, Medicis Pharmaceutical Corporation, Inc.,
Scottsdale, Arizona). The placebo consisted of the
nonmedicated gel vehicle. Other products used in the study How would you rate your acne and postinflammatory
included a cleansing bar (Vanicream™ Cleansing Bar, hyperpigmentation now?
Pharmaceutical Specialties, Inc., Rochester, Minnesota) and
sunscreen containing titanium dioxide 5%, zinc oxide 5% SCORE GRADE DEFINITION
(Vanicream™ Sunscreen SPF 30, Pharmaceutical Specialties,
Inc.). This brand of sunscreen was specifically chosen
0 Clear No signs of dark areas
because it lacks fragrances, parabens, and other potentially
irritating ingredients.
Study procedures. This 12-week, double-blind, 1 Almost Clear Minor evidence of dark areas
randomized, placebo-controlled study was performed at two
clinical trial sites. Following a 30-day washout period for oral
corticosteroids, antibiotics, and contraceptives and a 14-day 2 Significant Significant evidence of dark areas
washout period for topical acne medications, medicated
cosmetics, and bleaching products, eligible patients
underwent a baseline medical history and physical randomized to then apply a thin layer of either the
examination including assessment of acne and PIH severity clindamycin/tretinoin gel or the placebo gel. Each patient
and photographic and chromameter measures. Patients were returned to the center after 2, 4, 8, and 12 weeks of treatment
instructed to wash their face with the cleansing bar each for safety and efficacy assessments. Treatment compliance
morning, rinse, pat dry, and then apply the sunscreen. The was established by weighing the study drug or placebo at
use of a sunscreen was important because of the risk of each return visit.
photosensitivity and sunburn due to the retinoid in the study Efficacy endpoints. During the initial baseline visit, the
medication. Each evening, patients were to wash their face investigator selected and photographed a target skin area for
with the cleansing bar, rinse, and pat dry. Patients were evaluation. Objective changes in skin erythema and

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TABLE 4. Safety assessment scale

SCALING

SCORE GRADE DESCRIPTION

0 None No scaling

1 Mild Barely perceptible, fine scales present to limited areas of the face

2 Moderate Fine scale generalized to all areas of the face

3 Severe Scaling and peeling of skin over all areas of the face
ERYTHEMA
SCORE GRADE DESCRIPTION
0 None No evidence of erythema present

1 Mild Slight pink discoloration

2 Moderate Definite redness

3 Severe Marked erythema, bright red to dusky dark red in color

ITCHING
SCORE GRADE DESCRIPTION

0 None No itching

1 Mild Slight itching, not really bothersome

2 Moderate Definite itching that is somewhat bothersome

3 Severe Intense itching that may interrupt daily activities and/or sleep
BURNING

SCORE GRADE DESCRIPTION

0 None No burning

1 Mild Slight burning sensation, not really bothersome

2 Moderate Definite warm, burning sensation that is somewhat bothersome

Hot burning sensation that causes definite discomfort and may interrupt daily activities and/or
3 Severe
sleep

STINGING

SCORE GRADE DESCRIPTION

0 None No stinging

1 Mild Slight stinging sensation, not really bothersome

2 Moderate Definite stinging sensation that is somewhat bothersome

3 Severe Stinging sensation that causes definite discomfort and may interrupt daily activities and/or sleep

From: Leyden J, Wortzman M, Baldwin EK. Tolerability of clindamycin/tretinoin gel vs. tretinoin microsphere gel and adapalene gel. J Drugs Dermatol.
2009;8:383–388.13

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TABLE 5. Lesion counts

BASELINE CHANGE, WEEK 12

Clindamycin phosphate/ Clindamycin phosphate/

Endpoint, Mean (SD) tretinoin gel (N=17) Placebo (N=15) tretinoin gel (N=16) Placebo (N=15)

Lesion Counts

Inflammatory Lesions 11.9 (11.10) 13.6 (11.15) -5.5 (6.56)* -4.1 (11.36)

Noninflammatory Lesions 48.6 (46.10) 64.7 (73.08) -21.3 (22.60) -12.8 (40.08)

