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Figure 1.
Participant flow and treatment visits completed.

Participant flow and treatment visits completed.

Figure 2.
Mean percentage change in open and closed comedones. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Mean percentage change in open and closed comedones. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Figure 3.
Mean percentage change in papules and pustules. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Mean percentage change in papules and pustules. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Figure 4.
Mean percentage change in overall disease severity. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Mean percentage change in overall disease severity. See the "Study Protocol" subsection of the "Patients and Methods" section for descriptions of the treatment groups.

Figure 5.
A 16-year-old boy in the group receiving 0.1% tazarotene gel twice daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 2, indicating approximately 75% global improvement.

A 16-year-old boy in the group receiving 0.1% tazarotene gel twice daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 2, indicating approximately 75% global improvement.

Figure 6.
A 13-year-old girl in the group receiving 0.1% tazarotene gel once daily and vehicle gel once daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 1, indicating approximately 90% global improvement.

A 13-year-old girl in the group receiving 0.1% tazarotene gel once daily and vehicle gel once daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 1, indicating approximately 90% global improvement.

Figure 7.
A 16-year-old boy in the group receiving vehicle gel twice daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 4, indicating approximately 25% global improvement.

A 16-year-old boy in the group receiving vehicle gel twice daily shown at baseline (A) and at 12 weeks (B), with a global response to treatment score of 4, indicating approximately 25% global improvement.

Table 1. 
Comparability of Demographic Data, Acne Characteristics, and Facial Skin Signs and Symptoms Among Treatment Groups at Baseline
Comparability of Demographic Data, Acne Characteristics, and Facial Skin Signs and Symptoms Among Treatment Groups at Baseline
Table 2. 
Treatment Success by Length of Contact Time per Application at Last Visit in 81 Patients Completing 12 Weeks of Treatment*
Treatment Success by Length of Contact Time per Application at Last Visit in 81 Patients Completing 12 Weeks of Treatment*
1.
Kligman  AMFulton  JEPlewig  G Topical vitamin A acid in acne vulgaris. Arch Dermatol. 1969;99469- 476Article
2.
Weinstein  GDKrueger  GGLowe  NJ  et al.  Tazarotene gel, a new retinoid for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol. 1997;3785- 92Article
3.
Peris  KFargnoli  MCChimenti  S Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma [letter]. N Engl J Med. 1999;3411767- 1768Article
4.
Sefton  JKligman  AMKopper  SCLue  JCGibson  JR Photodamage pilot study: a double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel. J Am Acad Dermatol. 2000;43656- 663Article
5.
Hofmann  BStege  HRuzicka  TLehmann  P Effect of topical tazarotene in the treatment of congenital ichthyoses. Br J Dermatol. 1999;141642- 646Article
6.
Petkovich  MBrand  NJKrust  AChambon  P A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987;330444- 450Article
7.
Giguere  VOng  ESSegui  PEvans  RM Identification of a receptor for the morphogen retinoic acid. Nature. 1987;330624- 629Article
8.
Brand  NPetkovich  MKrust  A  et al.  Identification of a second human retinoic acid receptor. Nature. 1988;332850- 853Article
9.
Krust  AKastner  PPetkovich  MZelent  AChambon  P A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989;865410- 5414Article
10.
Chandraratna  RA Tazarotene: the first receptor-selective topical retinoid for the treatment of psoriasis. J Am Acad Dermatol. 1997;37 (suppl 2, pt 3) S12- S17Article
11.
Shroot  B Pharmacodynamics and pharmacokinetics of topical adapalene. J Am Acad Dermatol. 1998;39 (suppl 2, pt 3) S17- S24Article
12.
Nagpal  SAthanikar  JChandraratna  RAS Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. J Biol Chem. 1995;270923- 927Article
13.
Elder  JTFisher  GJZhang  O  et al.  Retinoic acid receptor gene expression in human skin. J Invest Dermatol. 1991;96425- 433Article
14.
Chen  SOstrowski  JWhiting  G  et al.  Retinoic acid receptor gamma mediates topical retinoid efficacy and irritation in animal models. J Invest Dermatol. 1995;104779- 783Article
15.
Esgleyes-Ribot  TChandraratna  RALew-Kaya  DASefton  JDuvic  M Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol. 1994;30581- 590Article
16.
Nagpal  SPatel  SAsano  ATJohnson  ATDuvic  MChandraratna  RAS Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor–responsive gene in skin. J Invest Dermatol. 1996;106269- 274Article
17.
Nagpal  SThacher  SMPatel  S  et al.  Negative regulation of two hyperproliferative keratinocyte differentiation markers by an RAR-selective retinoid: insight into the mechanism of retinoid action in psoriasis. Cell Growth Differ. 1996;71783- 1791
18.
Leyden  JJ Topical treatment of acne vulgaris: retinoids and cutaneous irritation. J Am Acad Dermatol. 1998;38 (suppl) S1- S4Article
19.
Bershad  S Developments in topical retinoid therapy for acne. Semin Cutan Med Surg. 2001;20154- 161Article
20.
Shalita  ARChalker  DKGriffith  RF  et al.  Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis. 1999;63349- 354
21.
Webster  GFBerson  DStein  LF  et al.  Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis. 2001;67 (suppl 6) 4- 9
22.
Leyden  JLowe  NKakita  LDraelos  Z Comparison of treatment of acne vulgaris with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene gel: a randomized trial. Cutis. 2001;67 (suppl 6) 10- 16
23.
Shalita  AWeiss  JSChalker  DK  et al.  A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34482- 485Article
24.
Ellis  CNMillikan  LESmith  EB  et al.  Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol. 1998;139 (suppl 52) 41- 47Article
25.
Rougier  ADupuis  DLotte  CRoquet  RSchaefer  H In vivo correlation between stratum corneum reservoir function and percutaneous absorption. J Invest Dermatol. 1983;81275- 278Article
26.
Rougier  ADupuis  DLotte  CRoquet  R The measurement of the stratum corneum reservoir: a predictive method for in vivo percutaneous absorption studies: influence of application time. J Invest Dermatol. 1985;8466- 68Article
27.
Rougier  ALotte  CMaibach  HI In vivo percutaneous penetration of some organic compounds related to anatomic site in humans: predictive assessment by the stripping method. J Pharm Sci. 1987;76451- 454Article
28.
Marks  R Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol. 1998;39 (suppl) S134- S138Article
29.
Lammer  EJChen  DTHoar  RM  et al.  Retinoic acid embryopathy. N Engl J Med. 1985;313837- 841Article
30.
Eckhoff  CNau  H Identification and quantification of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res. 1990;311445- 1454
31.
Tang-Liu  DDMatsumoto  RMUsansky  JI Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet. 1999;37273- 287Article
32.
Franz  TJLehman  PAFranz  S  et al.  Percutaneous absorption of AGN 190168, a new synthetic retinoid, through human skin in vivo [abstract]. Clin Res. 1992;40533
Study
April 2002

