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`JANUARY 2010
`
`COPYRIGHT © 2010
`
`.. .,,Mi§Mi-ih•N•4• JOURNAL OF DRUGS IN DERMATOLOGY
`
`VoWME 9 • lssUE 1
`
`33
`
`Dapsone Gel 5% in Combination With Adapalene
`Gel 0.1 %, Benzoyl Peroxide Gel 4% or Moisturizer
`for the Treatment of Acne Vulgaris:
`A 12-Week, Randomized, Double-Blind Study
`Alan B. Fleischer Jr. MD," Alan Shalita MD/ Lawrence F. Eichenfield MD;·d William Abramovits MD,e
`Anne Lucky MD/ Steven Garrett DDS,s for the Dapsone Gel in Combination Treatment Study Group*
`•Wake Forest University School of Medicine Medical Center, Winston-Salem, NC
`"SUNY Downstate Medical Center,Brooklyn, NY
`•Rady Children's Hospital and Health Center, San Diego, CA
`•University of California, San Diego, CA
`•Dermatology Treatment & Research Center, Dallas,TX
`rDermatology Research Associates, Inc., Cincinnati, OH
`•QLT USA, Inc., Fort Collins, CO
`* Additional members of the Dapsone Gel in Combination Treatment Study Group are listed in the Disclosures.
`
`ABSTRACT
`
`Purpose: To evaluate the safet y and efficacy of dapsone gel 5% in the treatment of acne w hen used in combination w ith adapalene
`gel 0.1 %, benzoyl peroxide gel 4% or moisturizer.
`Methods: This was a twelve-week, randomized, double-blind study. Patients aged 12 years and older (n=301) applied dapsone gel
`twice daily and were randomly assigned (1 :1 :1) to one of three additional treatments, applied once daily.
`Results: By week 12, dapsone gel combined w ith any of the three additional treatments reduced the mean number of inflamma(cid:173)
`tory lesions. However, the authors did not detect a significa nt difference in the reduction of inflammatory lesions w hen dapsone
`was used in combination w ith adapalene gel or w ith benzoyl peroxide gel compared to the dapsone plus moisturizer combination
`group (P=0.052 for both versus moisturizer combination). Patients treated w ith dapsone gel combined w ith adapalene showed a
`significa ntly better response in reduction in non-inflammatory and total acne lesion count than those w ho received the moisturizer
`combination. Local adverse reactions in all three treatment groups were minimal and generally mild in severity.
`Conclusion: Dapsone gel in combination w ith adapalene gel or benzoyl peroxide gel is safe and well tolerated for the treatment of
`acne vulgaris.
`
`INTRODUCTION
`
`A cne vulgaris is a complex skin disorder involving multiple
`
`abnormalities of the pilosebaceous unit, including hy(cid:173)
`perkeratinization, sebum production, bacterial prolifera(cid:173)
`tion and inflammation.' Disease onset occurs commonly during
`adolescence and is characterized by papules, pustules and come(cid:173)
`dones. The prevalence of acne is close to 100% of the population,
`with individuals differing only in severity of expression.2 Most an(cid:173)
`ti-acne medications do not act against all four of the pathophysi(cid:173)
`ologic features of acne, so combination therapy is often used in
`the management of all but the most severe fonns of acne.H
`
`Dapsone is a sulfone with anti-inflammatory properties. Its
`anti -inflammatory properties include inhibition of neutrophil
`myeloperoxidase and eosinophil peroxidase and suppression
`of hypochlorous acid production.• Dapsone scavenges reactive
`inflammation,'
`oxygen species and minimizes associated
`suppresses neutrophil
`recruitment and
`local production
`of toxic respiratory and secretory products, and inhibits
`
`chemoattractant-induced signal transduction.• A number of
`inflammatory as well as bullous diseases respond, in varying
`degrees, to oral dapsone, including acne vulgaris.~11 High
`doses of oral dapsone have been associated with systemic
`toxicity and dose-related hematological adverse events, so its
`use is generally reserved for the most severe forms of these
`skin diseases and when patients can be monitored closely.•-12
`
`to the
`in cutaneous pharmacology have led
`Advances
`development of a topical gel formulation of dapsone, dapsone
`gel 5% (Aczone®; Allergan, Inc., Irvine, CA). It allows clinically
`effective doses of dapsone to be administered topically
`with minimal systemic absorption.13 In two double-blind,
`randomized, 12-week, vehicle-controlled studies,14significantly
`better outcomes were observed for patients applying dapsone
`gel versus the vehicle. The safety profile, including adverse
`events, laboratory studies, and local signs and symptoms such
`as oiliness, dryness and erythema demonstrated virtually no
`difference between dapsone gel-treated and vehicle-treated
`
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`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • isSUE 1
`
`A. B. Fleischer, A. Shalilta, L. E Eichenfield, et al.
