Ju1.Y 2011
`
`COl'YHICIIT <f) 201 I
`
`783
`
`VoLUME ro • IssuE 7
`
`JOURNAi. Ol' Dnuc;s IN DERMATOLOGY
`
`Clinical Evidence for the Role of a Topical
`Anti-Inflammatory Agent in Comedonal Acne:
`Findings From a Randomized Study of Dapsone
`Gel 5% in Combination With Tazarotene
`Cream O .1 % in Patients With Acne Vulgaris
`
`Emil Tanghetti MD," Sunil Dhawan MD,h Lawrence Green MD,' Mark Ling MD PhD,c1 Jeanine Downie MD,"
`Marguerite A. Germain MD/ J. Scott Kasteler MD,g Leon Kircik MD,h Michael G. Oefelein MD,;
`Zoe Draelos MDi
`·'Center for Dermatology :md Laser Surgery, Sacramento, CA
`hCenter for Dern1atology, Cosmetic and Laser Surgery, Fremont, CA
`'Department of Dermatology, George Washington University, Washington, DC
`dMedaPhase, Inc., Newnan, GA
`''Image Dermatology PC, Montclair, NJ
`'Germain Dermatology, Mt. Pleasant, SC
`~Division of Dermatology, University of Louisville, Louisville, KY
`hPhysiciam Skin Care PLLC, Louisville, KY
`'Allergan, Inc., Irvine, CA
`1Departmrnt ofDennatology, Duke University School of Medicine, Durham, NC
`
`Background: Acne pathogenesis is multifactorial and includes inflammation. Combining drugs targeting multiple components of
`acne pathogenesis is standard practice.
`Objective: To assess the safety and efficacy of dapsone gel 5%, an anti-inflammatory agent, in combination with tazarotene cream
`o.1 % for treatment of acne vulgaris.
`Methods: Patients were randomized to receive combination therapy (dapsone gel 5% twice-daily plus tazarotene cream 0.1 % daily)
`or monotherapy (tazarotene cream 0.1 % daily). Efficacy and safety data were collected after 1, 2, 4, 8, and 12 weeks of treatment.
`Results: Patients in both arms (n=86, dapsone + tazarotene; n=85, tazarotene) showed significant reductions from baseline in in(cid:173)
`flammatory, noninflammatory and total lesion counts (P<.001 for all). At 12 weeks, patients treated with dapsone plus tazarotene
`showed a greater reduction from baseline in noninflammatory (comedonal) and total lesion counts than tazarotene-treated patients
`(noninflammatory, 59.7 percent vs. 46.5 percent, P=.01; total, 63.3% vs. 53.6%, P=.02). The percentage of patients achieving treat(cid:173)
`ment success (an investigator subjective score of 0 [none] or 1 [minimal]) was greater in dapsone plus tazarotene-treated patients
`(42.2%) than in tazarotene-treated patients (21.8%;P=.01). Both treatments were well tolerated.
`Conclusion: Combination therapy with dapsone gel 5% plus tazarotene cream 0.1 % was more effective than tazarotene mono(cid:173)
`therapy for treatment of comedonal acne. The results suggest that anti-inflammatory agents such as dapsone can effectively treat
`early stages of acne (both comedonal and noncomedonal) when used in combination with a retinoid.
`
`J Drugs Dermatol. 2011;10(7):783-792.
`
`11Nff.R0 Dl!J_GT-10 NI
`
`A cne, a common condition that can persist for years
`
`beyond adolescence, 1 may result in scarring and
`post-inflammatory hyperpigmentation (PIH). 2 The
`pathogenesis of acne is multifactorial and still not fully un(cid:173)
`derstood. Current dogma for acne pathogenesis suggests
`that follicular hyperkeratinization, abnormal epithelial des(cid:173)
`quamation and sebaceous gland hyperplasia lead to micro-
`
`comedo formation. Continuous accumulation of sebum and
`deposition of keratinous material lead to development of le(cid:173)
`sions (open and closed comedones) traditionally classified
`as noninflammatory or, with proliferation of Propionibacte(cid:173)
`rium acnes and induction of immunomodulatory events, in(cid:173)
`flammatory lesions. 3.4
`
`1 of 10
`
`Almirall EXHIBIT 2034
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`JOURNAL CW DRUGS IN DERMATOLOGY
`JULY 2011 • VOLUME ]() •
`ISSUE 7
`
`E.Tmghctti, S. Dhawan, L. Green, et al.
