Two randomized studies demonstrate the efficacy
`and safety of dapsone gel, 5% for the
`treatment of acne vulgaris
`
`Zoe D. Draelos, MD,a Eric Carter, MD,b J. Michael Maloney, MD,c Boni Elewski, MD,d Yves Poulin, MD,e
`Charles Lynde, MD,f and Steven Garrett, DDS,g for the United States/Canada Dapsone Gel Study Group*
`High Point, North Carolina; New York, New York; Denver and Fort Collins, Colorado;
`Birmingham, Alabama; Sainte-Foy, Quebec, and Markham, Ontario, Canada
`
`Background: A new aqueous gel formulation of dapsone has been developed that allows clinically
`effective doses of dapsone to be administered topically with minimal systemic absorption.
`
`Objectives: The goal of these studies was to evaluate the efficacy and safety of dapsone gel, 5% in the
`treatment of acne.
`
`Methods: Patients 12 years of age and older with acne vulgaris (N = 3010) participated in two identically
`designed 12 week, randomized, double blind studies of twice daily monotherapy with dapsone gel, 5%,
`versus a vehicle gel.
`
`treated patients achieved superior results in terms of the investigator’s global acne
`Results: Dapsone gel
`assessment (P \ .001) and the mean percentage reduction in inflammatory, noninflammatory, and total
`lesion counts (all, P \ .001) at week 12. Reductions in inflammatory lesion counts favoring dapsone gel
`over vehicle were apparent as early as 2 weeks and reached statistical significance by 4 weeks. No clinically
`significant changes in laboratory parameters, including hemoglobin, even among glucose 6 phosphate
`dehydrogenase deficient patients, were observed. Adverse events were comparable between the
`treatment groups and rarely led to discontinuation.
`
`Limitations: Adjunctive topical treatments and their impact on acne were not studied in this trial.
`
`Conclusions: Dapsone gel, 5% appears to be an effective, safe, and well tolerated treatment for acne
`vulgaris, with a rapid onset of action. ( J Am Acad Dermatol 2007;56:439.e1 10.)
`
`A cne is experienced almost universally by
`
`adolescents and young adults in westernized
`societies,1-3 and in the United States it is one
`of the most common complaints for which individ
`uals consult dermatologists.4 For many patients, acne
`poses a heavy psychosocial burden, negatively
`impacting mood, self esteem, body image, and
`
`isolation.5,6 Successful
`perceived levels of social
`treatment of acne significantly reduces symptoms
`of anxiety and depression and improves acne
`patients’ quality of life.7,8
`Dapsone, a sulfone that has both anti inflamma
`tory and antimicrobial properties, was shown to be an
`effective treatment for acne, including inflammatory
`
`From Dermatology Consulting Services, High Pointa;
`the
`Department of Dermatology, Columbia University Medical
`Inc, Denverc; the
`Center, New Yorkb; Cherry Creek Research,
`Department of Dermatology, University of Alabama, Birming
`hamd; Centre of Dermatology Research, Sainte Foye; Lynde Cen
`ter for Dermatology, Markhamf; and QLT USA, Inc, Fort Collins.g
`*Additional members of the United States/Canada Dapsone Gel
`Study Group are available at www.eblue.org as an online only
`appendix to this article.
`These studies were sponsored by QLT USA,
`Pharma US, Inc.
`Disclosure: Drs Draelos, Carter, Maloney, Elewski, Poulin, and
`Lynde were clinical investigators in the reported studies and
`
`Inc. and Astellas
`
`received research support from the sponsoring companies.
`Dr Garrett is an employee of QLT USA, Inc.
`These studies were presented in part at the 64th Annual Meeting
`of the American Academy of Dermatology, March 3 7, 2006,
`San Francisco, California.
`Accepted for publication October 8, 2006.
`Reprint requests: Zoe D. Draelos, MD, Dermatology Consulting
`Services, 2444 N Main St, High Point, NC 27262. E mail:
`zdraelos@northstate.net.
`Published online January 8, 2007.
`0190 9622/$32.00
`ª 2007 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2006.10.005
`
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`439.e2 Draelos et al
`
`J AM ACAD DERMATOL
`MARCH 2007
`
`Abbreviations used:
`
`GAAS: Global Acne Assessment Score
`G6PD: glucose 6 phosphate dehydrogenase
`ITT:
`intent to treat
`
`nodulocystic acne, in the era predating the availability
`of isotretinoin.9,10 However, the use of oral dapsone
`for acne was never widespread because of its poten
`tial to cause systemic toxicity, and, until recently,
`efforts to develop a topical formulation of dapsone
`were hindered by the poor solubility of dapsone in
`the aqueous vehicles that are typically used in der
`matologic products.