Successful Treatment of Acne Vulgaris Using a New MethodResults of a Randomized Vehicle-Controlled Trial of Short-Contact Therapy With 0.1% Tazarotene Gel

Author Affiliations

From the Department of Dermatology, Mount Sinai School of Medicine, New York, NY (Drs Bershad, Tan, Sherer, Persaud, and Lebwohl and Ms Kranjac Singer); and Integrated Research Inc, Dollard-des-Ormeaux, Quebec (Dr Parente). Dr Bershad holds US patents and reserves all rights to international patents for the short-contact method of topical retinoid therapy to treat acne, photoaging, and psoriasis (patents 6017938, 6048902, 6083963, and 6096765). She has received compensation for speaking engagements from Allergan Inc, Irvine, Calif. Dr Parente is a co-owner and managing director of Integrated Research Inc, which has received compensation for clinical research consulting services from Allergan Inc. Dr Lebwohl has received research grants and compensation for speaking engagements from Allergan Inc.

Arch Dermatol. 2002;138(4):481-489. doi:10.1001/archderm.138.4.481
Abstract

Context  Short-contact application of 0.1% tazarotene gel for acne was devised to minimize local adverse effects. Its efficacy and safety are unknown.

Objectives  To assess acne improvement and tolerability during 12 weeks of short-contact treatment with 0.1% tazarotene gel vs a nonmedicated gel control.

Design  A randomized, masked, vehicle-controlled trial.

Setting  Outpatient facilities at an urban medical school and an affiliated suburban office practice.

Participants  Ninety-nine volunteers with facial acne were enrolled; 81 completed the study.