`
`784
`
`The current model for acne pathogenesis, which focuses on the
`role of P. acnes in inflammatory lesion development, has been
`brought into question based on accumulating evidence suggest(cid:173)
`ing that inflammation is present throughout the development
`of acne lesions, even when not clinically apparent, from mi(cid:173)
`crocomedones to residual erythematous lesions and PIH. 5
`6 The
`•
`pro-inflammatory cytokines, interleukin (IL)-1 a, ll-1 p, and tumor
`necrosis factor (TNF)-a, have been found in open comedones. 7
`Moreover, follicular ll-1 a and IL-1 RTII expression in uninvolved
`skin of patients with acne was found to be three-fold and thirty(cid:173)
`fold higher, respectively, than corresponding levels in normal
`skin, despite a proliferative and differentiated state of the fol(cid:173)
`licles in uninvolved skin of patients with acne that was histologi(cid:173)
`cally comparable to that of follicles in normal skin. 5 Thus, ll-1a
`from uninvolved follicles in skin of patients with acne has been
`proposed as an initiating factor for a nonspecific inflammatory
`response in the skin around the pilosebaceous follicle that oc(cid:173)
`curs prior to, and not as a result of, hyperproliferative or aberrant
`differentiation events. 5 Early acne inflammation also appears to
`involve neutrophils, among other inflammatory cells and bio(cid:173)
`chemical mediators of inflammation. Once present at the acne
`site, neutrophils can recruit additional neutrophils and generate
`reactive oxygen species that further damage tissue. 811 This novel
`concept raises the possibility that early subclinical inflammation
`may play a pathogenic role in the formation of not only visible
`inflammatory lesions, but also in the development of microcom(cid:173)
`edonal lesions heretofore considered "noninflammatory:' This
`pathogenic model of acne in turn suggests that anti-inflamma(cid:173)
`tory therapies may be suitable for treating both early comedonal
`as well as later inflammatory lesions in acne.
`
`©Dapsone gel 5% (ACZONE""; Allergan, Inc, Irvine, CA) is a topical
`anti-acne medication with an anti-inflammatory mechanism of
`action. In two randomized studies involving more than 3,000
`patients, dapsone gel 5% was found to be safe and effective
`for the treatment of acne vulgaris (both comedonal and non(cid:173)
`comedonal acne). 12 With its anti-inflammatory mechanism of
`action and favorable tolerability profile, dapsone gel 5% seems
`well suited for use in combination with a retinoid for acne treat(cid:173)
`ment. The purpose of this study was to assess the safety and
`efficacy of dapsone gel 5% co-administered with tazarotene
`cream 0.1 % in patients with moderate-to-severe inflammatory
`and comedonal facial acne.
`
`Patients
`Male or female patients at least 12 years of age with stable, non(cid:173)
`rapidly progressing facial acne vulgaris were eligible for inclusion
`in the study. Facial acne vulgaris was characterized by the presence
`of 50 to 100 inflammatory lesions (papules, pustules), 25 to 100
`facial noninflammatory lesions (open/closed comedones), and no
`more than three facial nodules and/or cysts of diameter ~1 cm.
`
`Patients with a skin disease or disorder that might interfere
`with the diagnosis or evaluation of acne vulgaris or who failed
`to comply with the protocol-specified wash-out periods for
`prohibited medications were excluded. Additional exclusion
`criteria were a history of clinically significant anemia or hemo(cid:173)
`lysis and evidence of recent alcohol or drug abuse. Females of
`childbearing potential were required to use reliable methods
`of birth control. Patients with a history of poor cooperation or
`noncompliance with medical treatment or who failed to comply
`with specified procedures were also excluded.
`
`Study Design
`This was a 12-week, multicenter, single-blinded, randomized,
`parallel-group study. Patients were assigned 1 :1 by computer
`randomization to receive dapsone gel 5% in the morning and
`evening plus tazarotene cream 0.1 % in the evening, or tazarotene
`cream 0.1 % in the evening alone for 12 weeks. Patients were
`provided with coded treatment kits and the treatment was self(cid:173)
`administered. In the combination treatment arm, the evening
`application of dapsone gel 5% was applied before tazarotene
`cream 0.1 %. Use of facial moisturizer and cleanser was restricted
`to those products supplied within the study.
`
`Patient compliance with treatment was assessed verbally at
`each visit. Patients were asked by study personnnel whether
`any appliations of study medication were missed since the pre(cid:173)
`vious visit and their responses quantified.
`
`Patients attended study visits at baseline and at weeks 1, 2, 4,
`8, and 12 during treatment. The primary efficacy variable was
`the inflammatory lesion count at all time points, defined as the
`number of papules/pustules on the face only, from the hairline
`edge to the mandibular line.