`Advances in cutaneous pharmacology have pro
`duced an aqueous gel that allows clinically effective
`doses of dapsone to be administered topically with
`minimal systemic absorption. The efficacy and safety
`of a new formulation, dapsone gel, 5% (Aczone; QLT
`USA, Inc. Fort Collins, Colo), in the treatment of
`acne vulgaris have been studied in two identically
`designed, pivotal trials.
`
`METHODS
`Study design
`Two 12 week, double blind, randomized, parallel
`group, phase III studies were conducted under
`identical protocols to evaluate the efficacy and safety
`of dapsone gel, 5% (dapsone gel), compared with a
`vehicle gel control in the treatment of acne vulgaris.
`A total of 103 centers in the United States and Canada
`participated in the studies between November 2002
`and September 2003.
`Eligible patients were randomly assigned in a 1:1
`ratio to either dapsone gel or vehicle gel according
`to a fixed block computer generated randomization
`table. The investigators, patients, and sponsor per
`sonnel were blinded to the treatment assignment,
`and patients were instructed not
`to bring their
`medications to the examination room or discuss
`the appearance of their study medication with the
`investigator. These procedures were established
`because the active and vehicle test articles were of
`a slightly different color. To maintain blinding, per
`sonnel who were not involved in efficacy or safety
`assessments conducted the drug accountability and
`test article weight assessments.
`Patients were instructed to apply a thin layer of
`dapsone gel or vehicle gel
`twice daily to acne
`involved areas of the face. Patients could also treat
`acne affected areas other than the face; however,
`these areas were not assessed for efficacy. After
`washing with a standard noncomedogenic soap
`free cleanser (Cetaphil; Galderma Laboratories, LP),
`
`study drug was applied once in the morning and
`again at least 1 hour before bedtime to the entire
`affected area and rubbed in until
`it completely
`disappeared.
`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 or ethics committee. Written informed assent
`and consent was obtained from each patient or
`his/her parent or guardian, as appropriate, before
`the start of study procedures.
`
`Patients
`Male and female patients 12 years of age or older
`with a clinical diagnosis of acne vulgaris involving
`the face were enrolled in these studies. Patients were
`to have 20 to 50 inflammatory lesions (defined to
`include papules and pustules) and 20 to 100 nonin
`flammatory lesions (comedones) above the mandib
`ular 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 criteria
`included concurrent use of topical drugs or treat
`ments that could affect acne, including antibiotics
`and anti inflammatory agents; use within 4 weeks
`before baseline of systemic immunosuppressive
`drugs or systemic medications or therapy known to
`affect acne or inflammatory responses; use of iso
`tretinoin within 3 months of baseline; or known
`allergy or hypersensitivity to dapsone, sulfa drugs,
`or excipients of the dapsone gel product. 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 3 months. Systemic contraceptives were not to be
`initiated during the study.
`
`Efficacy and safety assessments
`All patients underwent a dermatologic examina
`tion at screening/baseline and at weeks 2, 4, 6, 8, and
`12. At each of these visits, investigators recorded a
`Global Acne Assessment Score (GAAS) (Table I) and
`counted the number of inflammatory and nonin
`flammatory acne lesions present. The total lesion
`count was the sum of both inflammatory and non
`inflammatory lesions.
`The primary efficacy end points were the propor
`tion of patients achieving success based on the GAAS
`and the mean percent reduction from baseline in
`acne lesion counts at week 12. Success for GAAS
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`Draelos et al 439.e3
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`Table I. The Global Acne Assessment Score
`
`GAAS
`
`Severity
`
`Description
`
`Success
`
`Failure
`
`0
`
`None
`
`1 Minimal
`
`No evidence of facial
`acne vulgaris
`A few noninflammatory
`lesions (comedones) are
`present; a few inflammatory
`lesions (papules/pustules)
`may be present
`Several to many
`noninflammatory lesions
`(comedones) are present;
`a few inflammatory lesions
`(papules/pustules) are
`present
`3 Moderate Many noninflammatory
`lesions (comedones) and
`inflammatory lesions
`(papules/pustules) are
`present; no nodulocystic
`lesions are allowed
`Significant degree of
`inflammatory disease;
`papules/pustules are a
`predominant feature; a few
`nodulocystic lesions may
`be present; comedones
`may be present
`
`2 Mild
`
`4
`
`Severe
`
`GAAS, Global Acne Assessment Score.