Intervention  Thirty-three patients were randomly assigned to each of 3 groups: T + T applied 0.1% tazarotene gel twice daily, T + V applied 0.1% tazarotene gel once daily and vehicle gel once daily, and V + V applied vehicle gel twice daily. Patients adjusted the contact period as tolerated, between 30 seconds and 5 minutes per application.

Main Outcome Measures  Acne efficacy by reduction in acne lesions, treatment success (50%-100% improvement in global response to treatment) and improvement in overall disease severity. Local adverse effects, scored from none to severe.

Results  By week 12, T + T and T + V achieved significantly greater improvement in acne than V + V based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P = .002) and inflammatory lesions (38% and 34% vs 9%; P = .01), percentage of treatment successes (64% and 61% vs 15%; P<.001), and reduction in overall disease severity (30% and 29% vs 3%; P<.001). Local adverse effects did not differ significantly among the 3 groups after week 4.

Conclusion  Short-contact 0.1% tazarotene gel therapy is a safe and effective new method of acne treatment.

ACNE TREATMENT with topical retinoids originated in 1969 with the discovery by Kligman et al1 of vitamin A acid for this disorder. Tazarotene, which was introduced in 1997, is the newest retinoid agent for treating acne and the sole member of this class approved by the Food and Drug Administration for topical psoriasis therapy.2 It is available in both gel and cream vehicles containing either 0.05% or 0.1% tazarotene, but only the 0.1% formulations are Food and Drug Administration approved for acne. Tazarotene has also been used successfully for basal cell carcinoma,3 chronic sun damage,4 and congenital ichthyosis.5

Retinoids as a group exert their effects after activation of 2 families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors, each having alpha, beta, and gamma subclasses.69 Whereas tretinoin is a flexible molecule that binds to all RAR subclasses, tazarotene and adapalene are rigid, receptor-selective retinoids.10,11 Tazarotene is converted in the skin to its active metabolite tazarotenic acid, which has a high affinity for RAR-beta and RAR-gamma.12 It does not activate the RAR-alpha subclass or retinoid X receptors. Retinoic acid receptor–gamma is the most ubiquitous RAR in mature keratinocytes.13 This subclass has been shown to mediate desirable and adverse retinoid effects in animal models.14 The mechanisms of action of tazarotene, most extensively studied in psoriatic skin, are normalization of keratinocyte proliferation and differentiation as well as reduction in keratinocyte-expressed markers that attract inflammatory cells.1517

Local adverse effects, including skin peeling, dryness, redness, burning, and itching, often limit topical retinoid use.18 During one author's (S.B.) early experience with tazarotene for facial acne, several patients noted skin discomfort within 10 minutes of application.19 In some cases, typical retinoid-induced skin irritation occurred, even when tazarotene was removed after such limited exposure. The possibility of avoiding adverse effects by shortening the period of skin contact with tazarotene was intriguing. Preliminary exploration suggested that acne improvement and good tolerability might result from exposure times shorter than 5 minutes repeated regularly for 12 weeks.19

The goal of this study was to assess acne progress and local skin irritation, using a novel short-contact method of applying 0.1% tazarotene gel (Tazorac; Allergan Inc, Irvine, Calif), in patients with mild to moderate facial acne. Comparisons of these measures were made among 3 groups: those using 0.1% tazarotene gel twice daily (T + T), those using 0.1% tazarotene gel once daily and nonmedicated (vehicle) gel once daily (T + V), and a control group using vehicle gel twice daily (V + V).

PATIENTS AND METHODS
PARTICIPANTS AND SETTING

A total of 99 patients aged 12 to 39 years with facial acne were enrolled at 2 study sites affiliated with the Department of Dermatology of the Mount Sinai School of Medicine. Forty patients were enrolled at a suburban office practice (site 1) and 59 were enrolled at an urban medical center outpatient facility (site 2). All patients were volunteers recruited via local advertisements or posters exhibited on site.

Patients were required to understand and follow the study protocol, which was approved by the medical school institutional review board. Patients and parents or legal guardians of those younger than 18 years gave written informed consent. Inclusion criteria required patients to be 12 years or older and to have mild to moderate facial acne, defined as 10 to 200 noninflammatory lesions (open and closed comedones), 10 to 60 inflammatory lesions (papules and pustules), and fewer than 3 nodulocystic lesions. Medication-free periods were required before study entry as follows: systemic retinoids, 24 months; oral antibiotics, 4 weeks; and topical acne medications, 2 weeks. Female patients were permitted to take oral contraceptives if initiated at least 3 months before study entry and continued throughout the study. Female patients were excluded if they were pregnant, breastfeeding, or sexually active without using reliable contraception.