`
`Secondary efficacy variables were assessed at all time points
`total (inflammatory +
`and
`included noninflammatory and
`noninflammatory) lesion counts. In addition, four other investi(cid:173)
`gator-completed assessments were conducted at baseline and
`at each clinic visit: investigator ~Jlobal assessment (IGA; also
`referred to as the global assessment of acne severity [GAAS]),
`overall disease severity, disease signs and symptoms, and PIH.
`The IGA was conducted using an ordinal scale ranging from
`zero to 4, where zero indicates no evidence of acne vulgaris,
`and 4 indicates a significant degree of inflammatory disease, a
`predominance of papules and pustules, and the possible pres(cid:173)
`ence of nodulo-cystic lesions and comedones. Overall disease
`severity (including size of lesions, overall degree of inflamma(cid:173)
`tion, general erythema and skin condition) was quantified using
`an ordinal rating scale ranging from zero to 6, whore zero indi(cid:173)
`cates no disease present (clear, no inflammatory lesions) and 6
`indicates severe disease (numerous comedonos, papulos, and
`pustules with larger inflamed lesions extending over much of
`the face, and erythema may be pronounced). Disease signs and
`
`2 of 10
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`

`

`785
`joUHNAL OI' I )Huc;s IN Dt:HMATOLO(;y
`ju LY 2011 • Vrn.uMI' 10 • lssui: 7
`
`E.T:mghetti, S. I )hawan, L. Grern, et al.
`
`TABLE 1.
`
`Gender, n (%)
`Male
`Female
`Age,y
`Mean± SD
`Median (range)
`
`Race, n (%)
`White
`Black
`Hispanic
`Asian
`Other
`Inflammatory lesions,
`mean± SD
`Noninflammatory
`lesions, mean ± SD
`Total lesions, mean ± SD
`IGA score, mean ± SD
`
`49 (57.6)
`36 (42.4)
`
`38 (44.2)
`48 (55.8)
`
`19.4 ± 6.5
`16.7 (12.1-42.9)
`
`20.2 ± 6.9
`17.8 ( 12.2-45.7)
`
`48 (56.5)
`22 (25.9)
`3 (3.5)
`4 (4.7)
`8 (9.4)
`40.8 ± 12.9
`
`46.5 ± 16.9
`
`87.3 ± 24.2
`
`3.04 ± 0.36
`----·-- - - - -·-· -
`
`52 (60.5)
`9 (10.5)
`8 (9.3)
`5 (5.8)
`12 (14.0)
`38.9 ± 11.7
`
`46.4 ± 17.4
`
`85.4 ± 22.3
`
`87 (50.9)
`84 (49.1)
`
`19.8 ± 6.7
`17.2 (12.1-45.7)
`
`100 (58.5)
`31 (18.1)
`11 (6.4)
`9 (5.3)
`20 (11.7)
`39.9 ± 12.3
`
`46.5 ± 17. 1
`
`86.3 ± 23.2
`
`.0783
`
`.3678
`
`.0649
`
`.1564
`
`.7316
`
`.5376
`
`.0619
`
`2.93 ± 0.37
`2.98 ± 0.37
`··- -.. -- -- ·--·--·-·--··· -·-··- ..
`··-----· ---------·----- ·-·- - -----------··--------.. ----
`
`symptoms relating to the current severity of erythema (disease
`related and/or related to retinoid use), dryness, peeling and
`oiliness were rated using an ordinal rating scale ranging from
`zero (no erythema or dryness, smooth skin, normal oiliness) to
`4 (beet red erythema; easily noted dryness with accentuation
`of skin markings, skin desquamation, and/or fissure forma(cid:173)
`tion; extensive peeling and prominent oiliness). In addition,
`the degree of pruritus and burning was quantified using a nu(cid:173)
`merical scale ranging from zero (normal, no discomfort) to 5
`(definite, continuous discomfort interfering with normal daily
`activities). Distribution and severity of PIH was determined us(cid:173)
`ing one scoring system to assess the percentage of the face
`affected, ranging from zero (none) to 6 (>50%); and a second
`scale was used to quantify the severity of PIH ranging from zero
`(absent) to 5 (severe).
`
`Statistical analyses were conducted on the intent-to-treat popu(cid:173)
`lation, which included all enrolled subjects. All statistical tests
`were two-sided and interpreted at a 5% significance level.
`Descriptive statistics were calculated for all continuous vari(cid:173)
`ables, and frequencies for all categorical variables. Where the
`necessary assumptions for parametric tests were satisfied,
`comparisons were performed using analysis of covariance with
`the baseline value as the covariate. The Wilcoxon rank sum test
`was used if the necessary assumptions for parametric tests
`were not satisfied. Safety analyses were performed according
`to the incidence and severity of local tolerability, signs and
`symptoms, and adverse and/or unexpected events.