* p=0.05 vs. placebo

hyperpigmentation were measured using a chromameter for all efficacy measures were not significantly different
(Mexameter MX 18; Courage+Khazaka Electronic GmbH, between treatment groups. Although patients treated with
Köln, Germany) and photographic images of the front, left, clindamycin/tretinoin gel consistently demonstrated
and right sides of the faces of each patient were recorded numerically superior efficacy results in acne improvement
(Canfield Imaging Systems, Fairfield, New Jersey). Efficacy compared to placebo treatment, the study was not
assessments consisted of improvements in acne and PIH sufficiently powered to achieve statistical significance for all
severity based on changes in Evaluator’s Global Acne Severity efficacy measures. The chromameter assessments for
Scale scores (Table 1) and PIH Severity Scale scores (Table melanin and erythema were highly variable and could not be
2). At Week 12, each study participant provided his or her interpreted.
opinion of the tolerability and effectiveness of the treatment Among patients treated with clindamycin/tretinoin gel, the
and the overall clinical results he or she achieved by mean (SD) baseline noninflammatory lesion count was 48.6
completing the Patient’s Global Assessment Scale (Table 3). (46.10), decreasing by 21.3 (22.60) after 12 weeks while the
Safety. Safety measures included the Safety Assessment mean baseline noninflammatory lesion count of 64.7 (73.08)
Scale (Table 4) at each visit and reports of adverse events for placebo-treated patients decreased by 12.8 (40.08)
(AEs) since the previous visit. Although rare, (Table 5). Among clindamycin/tretinoin gel-treated patients,
pseudomembranous colitis has been reported following the the mean (SD) baseline inflammatory lesion count was 11.9
application of topical clindamycin,18,19 and patients were (11.1), decreasing by 5.5 (6.56) after 12 weeks while the
specifically questioned by the investigators about any mean baseline inflammatory lesion count of 13.6 (11.15) for
episodes of diarrhea. placebo-treated patients decreased by 4.1 (11.36); (p=0.05,
Ethics. The protocol, informed consent document, and change from baseline to 12 weeks; clindamycin/tretinoin vs.
relevant supporting information were approved by a local placebo) (Table 5).
institutional review board (IRB). The study was conducted in Evaluator’s Global Acne Severity Scale scores ≥2 were
accordance with the regulations of the United States Food demonstrated by all patients at baseline, which decreased to
and Drug Administration as described in 21 CFR 50 and 56, 0 or 1 (clear or almost clear) at 12 weeks for 47 and 27
the ethical principles that have their origin in the Declaration percent of patients treated with clindamycin/tretinoin gel and
of Helsinki, and was consistent with Good Clinical Practice placebo, respectively (Table 6).
and applicable regulatory requirements. Each enrolled All patients had baseline PIH Severity Scale scores ≥2 and
patient provided written informed consent prior to a substantial proportion had scores of 3 or 4 in the
participating in any study-related procedures. clindamycin/tretinoin gel (70%) and placebo groups (69%)
(Table 6). The improvement in mean PIH score from Baseline
RESULTS to Week 12 was greater for clindamycin/tretinoin gel vs.
The 33 enrolled subjects included 26 women and seven placebo (-1.2 vs. -0.9) and this small improvement was
men with a mean age of 28.3 years (range, 13–51 years). consistent throughout the trial. The number of patients with
Patients described themselves as Black or African American ≥2-point improvements in PIH scores was similar between
(N=32) or African American/Caucasian (N=1) and exhibited clindamycin/tretinoin gel and placebo treatment groups
skin types IV (N=2), V (N=23), or VI (N=8). One patient was (N=5; 33%).
of Hispanic ethnicity. Patients were randomized to undergo At baseline, more than 80 percent of patients had Patient’s
treatment with clindamycin/tretinoin gel (N=17) or placebo Global Assessment scores of 2 (Table 7). The proportion of
(N=16); 15 patients in each group completed the 12-week clindamycin/tretinoin gel- and placebo-treated patients with
trial. Reasons for not completing the trial included being lost ≥1-point improvement in Patient’s Global Assessment at
to follow up (N=2) and withdrawal of consent (N=1). Week 12 was 67 and 40 percent, respectively. The proportion
Efficacy. At baseline, the mean scores/frequency counts of patients treated with clindamycin/tretinoin gel and placebo

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TABLE 6. Evaluator’s Global Acne Severity Scale and Postinflammatory Hyperpigmentation (PIH) Severity Scale Scores