`
`for the study to be deemed successful. Statistical
`comparisons of the two treatment groups used a
`significance level of 0.05. The sample size calcula
`tions for these studies are based on estimate success
`rates of 19.5% for active treatment versus 14% for
`vehicle treatment. It was determined that a total of
`1450 evaluable patients would provide an 80%
`power to detect this difference.
`Adverse events, regardless of relationship to study
`medication, were tabulated and summarized by
`incidence as application site or non application
`site events. Relationship to treatment was deter
`mined by the investigator. Common adverse events
`were defined as being those experienced by at
`least 2% of all patients. Laboratory evaluations
`were summarized using descriptive statistics.
`
`RESULTS
`Patient disposition and baseline
`characteristics
`A total of 3010 patients were enrolled and were
`dispensed dapsone gel (n = 1506) or vehicle gel (n =
`1504) and made up the ITT population (Fig 1). The
`safety evaluable population, defined as all enrolled
`subjects who applied study drug,
`included 1466
`
`on the 5 point static scale was defined as a rating of
`‘‘none’’ (0) or ‘‘minimal’’ (1). Success for acne lesion
`counts was defined as statistically greater mean
`percent reductions at week 12 in at least two of the
`three types of lesion counts (inflammatory, nonin
`flammatory, and total) in the dapsone gel
`treated
`patients compared with the vehicle gel
`treated
`patients. Secondary efficacy end points included
`mean lesion counts for inflammatory, noninflamma
`tory, and total acne lesions as well as mean reduction
`from baseline at week 12 for all of these.
`Adverse events, local signs and symptoms (ad
`verse reactions of facial oiliness, peeling, dryness,
`and erythema), physical examination findings (in
`cluding vital signs), and laboratory analyses were
`monitored throughout
`the study. Patients were
`specifically 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 hematology and serum chemistry
`determinations at baseline and week 12, and all
`patients were screened for glucose 6 phosphate
`dehydrogenase (G6PD) deficiency at baseline.
`Plasma dapsone concentrations were not routinely
`assessed in these studies; however,
`investigators
`were instructed to report any adverse event known
`to be associated with systemic dapsone exposure, at
`which time plasma dapsone concentration evalua
`tions would be conducted. All laboratory analyses
`were performed at a central laboratory (Quintiles
`Transnational Corp, Smyrna, Ga) and normal ranges
`for each analyte were provided.
`
`Statistical methods
`Data from both studies were analyzed indi
`vidually and combined for the statistical analyses.
`Efficacy results are presented for the combined
`analysis of the intent to treat (ITT) population (de
`fined as all enrolled patients to whom study drug was
`dispensed) with the last observation carried forward.
`The safety evaluable population includes all patients
`who applied study drug. The incidence of success
`based on a GAAS of 0 or 1 at week 12 was analyzed
`using the Cochran Mantel Haenszel procedure,
`stratifying by study center. Acne lesion counts were
`summarized using descriptive statistics
`(mean,
`median, range, standard deviation, standard error,
`minimum, maximum) for continuous data. For the
`combined analysis reported in this article, an analysis
`of variance was used to analyze the mean percent
`reduction in acne lesion counts with treatment,
`study, treatment by study, and center nested in study
`as factors. Both primary end points were to be met
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`439.e4 Draelos et al
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`
`Table II. Patient demographics and
`baseline characteristics
`
`Demographic parameter
`
`Sex, No. (%)
`Male
`Female
`Age, y
`Mean [SD]
`Minimum, maximum
`12-15, No. (%)
`$ 16, No. (%)
`Race, No. (%)
`Caucasian
`African American
`Hispanic
`Asian
`Other
`GAAS, No. (%)
`0 = None
`1 = Minimal
`2 = Mild
`3 = Moderate
`4 = Severe
`Lesion counts
`Inflammatory
`Mean [SD]
`Minimum, maximum
`Noninflammatory
`Mean [SD]
`Minimum, maximum
`Total
`Mean [SD]
`Minimum, maximum
`
`Dapsone gel, 5%
`(n = 1506)
`
`Vehicle gel
`(n = 1504)
`
`725 (48.1)
`781 (51.9)
`
`698 (46.4)
`806 (53.6)
`
`19.3 [7.5]
`12, 81
`578 (38)
`928 (62)
`
`1107 (73.5)
`209 (13.9)
`138 (9.2)
`31 (2.1)
`21 (1.4)
`
`0 (0.0)
`78 (5.2)
`500 (33.2)
`894 (59.4)
`34 (2.3)
`
`19.6 [7.6]
`11, 59
`547 (36)
`957 (64)
`
`1088 (72.3)
`211 (14.0)
`145 (9.6)
`35 (2.3)
`25 (1.7)
`
`0 (0.0)
`79 (5.3)
`516 (34.3)
`865 (57.5)
`44 (2.9)
`
`30.8 [10.2]
`11, 114
`
`30.3 [9.9]
`11, 114
`
`48.2 [24.3]
`13, 240
`
`47.8 [23.4]
`8, 172
`
`79.0 [28.3]
`39, 288
`
`78.1 [27.3]
`37, 261
`
`GAAS, Global Acne Assessment Score.