`
`Missing data were imputed by the method of last observation
`carried forward (LOCF).
`
`The safety of the study medication was assessed throughout
`the study by recording adverse events at each study visit.
`
`Assessments were performed by investigators blind to the
`treatment assignment.
`
`Statistical Analyses
`It was calculated that 80 patients per treatment group (total
`sample size 160 patients) were required to yield 80 percent
`power to detect a difference of 15 percent in the primary out(cid:173)
`come parameter, the percentage reduction of inflammatory
`lesions after 12 weeks of treatment, assuming a standard devia(cid:173)
`tion of 31 percent in both groups and an approximate drop-out
`rate of 15 percent.
`
`Patient Disposition and Demographics
`One hundred seventy-one patients were enrolled in the
`study (Table 1 ). Treatment groups were generally similar
`with regard to baseline demographic characteristics; how(cid:173)
`ever, the proportion of female patients was higher in the
`combination arm compared with the monotherapy arm.
`Baseline lesion counts were similar between treatment
`arms. Mean baseline inflammatory and noninflammatory
`lesion counts were 40 and 47 in the overall study popula(cid:173)
`tion, indicating that study patients had at least moderate
`acne. The median IGA score was 3.0, also consistent with a
`moderate acne severity designation.
`
`3 of 10
`
`

`

`JOURNAL OI' D1rncs IN DEHMATOI.O(;Y
`Jmv 2011 • VmuME 10 • Issu1: 7
`
`E.T:111ghctti, S. I )\Jawan, L. Green, et al.
`
`786
`
`(cid:127) Baseline
`(cid:127) 12Weeks
`
`P= .1564
`
`P= .1417
`
`FIGURE 2. Mean number of a) inflammatory, b) noninflammatory, and
`total c) lesions at baseline and at 12 weeks with tazarotene mono(cid:173)
`therapy or dapsone plus tazarotene combination therapy. Error bars
`represent standard deviations.
`I a)
`I I ~ 60
`' 0 "iii
`.2! 50
`~
`0
`'.;j 40
`E
`E
`Ill
`'.g 30
`0 ,_
`_2l 20
`E
`::,
`~ 10
`Ill
`Q)
`
`FIGURE 1. Schematic profile of patient disposition.
`
`Eligible patients
`(N=171)
`I
`Randomized patients
`(n=171)
`
`I
`i
`I
`
`I
`
`I
`
`Daposone
`gel 5% plus
`tazarotene
`cream 0.1%
`86)
`(n=
`
`Tazarotene cream 0.1%
`monotherapy
`(n=85)
`
`I
`
`I
`
`arly withdrawal Reasons for e
`
`(n
`=3)
`llow up (2)
`Lost to fo
`iolation (1)
`Protocol v
`
`Reasons for early withdrawal
`(n=8)
`Lost to follow up (2)
`Withdrew consent (2)
`Lack of efficacy ( 1)
`Protocol violation ( 1)
`Other (2)
`
`I
`
`I
`
`nned treatment
`Completed pla
`(n =83)
`
`Completed planned treatment
`(n=77)
`
`Of the 171 enrolled patients, 160 completed treutment and 11
`withdrew early (Figure 1 ). Three patients receiving dapsone
`plus tazarotene and eight patients receiving tuzurotene mono(cid:173)
`therapy withdrew prior to completion of the study. None of the
`withdrawals was due to adverse tolerability.
`
`Inflammatory lesion Count
`There was a significant reduction in inflammatory lesion
`count compared with baseline in both treatment arms (Fig(cid:173)
`ure 2), and at week 12 the mean change from baseline count
`was -25.77 ± 11.23 lesions in the dapsone plus tazarotene
`group and -24.82 ± 14.06 lesions in the tazarotene monother(cid:173)
`apy group (P< .0001 for both treatment groups vs. baseline).
`However, the magnitude of inflammatory lesion count reduc(cid:173)
`tion was not significantly different between the two treatment
`groups at any time point. At week 12, the mean percentage
`change from baseline inflammatory lesion count was 66.6
`percent for the dapsone plus tazarotene combination therapy
`group versus 60.9 percent for the tazarotene monotherapy
`group (P= 0.17).
`
`~ 0-1----...... -"""-... .....ill__~ _ _J...;.....;..;...u.....:::..;::.:J-._~
`Tazarotene cream 0.1%
`
`P= .7316
`
`(cid:127) Baseline
`(cid:127) 12Weeks
`
`"' C:
`-~ 60
`
`.!! f 50
`..