`
`34
`
`patients. Similar results were observed in an open-label safety
`study conducted over one year. 1
`•
`
`This report assessed the safety and efficacy of dapsone gel
`when coadministered with one of the following: adapalene gel
`0.1% (adapalene gel), benzoyl peroxide gel 4% (benzoyl peroxide
`gel) or moisturizer. Levels of dapsone exposure were also as(cid:173)
`sessed. Adapalene gel was selected because it has consistently
`demonstrated a more favorable tolerance profile than other topi(cid:173)
`cal retinoids,18 and benzoyl peroxide gel was chosen because it is
`often used in combination with other acne treatments.•
`
`METH ODS
`Study Design
`A three-arm, 12-week, randomized, double-blind study was
`conducted to evaluate the safety and efficacy of dapsone gel in
`combination with adapalene gel, benzoyl peroxide gel or mois(cid:173)
`turizer in the treatment of acne vulgaris. A total of 22 centers
`in the United States (U.S.) participated in the study between
`February 2005 and July 2005.
`
`All eligible patients applied dapsone gel and were also
`randomly assigned in a 1:1:1 ratio, according to a computer(cid:173)
`generated randomization table, to one of three additional
`treatment groups: adapalene gel, benzoyl peroxide gel or
`moisturizer (chosen as a nonactive control). The investigators,
`patients and sponsor personnel were blinded to the treatment
`assignment. To maintain blinding, personnel who were not
`involved in efficacy or safety assessments conducted the drug
`accountability and test-article-weight assessments.
`
`Patients applied a thin film of dapsone gel twice daily to the
`entire face after washing with a standard, noncomedogenic,
`soap-free cleanser (Cetaphil<il Cleanser; Galderma Laboratories,
`
`LP., Ft. Worth, TX): once in the morning and again at least one
`hour before bedtime. Ten minutes after the evening application
`of dapsone gel, patients applied a thin layer of adapalene
`gel (Differin® Gel, 0.1%; Galderma S.A.), benzoyl peroxide
`gel (Brevoxyl®-4 Gel, Stiefel Laboratories, Inc.) or moisturizer
`(Cetaphil® Daily Facial Moisturizer SPF 15; Galderma
`Laboratories, LP.), and gently rubbed it in until it completely
`disappeared. Patients were instructed
`to maintain
`their
`current skin care regimen throughout the study: moisturizers,
`sunscreens and cosmetics could be used one hour after study
`treatment applications, but use of new cosmetics, cleansers or
`medicated makeup was prohibited. Participants could also treat
`acne-affected areas other than the face, including chest and
`back; however, these areas were not assessed for efficacy.
`
`These studies were conducted in accordance with the ethical
`principles of the Declaration of Helsinki and in compliance with
`the Good Clinical Practice Guidelines. The protocols for each study
`center were reviewed and approved by an institutional review
`board. Written informed assent and consent was obtained from
`each patient or his/her parent or guardian, as appropriate, before the
`start of study procedures. If a patient did not understand English, a
`validated, translated informed consent agreement was provided.
`
`Patients
`Male and female patients 12years of age or older with a clinical di(cid:173)
`agnosis of acne vulgaris involving the face were enrolled in these
`studies. Patients were to have a Global Acne Assessment Score
`(GAAS) of at least 2 at baseline, and a minimum of 20 inflamma(cid:173)
`tory lesions (defined to include papules and pustules) and 20 non(cid:173)
`inflammatory lesions (comedones) above the mandibular line at
`baseline. Individuals with severe cystic acne, acne conglobata, or
`any active or developing nodules above the mandibular line at
`baseline were excluded from participation. Other exclusion crite-
`
`FIGURE 1. Flow chart of
`patient disposition.
`
`Intent to treat
`n=301
`
`Oapsone Gel + Mo1stunzer
`n= 103
`tcsafety evaluable
`n= 100
`
`Oapsone Gel+ AdapaleneGel
`n= 100
`tcsafety evaluable
`n=97
`
`Dapsone Gel + Benzoyl Peroxide Gel
`n=98
`tcsafety evaluable
`n=95
`
`Discontinued
`prematurely
`n = 17
`(1 7%)
`
`Oapsone gel : dapso ne gel 5%; adapalene gel: adapale ne gel 0.1%; benzoyl peroxide gel: benzoyl peroxide gel 4%.