`
`(ie, $ 28 inflammatory lesions, $ 40 noninflamma
`tory lesions, or $ 71 total lesions) or less severe (data
`not shown).
`treated patients experienced sig
`Dapsone gel
`nificantly greater reductions from baseline to 12
`weeks in noninflammatory and total lesion counts
`(both P\.001, Fig 3, A and B). However, the greatest
`reduction occurred in inflammatory lesion counts,
`which fell by nearly half after 12 weeks of treatment
`with dapsone gel (47.5% vs 41.8%, P \ .001, Figs 2
`and 3, C ).
`The onset of response to dapsone gel treatment
`was rapid, particularly in terms of reductions in
`inflammatory lesion counts. A small difference
`between active and vehicle was seen as early as 2
`weeks and approached statistical significance (P = .052)
`(Fig 3, C ). At 4 weeks this difference in inflammatory
`lesion counts was highly statistically significant (P =
`.008). By 8 weeks, statistically significant differences
`between the treatment groups were clearly apparent
`
`Fig 1. Patient disposition. Administrative reasons for
`withdrawal
`include loss to follow up, voluntary with
`drawal, protocol violation, and treatment noncompliance.
`
`patients who received dapsone gel and 1467 who
`received vehicle gel. Approximately equal numbers
`from each treatment group discontinued treatment
`prematurely: 15.9% (240/1506) of
`the dapsone
`gel
`treated patients and 17.5% (263/1504) of the
`vehicle gel
`treated patients. The vast majority of
`premature study discontinuations (92.2%, 464/503)
`were for administrative reasons, including loss to
`follow up, voluntary withdrawal, protocol violation,
`and treatment noncompliance (Fig 1). Very few
`patients treated with dapsone gel discontinued
`because of lack of efficacy (0.6%; 9/1506) or an
`adverse event (0.4%; 6/1506).
`Baseline characteristics for the ITT population
`were similar between treatment groups and are
`summarized in Table II. At baseline, both the acne
`severity scores and acne lesion counts were similar
`between treatment groups. Most patients (58.4%;
`1759/3010) had moderate acne, whereas 33.8% of
`patients (1016/3010) had mild acne.
`
`Efficacy results
`treated patients were significantly
`Dapsone gel
`more likely than vehicle gel
`treated patients to
`achieve treatment success at week 12 in terms of
`the investigator’s static global assessment (GAAS
`of none or minimal acne; P \ .001 in the combined
`studies, Fig 2). This finding was consistent across
`the participating centers. Superior GAAS 12 week
`success rates were achieved with dapsone gel treat
`ment, regardless of whether the baseline acne was,
`in terms of acne lesion counts, relatively more severe
`
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`
`Draelos et al 439.e5
`
`Fig 2. Success rate at week 12. Percentage of patients
`achieving success by Global Acne Assessment Score of
`‘‘none’’ (0) or ‘‘minimal’’ (1). Error bars represent 95%
`confidence intervals.
`
`in the mean percentage changes in counts of all 3
`lesion types (inflammatory, P \ .001, Fig 3, C;
`noninflammatory, P = .003, Fig 3, A; and total, P \
`.001, Fig 3, B). The magnitude of these differences
`steadily increased through the remaining weeks of
`the studies.