`E
`~ 40
`'E
`"i: g 30
`0
`I ~ 20
`E
`::,
`~ 10
`
`.. .,
`
`~
`
`c)
`
`120
`
`110
`
`Tazarotene cniarn 0.1 %
`
`Odrumne gel 5% + Tdzarotene creum 0.1 %
`
`(cid:127) IJasolino
`(cid:127) 12Wooks
`
`~ 100
`0 ·;;; 90
`.!!
`~ 80
`E 70
`0
`:;; 60
`.a
`E 50
`::,
`C: 40
`
`C: .. ., 30
`
`~
`
`20
`
`10
`
`0
`
`Despite the similarity in magnitude of response at week 12, the
`onset of effect with combination therapy occurred earlier than
`with tazarotene monotherapy. At week 2, significantly more
`patients receiving combination therapy than patients receiving
`monotherapy achieved a 50 percent reduction in inflammatory
`
`Tazaroteno cream 0.1%
`
`Dapsone uol 5% + Tornrotene cromn 0.1%
`
`'P<.0001 compared with baseline value. Combination treatment resulted
`in a significantly greater reduction in noninflammatory (P=.0376) and total
`(P=.0250) lesion numbers; however, inflammatory lesions were reduced to
`a similar extent in both treatment arms (P>.05).
`
`4 of 10
`
`

`

`787
`joUilNAI. OI' D1rnc;s IN DEHMATOL()(;y
`Ju1.v 2011 • Vmm1n 10 • lssm 7
`
`E.Tmghl'tti, S. Dhawan, L. Crl'l'll, l't al.
`
`·1
`
`1
`:
`!
`
`onset of effect with the combination therapy than with mono(cid:173)
`therapy was evident as early as week 1 when evaluating total
`lesion count. At week 1, significantly more patients receiv(cid:173)
`ing combination therapy than those receiving monotherapy
`achieved a 50 percent decline in total lesion count (10.6% vs.
`1.2%, P=.02), and at weeks 4 and 8, the proportions of patients
`achieving a 75 percent decline in total lesion count was also
`significantly greater in the combination arm than in the mono(cid:173)
`therapy arm (week 4, 9.8% vs. 1.3%, P=.03; week 8, 20.3% vs.
`3.8%, P=.002).
`
`Investigator global assessment score
`Mean baseline IGA scores were 2.93 ± 0.37 for patients randomized
`to dapsone plus tazarotene and 3.04 ± 0.36 for patients receiving
`tazarotene monotherapy, reflecting moderate acne severity, on
`average, in both treatment arms. Both treatment groups demon(cid:173)
`strated improvement from baseline acne severity at all time points
`based on the IGA end point. At week 12, the percentage of pa(cid:173)
`tients achieving treatment success (defined as achieving a score
`of O [none] or 1 [minimal]) was significantly greater in the dapsone
`plus tazarotene-treated patients than in the patients treated with
`tazarotene monotherapy (P=.006; Figure 3).
`
`Overall disease severity score
`Mean baseline overall disease severity scores were similar
`between treatment groups (combination dapsone plus tazar(cid:173)
`otene, 4.03, vs. tazarotene monotherapy, 4.08; P=.65), and at
`week 12, there were significant reductions in scores, indicating
`improvement in disease severity (P < 0.0001) in both treatment
`arms. However, at week 12, patients treated with combination
`therapy demonstrated a significantly lower mean disease se(cid:173)
`verity score than did patients treated with monotherapy (2.11
`vs. 2.44, P=.03).
`
`Dryness
`
`Erythema
`
`Peeling
`
`Pruritus corners of
`the mouth
`Sunburn on face,
`arms, and shoulders
`
`2 (2.4%)
`
`4 (4.8%)
`
`1 (1.2%)
`
`1 (1.2%)
`
`1 (1.2%)
`
`2 (2.3%)
`
`2 (2.3%)
`
`0 (0.0%)
`
`0 (0.0%)
`
`0 (0.0%)
`
`Note: Patients reporting a particular adverse event more than once are
`counted only once for that adverse event.
`
`FIGURE 3. Percentage of patients achieving treatment success at
`week 12 as measured by IGA score of O (none) or 1 (minimal).
`
`e so%
`
`0
`0
`
`P= .0057
`
`Tazarotene cream 0.1%
`
`Dapsone gel 5% + Tazarotene cream 0.1%
`
`lesion count (27.4% vs. 12.7%, respectively, P= 0.02). Similarly,
`at weeks 4 and 8, significantly more patients receiving com(cid:173)
`bination therapy than those receiving monotherapy achieved
`a 75 percent reduction in inflammatory lesion count (week 4,
`13.4% vs. 3.8%, P=.03; week 8, 22.8% vs. 10.1%, P=0.03).