`' Patients who received a t least 1 application of study drug .
`11lncludes loss to follow-u p, voluntary withd rawa l, p rotocol viol ation, treatment, no nco mpl ia nce, a nd other reasons not specified .
`
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`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • isSUE 1
`
`A. B. Fleischer, A. Shalilta, L. E Eichenfield, et al.
`
`35
`
`weeks 2, 4, 8 and 12. Missing values for the ITT data set were
`analyzed with a last-observation-carried forward method. Safe(cid:173)
`ty results use the safety-evaluable population (all patients who
`received at least one dose of study drug or reported an adverse
`event) and were also summarized at these time points.
`
`FIGURE 2. Mean percentage reduction in lesion counts. a) Inflam(cid:173)
`matory lesions (primary endpoint): Dapsone gel + moisturizer versus
`dapsone gel+ adapalene or dapsone gel + BP, both P=0.052 at week
`12. b) Non-inflammatory lesions: Dapsone gel+ moisturizer versus
`dapsone gel+ adapalene or dapsone gel + BP, P<0.001 and P=0.086,
`respectively, at week 12. c) Total lesions: Dapsone gel+ moisturizer
`versus dapsone gel+ adapalene or dapsone gel + BP, P=0.004 and
`P=0.056, respectively, at week 12. Wilcoxon/Mann Whitney test;
`BP=benzoyl peroxide gel 4%; adapalene=adapalene gel 0.1%.
`
`fl
`C:
`
`C:
`
`0 8
`-10 3 -20
`
`£
`0 ..,
`C:
`!!l
`al a:
`c s
`~ -50
`C:
`::l
`:i
`
`-30
`
`-40
`
`-60
`
`Inflammatory Lesfons
`
`0G+..,;st,ri10,~
`-
`-.- 06 + adapele11e
`...,._ 06 +BP
`
`Time (Weeks)
`
`12
`
`0
`
`Noninflammatory Lesions
`
`C:
`
`-10
`
`i1
`:,
`0 u
`0 5
`
`-211
`
`C:
`C:
`0
`
`ti -30 e .. CX:
`8
`i -50
`:
`-60
`::E
`
`-40
`
`C:
`
`_._ DG +moi.sturizar
`......, DG + adapalene
`~
`oG +BP
`
`Time (Weeks)
`
`ria included use within two weeks of baseline of topical drugs or
`treatments that could affect acne, including retinoids, antibiotics
`and anti-inflammatory agents; use within four weeks of baseline
`of systemic immunosuppressive drugs or systemic medications
`or therapy known to affect acne or inflammatory responses; use
`of isotretinoin within three months of baseline; or known allergy
`or hypersensitivity to dapsone, adapalene, benzoyt peroxide or
`any component of the study treatments. Women of childbearing
`potential could not be pregnant or nursing, had to be practicing
`an effective method of birth control as determined by the enrolling
`physician, and, if using hormonal contraception, had to have been
`using a stable dose for a minimum of three months. Systemic
`contraceptives were not to be initiated during the study.
`
`Efficacy and Safety Assessments
`All patients underwent a dermatologic examination at screening/
`baseline and weeks 2, 4, 8 and 12. At each of these visits, inves(cid:173)
`tigators recorded the patient's GAAS and counted the number of
`inflammatory and non-inflammatory acne lesions present.
`
`The primary efficacy endpoint was the mean percentage reduc(cid:173)
`tion from baseline in inflammatory acne lesion counts at week
`12 (or end of treatment). Secondary efficacy endpoints included
`mean percentage reduction from baseline for non-inflammato(cid:173)
`ry and total lesion counts; incidence of success based on the
`GAAS; and mean reduction from baseline in lesion counts for
`inflammatory, non-inflammatory and total acne lesions. Inci(cid:173)
`dence of success based on the 5-point GAAS scale was defined
`as a rating of zero (Nnone• or no evidence of facial acne vul(cid:173)
`garis) or 1 (#minimal," where a few non-inflammatory lesions
`are present and a few inflammatory lesions may be present).
`The total lesion count was the sum of both inflammatory and
`non-inflammatory lesions.