STUDY PROTOCOL

This study was randomized, investigator-masked, and controlled by using a nonmedicated (vehicle) gel identical to the base of tazarotene gel. The gels were distributed in identical boxed pairs of 30-g tubes labeled "morning application" and "evening application." 0.1% tazarotene gel and vehicle gel are odorless and colorless. Because of possible irritation from tazarotene, patient blinding was assumed to be potentially compromised. To maintain investigator masking, clinical assistants collected and recorded data regarding facial skin signs and symptoms, and physician-investigators assessed efficacy measures.

Patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: (1) patients in the T + T group received 0.1% tazarotene gel as the morning and evening application; (2) patients in group T + V received 0.1% tazarotene gel as the evening application and vehicle gel as the morning application; and (3) patients in group V + V received vehicle gel as the morning and evening application.

All patients received instruction cards detailing the short-contact method, which required twice-daily (morning and evening) application of the study gel, spread thinly to facial skin after washing with a nonsoap liquid cleanser (Cetaphil; Galderma Laboratories, LP, Fort Worth, Tex) and rinsing with lukewarm water. The dosage of gel per application was approximately 0.6 g, described and demonstrated to patients as a pea-sized amount. Patients rinsed with lukewarm water after contact periods starting with 2 minutes per application (timed using digital timers [Big-Digit Timer, RadioShack, Fort Worth] that were provided to monitor all applications). All patients were instructed to increase the contact period, if tolerated without local effects, in 1-minute increments at intervals of at least 3 days to a maximum of 5 minutes. The written instructions directed patients to reduce the contact period to 30 seconds if peeling, erythema, dryness, burning, or itching occurred. In such cases, patients were to increase the contact period in 30-second increments at intervals of at least 3 days, if tolerated, to the 5-minute maximum. Patients were requested to maintain diary records in which they recorded contact periods of all applications. Clinical assistants collected these records at each visit.

CLINICAL ASSESSMENTS

Patients were seen at baseline, defined as the visit when treatment was initiated, and again at 2, 4, 8, and 12 weeks of treatment. At each visit, physicians used 3 methods to assess efficacy for acne. First, facial lesion counts were performed of individual acne lesions, divided into noninflammatory lesions (open and closed comedones), inflammatory lesions (papules and pustules), and nodules (lesions ≥4 mm). Second, global response to treatment scores were assessed by comparing the patient's condition with baseline photographs and then were graded from 0 to 6 as follows: 0, completely cleared; 1, approximately 90% improved; 2, approximately 75% improved; 3, approximately 50% improved; 4, approximately 25% improved; 5, no change; and 6, exacerbation. Third, overall disease severity scores were assessed by physical examination and were graded from 0 to 6 as follows: 0, none; 1, less than mild; 2, mild (slightly noticeable); 3, worse than mild but less than moderate; 4, moderate (evident); 5, worse than moderate but less than severe; and 6, severe (very distinctive).

At site 1, one physician-investigator (S.B.) made all acne assessments throughout the 12-week study. At site 2, two physician-investigators (M.-H.T. and D.W.S.) assessed patients interchangeably. Global response to treatment scores were aided by high-resolution baseline 20.3 × 25.4-cm glossy photographs of 3 views per patient.

Nonphysician clinical assistants assessed facial skin signs and symptoms, including peeling, erythema, dryness, burning, and itching, by interview and physical examination. At each visit, patients were asked to report the occurrence and severity of all signs and symptoms that occurred since the previous visit, even if such signs and symptoms had resolved by the time of the visit. Signs and symptoms were graded on a scale from 0 to 5 as follows: 0, none; 1, trace (mild, localized, awareness without discomfort); 2, mild (mild, diffuse, intermittent discomfort); 3, moderate (moderate, diffuse, continuous discomfort); 4, marked (moderate, dense, continuous discomfort occasionally interfering with activities); and 5, severe (prominent, dense, continuous discomfort often interfering with normal activities).

Laboratory testing was limited to urine pregnancy tests at baseline and at 12 weeks for all female patients to exclude pregnant women from study entry and to identify pregnancies that might occur during the study despite warnings. No positive test results were recorded.