`
`Secondary End Points
`Noninflammatory and total lesion counts
`After 12 weeks of therapy, there was a significant reduction
`in noninflammatory lesion count compared with baseline in
`both treatment arms (Figure 2). Notably, the magnitude of re(cid:173)
`duction was significantly greater in the combination therapy
`arm than in the monotherapy arm (59.7% vs. 46.5%, P=0.01 ).
`Similarly, the decline in total lesion count at week 12 was also
`significantly greater in the dapsone plus tazarotene combina(cid:173)
`tion therapy group compared with the tazarotene monotherapy
`group (63.3% vs. 53.6%, P=.02). Furthermore, the more rapid
`
`Disease signs and symptoms
`Baseline scores for each of erythema, dryness, peeling, and oili(cid:173)
`ness were similar between treatment groups. After 12 weeks of
`therapy, there were significant improvements in the scores for
`erythema (P:::; 0.020) and oiliness (P < 0.001) compared with
`baseline in both treatment arms, but no significant change in
`dryness or peeling in either treatment arm (Figures 4 and 5).
`There was no difference between treatment groups in any of
`the disease signs/symptoms assessed.
`
`Post-inflammatory hyperpigmentation
`At baseline, the severity and distribution of PIH were similar
`between treatment groups (mean severity: 0.84 ± 1.20 and 0.84
`± 1.16; mean distribution: 0.90 ± 1.41 and 0.93 ± 1.40 for combi(cid:173)
`nation vs. monotherapy, respectively). At 12 weeks, the mean
`change in severity from baseline was -0.27 ± 0.84 with dapsone
`plus tazarotene combination treatment and -0.22 ± 0.71 with
`tazarotene monotherapy (P=.01 and P=.01 versus baseline for
`combination therapy and monotherapy, respectively; P=.48 be-
`
`TABLE 2.
`
`Adverse Event
`
`·
`
`11
`
`
`
`.
`
`rw@lflci•~•it,1,q·;
`Tazarotene H
`Dapsone +
`(n = 84)
`Tazarotene
`(n = 86)
`No. (%) of Patients l
`No. (%) of Patients
`
`5 of 10
`
`

`

`jOUl{Ni\L OI' ])l{UGS IN DEI/Mi\TOLOC:Y
`JULY 2011 • VOLUME 1 () • ISSUE 7
`
`788
`E.Tmglictti, S. I )!rnvan, L. Green, et al.
`
`FIGURE 5. Disease signs and symptoms over the course of treatment:
`mean scores over time. Severity of erythema, dryness, peeling, and
`oiliness were rated according to the following scale: 0 = absent; 1 =
`trace; 2=mild; 3=moderate; 4=severe.
`
`Severe 4
`
`Moderate 3
`
`Mild 2
`
`Trace 1
`
`.,
`0
`~
`C:
`" .,
`:E
`
`Erythema
`
`----0- Dapsone + tazarotene
`
`, - -0- - . Tazarotene
`
`~ ...... ........
`
`.,
`8
`"' C:
`" .,
`:E
`
`Severe 4
`
`Moderate 3
`
`Mild 2
`
`Trace 1
`
`Absent 0
`
`0
`
`Oiliness
`
`----0- Oapsone + tazarotene
`
`. - -0- -. Tazarotene
`
`2
`
`4
`
`6
`Week
`
`8
`
`10
`
`12
`
`Absent 0 + - - -~ - - -~ - - - - - -~ - - -~ - - -~
`12
`10
`4
`6
`0
`Week
`
`FIGURE 5. Representative patient photos. Patients at baseline (a, c)
`and after treatment with dapsone + tazarotene for 12 weeks (b, d).
`
`Dryness
`
`___.__ Dapsone + tazarotene
`
`. - •
`
`-. Tazarotene
`
`Severe 4
`
`Moderate 3
`
`Mild2
`
`.,
`~
`fij
`.,
`:E
`
`Absent 0 +---~---~---
`0
`4
`
`6
`Week
`
`10
`
`12
`
`,, .. , (
`
`f
`
`•
`
`f
`0
`~
`C: " .,
`:E
`
`Severe 4
`
`Moderate 3
`
`Mild2
`
`Trace 1
`
`Absent 0
`
`0
`
`Peeling
`
`___.__ Dapsone + tazarotene
`
`. -•-. Tazarotene
`
`\
`.
`
`2
`
`4
`
`6
`Week
`
`10
`
`12
`
`.,
`' .