`
`Adverse events and local signs and symptoms (adverse reac(cid:173)
`tions of facial oiliness, peeling, dryness and erythema) were
`monitored throughout the study. Physical examinations that
`included vital signs, height and weight were conducted at
`baseline and week 12 (or end of treatment). Patients were spe(cid:173)
`cifically queried at each study visit, including at baseline, for
`the presence of local signs or symptoms; a worsening of these
`symptoms from baseline or the appearance of any other local
`sign or symptom was reported as an application-site adverse
`event. Blood was drawn for the determination of plasma dap(cid:173)
`sone and N-acetyl plasma dapsone levels at baseline, week 2
`and week 12. Plasma dapsone analyses were performed at a
`central laboratory (MOS Pharma Services; Saint-Laurent, Que(cid:173)
`bec, Canada).
`
`Statistical Methods
`Efficacy results are presented for the intent-to-treat (ITT) popu(cid:173)
`lation (defined as all enrolled patients to whom study drug was
`dispensed) and were summarized for each treatment group at
`
`fl
`C:
`
`0 8 i -10
`
`-30
`
`-20
`
`E
`§
`'B
`~
`a: 40
`~
`~ OG+moisturizer
`~ -50 ~ OG + adapalene
`lf.
`......, OG + BP
`fi;
`i -60
`
`Time (Weeks)
`
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`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • isSUE 1
`
`A. B. Fleischer, A. Shalilta, L. F. Eichenfield, et al.
`
`36
`
`TABLE 1.
`Patient Demographics and Baseline Characteristics
`
`Dapsone Gal Dapsone Gel
`+ Moisturizer + Adapalene
`(n=103)
`Gel
`n=100
`
`DapsoneGel
`+ Benzoyl
`Peroxide Gel
`n=98
`
`TABLE 2.
`Mean Percentage Reduction in Lesion Counts by Week 12
`Dapaone Gel +
`Adapalene Gel
`(n=100)
`
`DapaoneGal
`+ Moisturizer
`(n=103)
`
`DapsoneGel
`+ Benzoyl
`Peroxide Gel
`(n=IS}
`
`52 (50)
`51 (50)
`
`48(48)
`52 (52)
`
`47(48)
`51 (52)
`
`Sex, n (%}
`Male
`Female
`Race/Ethnicit y, n (%}
`63(63)
`61 (59)
`Wh ite
`15 (15)
`15 (15)
`Black
`16 (16)
`20 (19)
`Hispanic
`2 (2)
`4(4)
`Asian
`4(4)
`3(3)
`Other
`20 (12-44)
`18 (12-38)
`M ean Age, y (Range)
`Acne lesion Counts at Baseline, m ean [:tSDJ
`33 [:t13)
`Inflammatory
`32 [:t15)
`Non-i nflammatory 52 [:t32)
`50 [:t36)
`85 (:t35)
`81 [:t43)
`Total'
`GAAS" at Baseline, n (%}
`14 (14)
`16 (16)
`11 (11)
`Mild
`82(84)
`81 (81)
`83 (81)
`Moderate
`5(5)
`5(5)
`4(4)
`Severe
`Oapsone gel: dapsone gel 5¾; adapa lene gel: adapa lene gel 0.1%; benzoyl
`peroxide gel: benzoyl peroxide gel 4%.
`• Total lesions = inflammatory -+ non-inflammatory lesions.
`0 Globa l Acne Assessment Sco re, w here 2 = mild, 3 = moderate, 4 = severe.
`No patient had a score of O (no acne) or 1 (minim al) at baseline.
`
`56(57)
`21 (21)
`16 (16)
`2 (2)
`3(3)
`18 (12-44)
`
`31 [:t11)
`34 [:t41)
`80 (:t37)
`
`The primary efficacy endpoint was the mean percentage reduc(cid:173)
`tion from baseline in inflammatory lesion counts at week 12 (ITT
`population). The planned sample size of 300 evaluable patients
`(100 per treatment arm) was based on the expected difference
`between the dapsone gel + moisturizer group and the other
`treatment groups for the primary endpoint. A 40% response for
`the dapsone gel+ moisturizer group and a 45% response for the
`other dapsone gel combination-treatment groups, with a com(cid:173)
`mon standard deviation of 10, would provide adequate(;,, 80%)
`power to detect a difference between the treatment groups. A
`test for normality using the Kolmogorov-Smirnov statistic was
`performed. Because this test was significant at ~0.05, a Wil(cid:173)
`coxon/Mann-Whitney test was used to analyze the percentage
`reduction in inflammatory lesion counts.