PHOTOGRAPHY

During each visit, front and bilateral 45° side facial views of every patient were taken using a platform-mounted 35-mm SLR camera system (Nikon Corp, Tokyo, Japan) with a fixed-magnification 60-mm lens (f2.8) (Nikkor; Nikon Corp) and a dual-point light system (Twinflash; Canfield Scientific, Inc, Fairfield, NJ). Patients were positioned in a stereotactic device (Canfield Scientific, Inc) designed to capture registered serial photographs using standardized subject angles, framing, lighting, exposure, and reproduction ratio.

STATISTICAL ANALYSIS

Treatment success, one of the primary outcome measures, was based on achievement of a global response to treatment score of 0 to 3 (50%-100% improvement). A sample size of 99 patients (33 patients per treatment arm) was required based on the following assumptions: (1) use of a 2-sided test with α = .05 and a power of 0.8; (2) an average difference between the active treatment regimens and the control regimen of 35% (ie, "successes" in the treatment groups = 50% and successes in the control group = 15%); and (3) a dropout rate of 15%.

Analyses were conducted on an intent-to-treat basis and included all patients randomized to the study treatment. The χ2 procedure was used to compare the sex and race of the 3 treatment groups at baseline and to compare nodule counts. Analysis of variance was used to compare all other measures, including other baseline characteristics, lesion counts, global response to treatment scores, overall disease severity scores, and facial skin sign and symptom scores. Comparisons between active treatment and control pairs were computed using the Dunnett 2-tailed t test. In the analyses of all outcome measures, including lesion counts, global response to treatment scores, overall disease severity scores, and facial skin signs and symptoms, the last recorded score for each patient was carried forward to all subsequent visits.

The SAS PLAN procedure computer program (SAS Institute Inc, Cary, NC), using 3 treatments in blocks of 6, was used to generate treatment allocation for 102 patients and to obtain randomization. Patients were randomized to treatment through the sequential allocation of patient numbers at the first study visit. Sealed opaque envelopes containing treatment allocation information for each patient number were maintained at a separate location by a contract research organization (Integrated Research Inc, Dollard-des-Ormeaux, Quebec). Treatment allocation was not revealed for any study patient efore the completion of statistical analyses.

RESULTS
PATIENT CHARACTERISTICS

Of 99 patients enrolled, 64 were female and 35 were male. The median age was 25 years (range, 12-39 years). There were no significant differences in demographic characteristics among the 3 treatment groups (Table 1).

Eighteen (18%) of 99 patients did not complete the study: 6 in the T + T group, 4 in the T + V group, and 8 in the V + V group (Figure 1). The differences in discontinuation rates in the 3 treatment groups were not significant (P = .44).

Treatment groups demonstrated similar baseline distributions of acne lesions (open comedones, closed comedones, papules, pustules, and nodules) and facial skin signs and symptoms (Table 1). The mean overall disease severity score at baseline of the V + V group was lower than that of the active treatment groups (P = .05).

ACNE EFFICACY

Reductions from baseline in noninflammatory lesions in the T + T and T + V groups, expressed as mean ± SD percentage change, were significantly greater than in the V + V group from week 4 to week 12 (P = .002) (Figure 2). At week 12, reductions of 46.06% ± 38.31%, 41.19% ± 39.24%, and 2.48% ± 35.84% were observed in the T + T, T + V, and V + V groups, respectively.

At week 12, inflammatory lesions, excluding nodules, were significantly reduced in the T + T and T + V groups compared with the V + V group, as demonstrated by the mean ± SD percentage change from baseline in papules and pustules: 38.06% ± 36.22%, 33.58% ± 53.25%, and 8.76% ± 34.59%, respectively (P = .01) (Figure 3). Nodule counts were insufficient to accommodate statistical comparison. There were no significant differences between the 2 study sites in mean percentage reduction in noninflammatory or inflammatory lesions in any treatment group.

Achievement of treatment success was defined as global response to treatment of 0 to 3 (50%-100% improvement) by week 12. Significantly more treatment successes were observed in the T + T and T + V groups than in the V + V group: 64%, 61%, and 15%, respectively (P<.001).

Of 81 patients completing 12 weeks of treatment, 58 submitted complete diary records. These data show no evidence of a trend correlating treatment success with length of drug contact (Table 2). Statistical comparisons of subgroups, based on contact duration, were precluded by insufficient subgroup size.