`Statistically significant differences in favor of
`dapsone gel were noted for each of the secondary
`efficacy variables, including mean lesion counts at
`week 12 for inflammatory, noninflammatory, and
`total acne lesions (all P\.001 compared with vehicle
`gel), and mean change from baseline in lesion counts
`at week 12 for each of these assessments (all P\.001
`compared with vehicle gel).
`Reduction of acne lesions over time can be seen in
`facial photographs of patients in the dapsone gel
`treatment group (Figs 4 and 5). These images are
`representative of the treatment group as a whole.
`
`Safety results
`Overall, patients experienced adverse events
`at similar rates in the two treatment groups: 58.2%
`(853/1466) of dapsone gel
`treated patients and
`58.6% (860/1467) of vehicle gel
`treated patients.
`Most events were of mild to moderate intensity,
`resolved during treatment, and did not result in
`treatment discontinuation.
`Patients were asked at each visit about local signs
`and symptoms, including skin dryness, erythema,
`oiliness, and peeling. Oiliness and erythema were
`the most frequent symptoms reported at a level of
`moderate or greater severity by patients in both
`treatment groups at baseline and week 12 (Table III).
`Substantial declines in all of the local signs and
`symptoms occurred in both treatment groups over
`the course of the study.
`
`Fig 3. Mean percent reduction in noninflammatory (A),
`total (B), and inflammatory (C) lesion count over time.
`Error bars represent standard error.
`
`Patients were also monitored for application site
`adverse events, including any local cutaneous ab
`normalities that emerged during treatment, irrespec
`tive of whether the abnormalities were judged by the
`investigator to be related to the study medication.
`Comparable numbers of patients in each treatment
`group experienced application site adverse events
`
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`439.e6 Draelos et al
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`
`Fig 4. Effect of dapsone gel, 5% on a 12 year old patient
`with a Global Acne Assessment Score of ‘‘moderate’’ (3) at
`baseline (A) and ‘‘minimal’’ (1) at week 12 (B).
`
`Fig 5. Effect of dapsone gel, 5% on a 16 year old patient
`with a Global Acne Assessment Score of ‘‘severe’’ (4) at
`baseline (A) and ‘‘mild’’ (2) at week 12 (B).
`
`(Table IV). The most common of these events were
`dryness (in approximately 20% of either group),
`erythema (16%), and other reactions (including facial
`oiliness, peeling, sensitivity to touch, stinging,
`
`flaking, greasiness, sun sensitivity, acne break out,
`tingling, and tightness). Application site adverse
`events judged related to treatment were also com
`parable between treatment groups: 38.0% (557/1466)
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`Draelos et al 439.e7
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`Table III. Patients treated with dapsone gel, 5%,
`or vehicle gel who experienced local signs and
`symptoms that were moderate to severe in
`intensity (safety evaluable population)*
`
`No. (%) of patients
`
`Dapsone gel, 5%
`
`Vehicle gel
`
`Baseline
`(n = 1466)
`
`Week 12
`(n = 1348)
`
`Baseline
`(n = 1467)
`
`Week 12
`(n = 1333)
`
`Oiliness
`Erythema
`Dryness
`Peeling
`
`273 (18.6)
`217 (14.8)
`39 (2.7)
`19 (1.3)
`
`76 (5.6)
`83 (6.2)
`9 (0.7)
`5 (0.4)
`
`282 (19.2)
`229 (15.6)
`45 (3.1)
`16 (1.1)
`
`96 (7.2)
`106 (8.0)
`20 (1.5)
`5 (0.4)
`
`*Local adverse effects were assessed according to the following
`scoring scale: none (absent) = 0, mild (barely perceptible) = 1,
`moderate (definitely present) = 2, and severe (marked, intense) = 3.
`
`Table IV. Application-site adverse
`events occurring in two or more patients*
`
`No. (%) of patients
`
`y
`Other reactions
`Dryness
`Erythema
`Burning
`Pruritus
`Irritation
`Rash
`
`Dapsone gel, 5%
`(n = 1466)
`
`320 (21.8)
`293 (20.0)
`239 (16.3)
`20 (1.4)
`14 (1.0)
`2 (0.1)
`0
`
`Vehicle gel
`(n = 1467)
`
`331 (22.6)
`277 (18.9)
`236 (16.1)
`23 (1.6)
`19 (1.3)
`2 (0.1)
`6 (0.4)
`
`*Regardless of relationship to treatment.