`
`Inflammatory Lesions
`Mean % reduction in acne lesion counts [:tSD)
`26 [:t 28)
`30 [:t 29)
`Week2
`Week4
`42 [:t 32)
`43 [:t 29)
`47 [:t 33)
`51 [:t 31 )
`49 [:t 35)
`57 [:t 36)
`
`Week8
`Week 12'
`PValues'
`DG + moisturizer versus DG + adapalene gel•
`DG + moisturizer versus DG + BP gel•
`
`DG + adapalene gel versus DG + BP gel'
`Non-inflammatory lesion s
`Mean % reduction in acne lesion counts [:tSD)
`3 [:t 36)
`21 [:t 28)
`11 [:t 36)
`26 [:t 36)
`21 [:t 35)
`40 [:t 31 )
`30 [:t 38)
`47 [:t 38)
`
`Week2
`Week4
`Week8
`Week 12•
`PValues•
`DG + moisturizer versus DG + adapalene gel
`DG + moisturizer versus DG + BP gel
`DG + adapalene gel versus DG + BP gel
`Total Lesion s
`Mean % reduction in acne lesion counts [:tSD)
`13 (:t 26)
`24 [:t 24)
`Week2
`33 [:t 28)
`Week4
`24 [:t 28)
`31 [:t 28)
`44 [:t 26)
`39 [:t 29)
`51 [:t 31 )
`
`Week8
`Week 12'
`PValues'
`DG + moisturizer versus DG + adapalene gel
`DG + moisturizer versus DG + BP gel
`
`31 [:t 35)
`47 [:t 30)
`54 [:t 38)
`58 [:t 36)
`
`0.052
`0.052
`0.893
`
`12 [:t 33)
`26 [:t 34)
`31 [:t 45)
`38 [:t 43)
`
`<0.001
`0.087
`0.210
`
`19 [:t 27)
`34 [:t 28)
`40 [:t 39)
`46 [:t 36)
`
`0.004
`0.056
`DG + adapalene gel versus DG + BP gel
`0.620
`DG: dapsone gel 5%; adapalene gel: adapalene gel 0.1%; BP gel : benzoyl
`peroxide gel, 4%.
`' Prim ary analysis.
`11 Wilcoxon/ Mann W hitney test. Ps:0.05 was considered significant.
`0 Seconda ry ana lysis.
`
`a GAAS score of O (none) or 1 (minimal) at week 12 was com(cid:173)
`pared using pair-wise chi -square tests.
`
`The secondary endpoints of mean percentage reduction in non(cid:173)
`inflammatory and total lesion counts, mean reduction in acne
`lesion counts from baseline (all three categories), and acne le(cid:173)
`sion counts (all three categories) were analyzed in the same
`way as the primary endpoint. Most study centers randomized
`fewer than 15 study subjects, so the effect of centers was con(cid:173)
`sidered negligible; therefore, the incidence of success based on
`
`Adverse events, regardless of relationship to study medication,
`were tabulated and summarized by incidence as application(cid:173)
`site or non-application-site events, using the safety-evaluable
`data set. The local adverse reaction assessments were summa(cid:173)
`rized using frequencies and percentages by treatment group
`for each time point. Relationship to treatment was determined
`by the investigator.
`
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`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • ISSUE 1
`
`A. B. Fleischer, A. Shalilta, L. F. Eichenfield, et al.
`
`37
`
`TABLE 3.
`Adverse Events Occurring in at Least 2% of Patients in Any
`Treatment Group (Safety-Evaluable Population)
`N o. (%1 of Patients
`
`TABLE 4.
`Patients Who Experien ced Treatment-Related Local Signs
`and Symptoms Which Were Moderate-to-Severe in Intensity
`(Safety-Evaluable Population)
`
`N o. (%1 of Patients
`
`Dapsone Gel +
`Dapsone Gel + Dapsone Gel +
`Moisturizer
`Adapalene Gel Benm yl Peroxide
`(n=1001
`Gel
`(n::971
`(n::951
`Baseline Week Baselin e Week Baseline Week
`12
`12
`12
`
`Oiliness
`25 (25)
`Erythema 19 (19)
`2 (2)
`Dryness
`Peeling
`Rash
`
`0
`2 (2)
`
`6(6)
`8 (81
`0
`0
`
`21 (22)
`16 (17)
`0
`0
`0
`
`5(5)
`3 (3)
`1 (1)
`
`0
`
`13 (14)
`15 (16)
`3 (3)
`
`0
`0
`
`4 (4)
`4 (4)
`1 (1)
`2 (2)
`
`TABLE 5.