≥>2-POINT IMPROVEMENT,
BASELINE
WEEK 12

Clindamycin Clindamycin
phosphate/ Placebo, N=16 phosphate/ Placebo, N=15 Significance
tretinoin gel, N=17 tretinoin gel, N=15

EVALUATOR’S GLOBAL ACNE SEVERITY

SCORE, N (%)

0 — —
7 (46.7) 4 (26.7) p=0.45
1 — —

2 9 (52.9) 7 (43.8) 3 (20.0) 1 (6.7)

3 7 (41.2) 9 (56.3)

4 1 (5.9) —

PIH SEVERITY SCORE, N (%)

2 4 (23.5) 3 (18.8)

3 5 (29.4) 5 (31.1) 5 (33.3) 5 (33.3) p=1.00

4 7 (41.2) 6 (37.5)

5 1 (5.9) 2 (12.5)

TABLE 7. Patient’s global assessment scores

≥>1-POINT IMPROVEMENT,
BASELINE
WEEK 12

Clindamycin Clindamycin
phosphate/ Placebo, N=16 phosphate/ Placebo, N=15 Significance
tretinoin gel, N=17 tretinoin gel, N=15

PATIENT’S GLOBAL ASSESSMENT

SCORES, N (%)

1 3 (17.6) 2 (12.5)
10 (66.7) 6 (40.0) p=0.27
2 14 (82.4) 14 (87.5)

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TABLE 8. Safety assessments

BASELINE ≥>2-POINT IMPROVEMENT, WEEK 12

Clindamycin Clindamycin
phosphate/ Placebo, N=16 phosphate/ tretinoin Placebo, N=15
tretinoin gel, N=17 gel, N=15
SCALING SCORE, N (%)
0 11 (64.7) 10 (62.5)

1 3 (17.6) 4 (25.0)
2 (100.0) 2 (66.7)
2 2 (11.8) —
3 1 (5.9) 2 (12.5)
ERYTHEMA SCORE, N (%)
0 11 (64.7) 11 (68.8)
1 3 (17.6) 4 (25.0)
3 (100.0) 1 (100.0)
2 3 (17.6) —
3 — 1 (6.3)
ITCHING SCORE, N (%)
0 11 (64.7) 12 (75.0)
1 4 (23.5) 4 (24.0) —
2 (100.0)
2 1 (5.9) — —
3 1 (5.9) —
BURNING SCORE, N (%)
0 14 (82.4) 14 (87.5)
1 2 (11.8) 2 (12.5) —
1 (100.0)
2 1 (5.9) — —
3 — —
STINGING SCORE, N (%)
0 15 (88.2) 12 (75.0)
1 1 (5.9) 2 (12.5)
1 (100.0) 2 (100.0)
2 1 (5.9) 2 (12.5)
3 — —
* For each assessment, there was no significant difference between groups

with Patient’s Global Assessment scores of 0 or 1 at Week 12 gel, but did not lead to discontinuation of treatment. The
was 80 and 53 percent, respectively. other was described as periorbital edema of moderate
Safety. For the majority of patients, the severity of severity, which was believed to be possibly related to
scaling, erythema, burning, stinging, and itching was very clindamycin/tretinoin gel and lead to withdrawal from the
low. Baseline scores of 0 or 1 were reported by more than 80 study. There were no AEs suggestive of pseudomembranous
percent of patients for scaling and more than 90 percent of colitis.
patients for itching and burning (Table 8). The severity of
scaling, erythema, burning, stinging, and itching remained DISCUSSION
low for both treatment groups throughout the trial, and The clindamycin phosphate 1.2% and tretinoin 0.025% gel
severity scores remained 0 or 1 for 85 to 100 percent of used in this study is known to be an effective treatment for
patients at the end of the 12-week trial. acne vulgaris11 without causing the inflammatory flare16
Two additional AEs were reported by two patients. One associated with the use of retinoids alone.20,21 During two
patient reported mild crusting of the cheek, which was Phase III clinical trials, 845 patients, including 105 Black
determined to be probably related to clindamycin/tretinoin patients (12%), were randomized to undergo treatment with

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clindamycin/tretinoin gel for 12 weeks.11 Based on the REFERENCES

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