`,,;
`.. ~·•!.::--. ,,_,
`-~"
`i.J~O~••:,··-
`
`•
`
`~:Ve\,~:
`,· ~~-·,,
`
`:,,...
`
`.. ,,.i
`···i•~v~~~
`
`6 of 10
`
`

`

`JouHNAL OI' D1m(;s IN DEHMATOI OCY
`JULY 2011 • VOLUl\11' 10 • Jssun 7
`
`E.Tmghetti, S. I )hawan, L. Green, et al.
`
`789
`
`tween groups).The mean change in PIH distribution at 12 weeks
`was -0.31 ± 0.87 with combination treatment and -0.27 ± 0.91
`with monotherapy (P = .001 and P=.01 vs baseline for combi(cid:173)
`nation therapy and monotherapy groups, respectively; P=.39
`between groups).
`
`Safety
`Adverse events related to treatment were limited to local
`application-site reactions for both treatment groups, and dry(cid:173)
`ness and erythema were the most frequently reported adverse
`events. The majority of adverse events were mild or moderate
`and resolved without sequelae. In total, four adverse events
`reported for patients treated with combination therapy were
`considered related to study treatment (erythema, n=2; dryness,
`n=2); all were mild or moderate and in each case study medica(cid:173)
`tion was temporarily discontinued and then reintroduced with
`no further adverse events (Table 2). Nine adverse events report(cid:173)
`ed in 6 monotherapy-treated patients were considered related
`or probably related to therapy (erythema, n=4; dryness, n=2;
`and sunburn, pruritus, peeling, n=1 each). These events were
`mild or moderate, except for the occurrence of dryness (n=1)
`and peeling (n=1) in a single patient, which were considered
`severe. In all cases, either no action was necessary or study
`medication was temporarily discontinued and then reintro(cid:173)
`duced with no further adverse events. There were no serious
`adverse events reported and no patients were withdrawn from
`treatment due to an adverse event.
`
`Most anti-acne medications do not act against all of the in(cid:173)
`flammatory and other pathophysiologic features of acne. Thus,
`the standard of care in acne treatment in the U.S. is treatment
`with combinations of drugs that target multiple components
`of acne pathogenesis. ACZONE is a topical formulation of 5%
`dapsone approved in the U.S. for the treatment of acne vulgar(cid:173)
`is. It has an anti-inflammatory profile that includes inhibition
`of neutrophil recruitment and adhesion,8·10•13 and inhibition of
`the production and release of tissue-damaging agents such as
`matrix-degrading enzymes and superoxides. 11 •14 Dapsone also
`blocks macrophage infiltration and activation, as well as the
`production of, and signaling by, inflammatory mediators such
`as prostaglandins, leukotrienes and cytokines. 8· 10-15-17 There are
`no published reports of dapsone having any activity against P.
`acnes. Despite its anti-inflammatory profile, dapsone 5% gel
`has demonstrated efficacy against both noninflammatory and
`inflammatory components of acne, as demonstrated in the two
`pivotal trials.12
`
`The efficacy of dapsone gel 5% monotherapy has been demon(cid:173)
`strated in randomized clinical trials, and its safety profile has
`been confirmed for up to 12 months in long-term follow-up
`studies. 12
`19 Additional studies have shown that dapsone gel
`18
`
`·
`
`·
`
`I
`
`5% is also an effective treatment when used in combination
`with other acne treatments with apparently nonoverlapping,
`complimentary mechanisms of action, such as adapalene gel
`0.1 %, a retinoid, and benzoyl peroxide (BPO) gel 4%, an anti(cid:173)
`bacterial agent. 20 The findings of the present study extend the
`observations from previous studies by evaluating the efficacy
`of the retinoid, tazarotene, in combination with dapsone gel
`5%. The patients enrolled in this study had, on average, mod(cid:173)
`erate acne. The results from our study show that combination
`therapy with dapsone gel 5% and tazarotene cream 0.1 % is a
`safe and effective treatment for patients with at least moderate
`acne vulgaris.
`
`Both tazarotene cream 0.1 % monotherapy and the combination
`of tazarotene cream 0.1 % with dapsone gel 5% were well tol(cid:173)
`erated in this study. Adverse events related to treatment were
`limited to local application-site reactions for both treatment
`groups. Importantly, addition of dapsone to tazarotene did not
`appear to be associated with additional tolerability concerns.
`
`Efficacy was demonstrated in this study by evaluation of in(cid:173)
`vestigator ratings (IGA and disease severity scores), signs
`and symptoms of acne, PIH, and lesion counts. Investigator
`ratings indicated significantly greater improvements in both
`the IGA and disease severity scores with tazarotene plus dap(cid:173)
`sone combination therapy than with tazarotene monotherapy.