`
`iMllii:MWll!i4lli~
`
`Treatment Group
`
`Dapsone Gel
`+ M oisturizer
`
`DapsoneGel
`+Adapalene
`Gel
`
`DapsoneGel
`+ Benzoyl
`Peroxide Gel
`
`Plasma Dapsone Concentrations
`Baseline
`
`0.051 :t 0.015
`
`0.052 :t 0.028
`
`6.37 :t 5.71
`
`9.50 :t 9.87
`
`0.049 :t 0.00
`
`0.049 :t 0.00
`
`3.09 :t 3.23
`
`4.00 :t 5.24
`
`0.049 :t 0.000
`
`11.13 :t 9.90
`
`6.72 :t 7.68
`
`0.049 :t 0.00
`
`4.13 :t4.67
`
`Mean :t SD
`Week 2
`Mean :t SD
`Week 12
`4.75 :t 5.97
`7.10 :t 8.95
`Mean :t SD
`Plasma N-acetyl Dapsone Concentrations
`Baseline
`Mean :t SD
`Week 2
`Mean :t SD
`Week 12
`Mean :t SD
`
`Dapsone
`Gel+
`Moisturizer
`(n=1001
`
`DapsoneGel DapsoneGel
`+ Benzoyl
`+Adapalene
`Gel
`Peroxide Gel
`(n=971
`(n=951
`
`All Adverse Events•
`
`31 (31)
`5 (5)
`4 (4)
`
`Any event
`Nasopharyngitis
`Upper respiratory
`tract infection
`2 (21
`Headache
`2 (21
`Pharyngitis
`Nasal congestion
`3(31
`2 (21
`Cough
`Sinusitis
`1 (11
`2 (2)
`Abrasion
`Ear pain
`0
`Vaginosis fungal
`0
`Treatment-Related Adverse Events•
`Any treatment-
`4 (4)
`related event
`
`41 (42)
`4 (4)
`3 (3)
`
`29 (311
`4 (4)
`2 (2)
`
`2 (2)
`1 (1)
`1 (1)
`2 (2)
`2 (2)
`1 (1)
`0
`2 (2)
`
`2 (2)
`3 (3)
`1 (1)
`0
`0
`0
`2 (2)
`0
`
`17 (18)
`
`9 (10)
`
`Burning
`
`1 (1)
`
`10 (10)•
`
`1 (1)
`
`Drug interaction
`7 (7)0
`0
`0
`1 (1)
`4 (4)
`1 (1)
`Pruritus
`2 (2)
`Rash
`0
`0
`Oapsone gel: dapsone gel 5¾; adapa lene gel : adapa lene gel 0. 1%; benzoyl
`peroxide gel: ben zoyl peroxide gel 4%.
`'Rega rd less of relatio nship to treatment .
`0 Investigators determi ned relatio nship to treatment .
`° Consistent w it h t he 10% t o 40% i ncidence described in the adapa lene gel
`0. 1 % package insert.
`0 A ll d rug interactio ns in the dapsone g el+ benzoyl peroxide g r ou p w ere
`appl icatio n-site adverse events involving a te m po rary ta n resid ue at the
`appl icatio n site.
`
`Baseline patient demographics and lesion characteristics, vital
`signs, and plasma levels of dapsone and N-acetyl dapsone were
`summarized using descriptive statistics (mean, standard devia(cid:173)
`tion, median, minimum and maximum for quantitative variables,
`and numbers and percentages for categorical variables).
`
`RESULTS
`Patient Disposition and Baseline Characteristics
`A total of 301 patients were enrolled in the study and received
`the study drug; this group composed the ITT population (Fig(cid:173)
`ure 1 ). The safety-evaluable population, defined as all enrolled
`subjects who applied the study drug or reported an adverse
`event, included 292 patients. There were minor differences in
`patients who discontinued the study, with 11 % of patients in
`the dapsone gel + benzoyl peroxide group discontinuing versus
`approximately 17% in the dapsone gel + adapalene or dapsone
`
`2.35 :t 2.53
`Va lues below the limit o f detection (0.05 ng/ml ) were set to 0.049 ng /ml
`for both p lasma m easure ment s,
`
`2.34 :t 3.07
`
`2.73 :t 4.63
`
`gel + moisturizer groups. Most premature study discontinua(cid:173)
`tions were for administrative reasons, including loss to follow(cid:173)
`up, voluntary withdrawal, protocol violation and treatment
`noncompliance (Figure 1). Nine subjects discontinued the study
`due to 16 adverse events (application-site and non-application(cid:173)
`site) and/or local adverse reactions (see Safety Results).