`y
`Includes facial oiliness, peeling, sensitivity to touch, stinging,
`flaking, greasiness, sun sensitivity, acne breakout, tingling, and
`tightness.
`
`treated group and 37.8% (555/
`of the dapsone gel
`1467) of the vehicle gel
`treated group.
`A total of 31.2% (458/1466) of patients treated with
`dapsone gel and 32.0% (469/1467) of patients treated
`with vehicle gel experienced non application site
`adverse events, the most common being nasophar
`yngitis and headache (Table V).11 Non application
`site adverse events considered related to treatment
`were experienced by only 1.0% of patients treated
`with dapsone gel (14/1466) versus 1.3% of patients
`treated with vehicle gel (19/1467).
`Fifteen patients (6 dapsone gel and 9 vehicle gel)
`discontinued treatment as a result of one or more
`adverse events. Of these patients, 2 in the dapsone
`gel group and 6 in the vehicle gel group experi
`enced application site adverse events considered
`related to treatment. One of the 2 dapsone gel
`treated patients experienced pruritus;
`the other
`experienced burning, dryness, erythema, stinging,
`and peeling. The 6 vehicle gel
`treated patients
`who withdrew from the studies experienced dry
`ness and pruritus; erythema; pruritus; burning and
`dryness; sensitivity; and erythema and rash, respec
`tively. All events were mild to moderate in intensity,
`except for one incident of pruritus in the vehicle
`gel
`treated group, which was severe. Nine patients
`(4 dapsone gel
`treated; 5 vehicle gel
`treated)
`were hospitalized during the study for serious
`adverse events that were not considered related to
`treatment; none were application site or life threat
`ening events, but 2 of these patients (1 each in the
`dapsone gel and vehicle gel groups) subsequently
`withdrew from the study.
`
`Laboratory evaluations
`Overall,
`there were no significant changes in
`hemoglobin or other laboratory values, even among
`
`Table V. Common non application-site adverse
`events*
`
`Nasopharyngitis
`y
`Headache
`Upper respiratory tract
`infection
`Pharyngitis
`
`No. (%) of patients
`
`Dapsone gel, 5%
`(n = 1466)
`
`Vehicle gel
`(n = 1467)
`
`71 (4.8)
`45 (3.1)
`47 (3.2)
`
`93 (6.3)
`49 (3.3)
`42 (2.9)
`
`37 (2.5)
`
`38 (2.6)
`
`*Common: experienced by at least 2% of all patients.
`y
`Rate for headache was consistent with the expected rate in the
`general population.11
`
`the 44 patients with G6PD deficiencies. No clinically
`important differences in mean change from baseline
`for hematology or chemistry parameters were iden
`tified between the treatment groups. Laboratory
`abnormalities reported as adverse events were
`similar between treatment groups and occurred in
`20 dapsone gel
`treated patients and 22 vehicle
`gel
`treated patients; these events were generally
`mild or moderate in severity. The most frequently
`reported laboratory abnormality was elevated crea
`tine kinase (12 dapsone gel; 11 vehicle gel). Four of
`these events were judged to be possibly related to
`treatment (1 dapsone gel; 3 vehicle gel); the majority
`(14/23; 61%) were reported by the investigator to be
`related to physical activity. No adverse events related
`to dapsone systemic exposure were reported that
`would have prompted investigators to test for dap
`sone plasma concentration.
`At baseline, 44 patients (19 dapsone gel treated;
`25 vehicle gel treated) were G6PD deficient. Thirty
`two patients with G6PD deficiencies had hemoglo
`bin values within the normal range at baseline and
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`
`throughout the study. The remaining 12 patients had
`hemoglobin values that were low at baseline and
`remained low throughout the study, or had hemo
`globin levels that shifted from normal to low; these
`shifts were comparable between treatment groups.
`One vehicle gel
`treated patient had a low hemo
`globin level at baseline (9.7 g/dL) which decreased
`to a level at week 12 (8.6 g/dL) that prompted the
`laboratory to alert the physician. No hematologic
`adverse events were experienced over the course of
`the studies.