`In addition, the IGA revealed a greater proportion of patients
`achieving a response of "clear" or "almost clear" with combi(cid:173)
`nation therapy versus monotherapy (P<0.006). The IGA metric
`is important, and the IGA and other similar subjective global
`assessments have been acknowledged as being more clinically
`relevant than lesion counts alone. Indeed, the U.S. Food and
`Drug Administration (FDA) has recommended the use of both
`lesion counts and subjective global assessments as co-primary
`end points in acne clinical trials. 21 The recommendation stems
`from the recognition that acne lesion counts can be imprecise
`and impractical in the clinical setting. 22 Moreover, unlike lesion
`counts, subjective global assessments consider other signs
`and symptoms, such as erythema and oiliness among others,
`in the determination of acne severity, and thus more accurately
`reflect the pleomorphic nature of this disease. 22 When used to
`evaluate treatment effectiveness, these subjective assessments
`measure subtle treatment effects that may be overlooked with
`lesion count reductions alone.
`
`Both tazarotene monotherapy and tazarotene in combina(cid:173)
`tion with dapsone favorably impacted signs and symptoms of
`acne and PIH. The two treatment regimens decreased oiliness
`and erythema to a similar degree relative to baseline assess(cid:173)
`ments. The reduction in severity and distribution of PIH was
`also comparable between treatment groups. This is particularly
`important for patients with skin of color, for whom PIH is a con(cid:173)
`cern when treating their acne. 23
`
`7 of 10
`
`

`

`joUHNAL 01' Dnucs IN DEHMATOLOCY
`Jmv 2011
`• VmuME 10 • Issun 7
`
`790
`E.Tlmghl'tti, S. Dhawan, L. Grl'l'll, l't al.
`
`In this study, dapsone gel 5% plus tazarotene cream 0.1% com(cid:173)
`bination treatment and tazarotene cream 0.1 % monotherapy
`were associated with a reduction in the numbers of both in(cid:173)
`flammatory and noninflammatory lesions. It is acknowledged
`that this study failed to meet its primary end point, since at
`12 weeks, the between-group difference in reduction of in(cid:173)
`flammatory lesion counts did not reach statistical significance.
`However, we found an intriguing between-group difference in
`the reduction of noninflammatory (and total) lesions; this dif(cid:173)
`ference was statistically significant and favored combination
`dapsone plus tazarotene treatment, indicating that dapsone is
`active against noninflammatory lesions.
`
`Consistent with this observation, a combined analysis of two
`previous studies demonstrated the effect of dapsone gel 5%
`monotherapy on comedonal acne.12 Dapsone 5% gel reduced
`comedonal acne lesion counts from baseline by 32 percent
`at 12 weeks, compared with a 24 percent reduction seen with
`placebo treatment. The eight percent treatment effect was
`significant and suggested a role for dapsone 5% gel in the treat(cid:173)
`ment of comedonal acne. Thus, despite its anti-inflammatory
`profile, dapsone 5% gel is effective against comedonal acne,
`a lesion type traditionally considered to be noninflammatory.
`
`Other clinical studies have reported that the antibiotic and
`anti-inflammatory agent clindamycin, when combined with
`topical BPO, significantly reduces comedonal lesions.2426 A
`12-week clinical study evaluating the combination of tazaro(cid:173)
`tene cream 0.1% plus clindamycin/BPO in comparison with
`tazarotene cream 0.1 % monotherapy also demonstrated that
`patients treated with the combination therapy (rctinoid plus
`antibacterial/anti-inflammatory agent) achieved a significantly
`greater reduction in comedonal lesion counts after 12 weeks
`than with the retinoid alone.2'These findings, together with our
`observations of dapsone effects in this and previous studies,
`suggest that topical anti-inflammatory therapy may impact tho
`initiation and propagation of inflammatory events, which in
`turn may interfere with the development of comedonal acne.
`However, BPO (in the clindamycin/BPO combination) has direct
`comedolytic properties as well as anti-inflammatory character(cid:173)
`istics, and these may have contributed to the effects observed
`in studies of this agent.
`
`The involvement of inflammation as part of immune system
`activation in the development of early-stage acne is supported
`by the following findings: inflammatory cells are found within
`the peripheral dermis of the microcomedo5; the pro-inflam(cid:173)
`matory cytokines, IL-1a, IL-113, and TNF-a, are present in open
`comedones 7
`; and inflammatory lesions can arise from clinically
`unaffected skin and sebaceous follicles. 28 Innate immune sys(cid:173)
`tem components also may contribu