`
`Patients in the dapsone gel + moisturizer and dapsone gel +
`adapalene gel groups were treated for a mean of 76.2 days,
`
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`
`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • ISSUE 1
`
`A. B. Fleischer, A. Shalilta, L. F. Eichenfield, et al.
`
`38
`
`while the dapsone gel+ benzoyl peroxide gel group was treated
`for a mean of 78.7 days. The mean number of applications of
`dapsone gel or combination treatment ranged from 148.6-154.5
`and 73.2-76.7, respectively. Subjects in all treatment groups ap(cid:173)
`plied combination therapy on most of the days they applied
`dapsone gel. The total amount of dapsone gel used was similar
`among the treatment groups (range 66.5--72.7 g), whereas for
`combination treatment, the total amount of moisturizer used
`(51.0 g) was greater than the amount of adapalene (38.4 g) or
`benzoyl peroxide gel (43.0 g) used.
`
`At baseline, all three treatment groups were balanced with re(cid:173)
`spect to demographics (i.e., age, race and sex), inflammatory
`and total acne lesion counts, and GAAS (Table 1 ). Patients in the
`dapsone gel+ benzoyl peroxide gel group had fewer non-inflam(cid:173)
`matory lesions at baseline than the other two treatment groups.
`In total, most patients (82%; 2461301) had moderate acne.
`
`Efficacy Results
`For the primary efficacy evaluation, dapsone gel in combination
`with any of the three treatments reduced the number of inflam(cid:173)
`matory lesions from baseline (mean reduction from baseline was
`57.3% for dapsone gel+ adapalene, 57.5% for dapsone gel+ benzoyl
`peroxide, and 49.2% for dapsone gel + moisturizer). However,
`no statistical difference was observed in the reduction of in(cid:173)
`flammatory lesions between the three treatment arms (dap(cid:173)
`sone gel combined with either adapalene gel or benzoyl perox(cid:173)
`ide gel were both P=0.052 versus dapsone gel + moisturizer at
`12 weeks;Table 2 and Figure 2).
`
`For the secondary variables, patients treated with dapsone gel
`+ adapalene had a significantly better response compared to
`dapsone gel + moisturizer for both non-inflammatory and total
`
`FIGURE 3. Global Acne Assessment Score {GAAS) success rate
`at week 12. Percentage of patients achieving success, defined
`as a GAAS score of zero (none) or 1 (minimal}. Chi-square test;
`BP=benzoyl peroxide gel 4%; adapalene=adapalene gel 0.1%.
`
`acne lesion counts (P<0.001 and P=0.004, respectively) (Table 2
`and Figure 2). Results for the dapsone gel+ benzoyl peroxide gel
`group were also numerically better than dapsone gel + moistur(cid:173)
`izer for both of these lesion count parameters, but the differences
`were not significant. Overall, efficacy in all treatment groups for
`all lesion categories (inflammatory, non-inflammatory, and total
`lesions) was observed as early as week 2 and showed further
`improvement throughout the 12-week period (Figure 2).
`
`The combination of dapsone and adapalene showed signifi(cid:173)
`cantly better results compared to the dapsone gel+ moisturizer
`combination (P=0.0395) in terms of GAAS treatment success.
`GAAS success was defined as none or minimal disease at the
`end of treatment (Figure 3). The incidence of GAAS success
`for dapsone gel + benzoyl peroxide gel versus the moisturizer
`combination was not significant (f'=0.318).
`
`Safety Results
`The incidence of adverse events and local adverse reactions
`was similar in the dapsone gel+ moisturizer and dapsone gel +
`benzoy1 peroxide gel groups, but was somewhat greater in the
`dapsone gel + adapalene group (Table 3). This was likely due to
`the higher incidence of application-site burning in the adapalene
`group, which is consistent with the 10% to 40% incidence
`described in the Differin (adapalene) Gel 0.1% package insert.17
`The most common adverse events in the study, occurring at an
`incidence of at least 2% of patients, are listed in Table 3. Local
`adverse reactions were minimal, were generally mild in severity,
`and typically improved during treatment. Local adverse reactions
`that were moderate or severe are listed in Table 4. Seven patients
`in the dapsone gel + benzoyl peroxide gel group experienced a
`possible drug interaction involving a temporary tan residue at
`the application site. These events were generally mild in severity
`and most resolved in 4-57 days.The residue was not permanent
`and could be wiped away if observed. No drug interactions were
`reported for the other two groups. Nine of 292 patients (3%)
`discontinued the study due to an adverse event or local adverse
`reaction. The events leading to discontinuation included reports
`of residue on the face (two events), application-site dryness
`(two events), application-site erythema (two events), increased
`sweating (one event), contact dermatitis (one event), dermatitis
`(one event), eye swelling (one event), application-site burning
`(one event), application-site pruritus (one event), generalized
`pruritus (one event), application-site rash (one event), rash (one
`event) and application-site reaction (i.e., peeling, one event).