By week 12, significant reductions from baseline in mean ± SD overall disease severity scores were observed in the T + T and T + V groups, 30.40% ± 30.96 and 29.09% ± 26.01, respectively, compared with 2.78% ± 17.26 in the V + V group (P<.001) (Figure 4). Significant differences in this variable became apparent by week 8 (T + T and T + V vs V + V; P<.001).

Individuals from the 3 treatment groups demonstrating various global response to treatment scores are shown in Figure 5, Figure 6, and Figure 7.

FACIAL SKIN SIGNS AND SYMPTOMS

The highest mean scores for peeling, erythema, dryness, burning, and itching were observed in the T + T group at week 2 or week 4; the maximum mean ± SD scores achieved for these signs and symptoms were 0.76 ± 0.94, 0.67 ± 0.82, 0.85 ± 0.97, 0.42 ± 0.79, and 0.45 ± 0.79, respectively. Mean scores of signs and symptoms did not exceed 1.0, or trace level, for any group throughout treatment. Increases in these signs and symptoms were significantly greater in the T + T group than in the V + V group at weeks 2 and 4 for peeling and erythema and at week 2 for dryness and burning.

Transient increases in these signs and symptoms were more prominent in the T + V group than in the V + V group at weeks 2 and 4 but did not reach significance. After week 4, the occurrence and severity of these signs and symptoms in the active treatment groups did not differ significantly from those in the control group.

No patient discontinued study medication because of adverse events, but significantly more related adverse events were observed in the T + T and T + V groups than in the V + V group (P = .002). Specifically, 1 or more of the signs and symptoms of local skin irritation was reported by 16 (48%) of 33 patients in the T + T group, 17 (52%) of 33 in the T + V group, and 3 (9%) of 33 in the V + V group.

Local skin irritation tended to be better tolerated by the T + V group than by the T + T group. Of patients completing therapy and submitting full diary records, 10 (50%) of 20 T + T patients reduced the contact period to less than 2 minutes at some time during the study, whereas 1 (4%) of 23 T + V patients reduced the contact period to less than 2 minutes.

COMMENT

The benefits achieved by patients in this study compare favorably with those reported in a large, multicenter study20 of overnight tazarotene therapy for acne. The mean percentage decrease in noninflammatory lesions after 12 weeks of overnight 0.1% tazarotene gel was 55% (vs 35% in the control group) compared with 46% and 41% (vs 2% in the control group) for twice-daily and once-daily short-contact therapy, respectively. Using overnight therapy, the mean percentage decrease in inflammatory lesions was 42% (vs 30% in the control group), whereas results achieved using the short-contact method were 38%, 34%, and 9% for the T + T, T + V, and V + V groups, respectively.

Two differences in study design might account for the relatively better response of the control group in the overnight study. First, patients in the overnight study washed with a soap-based cleanser twice daily, whereas our patients were prohibited from using soap and surfactant-based cleansers on facial skin throughout the study. Second, prolonged application of vehicle gel may have an unexplained palliative effect on acne not seen to the same extent with short-contact use.

Measures of efficacy in the present study showed continuing trends toward improvement at week 12 (Figure 2, Figure 3, and Figure 4), suggesting that more than 3 months of therapy may be required to achieve the maximum benefit. Gradual improvement over a several-month period is the typical acne response to retinoids.2024

Comparing overnight tazarotene with other topical retinoids, a recent clinical study21 showed that nightly 0.1% tazarotene gel is more effective than nightly 0.025% tretinoin gel in the treatment of comedonal acne. Furthermore, 0.1% tazarotene gel applied every second night seems to be equivalent therapeutically to 0.1% adapalene gel applied every night.22

The degree of acne improvement demonstrated in the present study is similar to that observed in a large multicenter trial23 comparing 0.025% tretinoin gel with 0.1% adapalene gel. Both agents were applied in the traditional overnight manner. After 12 weeks, the mean percentage reductions in noninflammatory lesions were 33% and 46% for tretinoin and adapalene, respectively. Mean inflammatory lesion counts were reduced by 38% in the tretinoin group and by 48% in the adapalene group. There were significantly fewer incidents of local skin irritation in the adapalene users than in the tretinoin users, but more than 30% of the former group and more than 40% of the latter had erythema and/or scaling of the facial skin persisting at week 12.