`
`DISCUSSION
`These randomized, double blind, vehicle con
`trolled studies show dapsone gel to be effective in
`the treatment of acne, as demonstrated by signifi
`cantly greater success based on the investigator’s
`GAAS and by the reduction of inflammatory, nonin
`flammatory, and total lesion counts at the end of
`treatment. A significantly greater number of patients
`treated with dapsone gel than patients treated with
`vehicle gel had no acne or minimal acne on com
`pletion of treatment. Combined results from these
`two studies were consistent with the results obtained
`from the individual studies. The responses seen in
`the dapsone gel
`treated patients for the percent
`reduction of acne lesion counts at week 12 fall within
`the range of those observed in clinical
`trials of
`currently available topical acne therapies.12-14
`Although clinical
`improvement was observed
`with both inflammatory and noninflammatory
`lesions, dapsone gel was particularly effective for
`inflammatory acne lesions. Reductions in inflamma
`tory lesions occurred earlier and were of greater
`magnitude by the end of treatment. These findings
`were not unexpected, given the known anti inflam
`matory properties of dapsone, which has long been
`used in dermatology for treatment of inflammatory
`dermatoses, particularly those characterized by neu
`trophilic inflammation such as dermatitis herpetifor
`mis and linear IgA bullous dermatosis.15 A potential
`mechanism of action of dapsone in acne could be the
`direct inhibition of leukocyte trafficking and the
`generation by leukocytes of chemical mediators of
`inflammation. However, it is also possible that, as a
`sulfone with structural similarities to trimethoprim
`sulfamethoxazole and other sulfonamides, topical
`dapsone may act indirectly in acne by altering the
`levels and/or activity of propionibacteria located in
`the upper third of the follicles.
`The onset of action of dapsone in these studies
`was rapid, with some difference in the mean
`decreases in inflammatory lesions of active versus
`vehicle occurring as early as 2 weeks after beginning
`treatment; the difference in favor of dapsone gel
`
`became highly significant by the fourth week of
`treatment. Counts of both inflammatory and nonin
`flammatory lesions fell throughout the 12 weeks of
`treatment and may not have reached their nadirs by
`the end of the studies. This observation is consistent
`with the findings of a 12 month, long term safety
`study of dapsone gel, in which acne lesion counts
`steadily fell for the first 6 months before reaching a
`plateau that was maintained for
`the remaining
`the study.16 Topical dapsone was
`6 months of
`exceptionally well tolerated in these studies. Rates
`of overall adverse events as well as application site
`adverse events were similar between dapsone
`gel
`treated patients and the control group, and
`few patients discontinued treatment because of
`adverse events or lack of efficacy. Most of
`the
`adverse events associated with dapsone gel were
`local application site events. The few non applica
`tion site adverse events observed were consistent
`with what would be expected for a healthy young
`population.
`Local signs and symptoms of acne and cutaneous
`irritation such as skin dryness and erythema were
`also comparable between the two treatment groups
`throughout the studies and declined markedly in
`both groups over the course of treatment, suggesting
`that
`the emollient base of the vehicle gel
`itself
`may have been of therapeutic value. The use of a
`noncomedogenic cleanser by all of the study partic
`ipants also may have favorably affected the inci
`dence of local signs and symptoms, leading to further
`improvement in acne.17,18
`Oral dapsone has been associated with adverse
`hematologic reactions; individuals with G6PD defi
`ciency are particularly susceptible to these reac
`tions.19 However, because dapsone gel, 5%,
`is a
`topical formulation, minimal systemic absorption
`was expected.16,20 Overall, in these studies there
`was no significant change in hemoglobin or other
`laboratory values, even among the 44 patients with
`G6PD deficiencies.
`In conclusion, topical dapsone gel, 5%, as a single
`agent has a rapid onset of action,
`is minimally
`irritating, and appears to be safe and effective in
`the treatment of acne vulgaris. Furthermore, this new
`antiacne treatment affords the opportunity to target
`the inflammatory aspects of acne by mechanisms
`that may differ
`from conventional antibiotics,
`the efficacy of which may be diminished by the
`rising prevalence of antibiotic resistant strains of
`Propionibacterium acnes.
`
`We thank Christy V. Costello (QLT Inc) for editorial
`assistance and Craig Wesselman (QLT USA, Inc) for data
`analysis and statistical support. Representatives from the
`
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`J AM ACAD DERMATOL
`VOLUME 56, NUMBER 3
`
`Draelos et al 439.e9
`
`Medical Affairs department of Astellas Pharma US, Inc,
`also provided writing assistance.
`
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