`These events were generally mild in severity and most resolved
`within a week. The number of adverse events and/or local
`adverse reactions that led to discontinuation was similar among
`the treatment groups (two moisturizer, three adapalene gel, four
`benzoy1 peroxide gel).
`
`50
`
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`Global Acne Assessment Score (GAAS) success rate at week 12
`
`P =0.28f I I
`
`06 + inoisturizer
`(n=103)
`
`06 + adapalono
`(n=100)
`
`DG +BP
`(n:98)
`
`Blood samples for the determination of plasma dapsone and N(cid:173)
`acety1 dapsone concentrations were drawn at baseline (day 0),
`
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`
`JOURNAL OF DRUGS IN DERMATOLOGY
`JANUARY 2010 • VOLUME 9 • ISSUE 1
`
`A. B. Fleischer, A. Shalilta, L. F. Eichenfield, et al.
`
`39
`
`week 2, and week 12 ( or end of treatment). Mean plasma dapsone
`concentrations and mean N-acetyl dapsone concentrations for all
`three treatment groups were low and remained low throughout
`the study (Table 5). No systemic adverse events occurred that
`could be attributed to the known safety profile of oral dapsone.
`
`be used instead of a leave-on formulation. These steps can greatly
`reduce the likelihood of residue formation. If the reaction does<»
`cur, patients can rub the residue off. Combination treatments with
`dapsone gel and either adapalene gel or moisturizer were well tol(cid:173)
`erated and did not demonstrate any safety concerns.
`
`DISCUSSION
`This study assessed dapsone gel in combination with one of
`three additional treatments for acne vulgaris: adapalene gel
`0.1 ¾, a topical retinoid with a more favorable tolerance pro(cid:173)
`file than other topical retinoids;1
`• benzoyl peroxide 4%, which
`is often used in combination with other anti-acne agents;• or a
`moisturizer as a nonactive control. In all three treatment groups,
`improvements in acne were observed as early as week 2, with
`further improvements evidentthroughoutthe study. For the pri(cid:173)
`mary efficacy outcome, a trend in mean percentage reduction of
`inflammatory lesions from baseline was observed for patients
`who received dapsone gel in combination with adapalene gel
`or benzoyl peroxide gel, but the differences compared to the
`dapsone gel plus moisturizer group were not significant. Dap(cid:173)
`sone gel results were consistent with previous controlled trials,
`while patients who received dapsone gel in combination with
`either adapalene gel or benzoyl peroxide gel show a further re(cid:173)
`duction in inflammatory and non-inflammatory lesion counts
`beyond those seen in earlier controlled trials.14 Furthermore,
`patients treated with dapsone gel and adapalene gel had sig(cid:173)
`nificantly better responses for the mean percentage reduction
`in both non-inflammatory and total acne lesion counts and a
`significantly higher incidence of success ("none" or "minimal
`disease" at the end of treatment) based on the GAAS, com(cid:173)
`pared to those receiving dapsone gel and moisturizer.
`
`This study showed that systemic exposure to dapsone remained
`low, without accumulation following twice-daily application of
`topical dapsone gel. Mean plasma dapsone concentrations and
`mean plasma N-acetyl dapsone concentrations for all three
`treatment groups were low and remained low throughout the
`study (<11.1 ng/mL and <4.1 ng/mL, respectively). No systemic
`adverse events that could be attributed to the known safety
`profile of oral dapsone were observed, likely due to minimal
`systemic absorption following topical application.13
`
`The results of this study demonstrate that dapsone gel 5% in
`combination with either adapalene gel 0.1 ¾ or benzoy1 peroxide
`gel 4% is safe and well tolerated for the treatment of acne vul(cid:173)
`garis. The statistically significant response in favor of dapsone
`gel combined with adapalene gel compared to dapsone gel com(cid:173)
`bined with moisturizer may justify further investigation.
`
`ACKN<)WLEDGEMENTS
`The authors wish to