Of 446 patients applying tazarotene overnight, 39 (9%) withdrew because of treatment-related adverse effects, particularly local skin irritation.20 In a 12-week acne study24 comparing 0.1% adapalene solution with 0.025% tretinoin gel, 8 of 149 patients using adapalene solution and 4 (3%) of 146 patients using tretinoin gel withdrew because of retinoid-induced effects.

In the present study, signs and symptoms of local skin irritation did not differ significantly between the once-daily tazarotene group and the control group at any visit. There were no withdrawals due to treatment-related adverse effects because the study protocol allowed patients to adjust the contact period within well-defined limits to avoid such effects. In the previous experience of Bershad,19 tazarotene sensitivity differed substantially among individual patients, an observation supported herein. Data from patients' diary records at week 12 suggest that approximately half of all patients using active treatment had contact times of 3.5 minutes or less, whereas the remainder tolerated longer contact periods (Table 2).

A problem inherent in most topical retinoid studies is that noticeable skin irritation may interfere with investigator blinding. In the present study, the risk of obvious retinoid dermatitis was virtually eliminated by the patient's ability to shorten the contact period at the earliest sign or symptom of irritation. Adverse effects were generally subjective, minor, and transient, mostly occurring during intervals between visits. In no case was the degree of local skin irritation so apparent as to be inconsistent with the control regimen.

To our knowledge, this is the first randomized study showing that a topical retinoid medication can produce pharmacological effects and clinical improvement after exceedingly short periods of skin contact.

A possible explanation for the efficacy of short-contact therapy may be found in the percutaneous absorption studies of Rougier and colleagues.2527 Their work demonstrated that some topically applied substances achieve a reservoir effect in the stratum corneum after contact periods as short as 30 minutes.

Percutaneous absorption of tazarotene is a critical issue, as evidenced by its Food and Drug Administration designation of Pregnancy Category X, prohibiting its use during pregnancy and breastfeeding. Females of childbearing potential must use reliable birth control during tazarotene treatment. Although birth defects have not been reported in humans or laboratory animals after topical exposure to tazarotene, oral administration of high doses is teratogenic in animals.28 Another retinoid, isotretinoin, is well-known to cause birth defects in humans.29 Absorption studies20 in patients with facial acne using tazarotene gel overnight showed detectable plasma concentrations of tazarotene ranging from 0.06 to 0.22 ng/mL in 3 patients, and the active metabolite tazarotenic acid was detected in samples from 4 patients, ranging from 0.06 to 0.13 ng/mL. These levels are considerably lower than levels of endogenous retinoids in normal plasma.30

Two of the studies by Rougier and coauthors are particularly relevant to the issue of systemic absorption. In one study,26 after application of various topical agents to hairless rats, the total doses absorbed were directly proportional to the duration of application, suggesting lower systemic levels with shorter contact periods. Another investigation27 found that facial skin, compared with other anatomical sites, exhibited the most rapid rate of percutaneous absorption, which may partially offset the theoretical benefit of shorter contact.

Neither the rate of tazarotene absorption into epidermal cells nor the plasma levels achieved after short-contact therapy have been studied to date, to our knowledge.28,31 The dose absorbed after 5 minutes is likely to be minuscule, since a previous study32 showed that total systemic absorption of tazarotene was less than 6% of the applied dose after 10 hours under occlusion. If future investigations confirm that the short-contact method limits tazarotene absorption, it may have an important safety advantage for premenopausal females.

Another benefit of short-contact therapy is the lack of medication residue on the skin. Users of short-contact therapy can apply cosmetics, sunblocks, moisturizers, and other topical preparations without concerns about dilution or noncompatibility caused by layering of 2 products. This property also facilitates combination antiacne regimens.

Drawbacks of short-contact therapy are the need for careful timing of the application and individualized adjustment of the contact period. Some patients consider overnight therapy simpler for these reasons.

Finally, once-daily short-contact tazarotene therapy offers clear advantages over the twice-daily regimen. In the present study, the former was about as effective but less irritating than the latter. Comparing the two, the less frequent regimen is also more convenient and cost-effective.

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Article Information

Accepted for publication July 6, 2001.

This study was funded by an unrestricted educational grant from Allergan Inc, Irvine, Calif, to the Mount Sinai Department of Dermatology (Dr Lebwohl, Chairman).

This study was presented in part at the American Academy of Dermatology Summer Meeting, Nashville, Tenn, August 3, 2000.

We thank Betty O'Brien, Natalie Ghosh, and Megan Roddy for their valuable clinical assistance; Rick Kozloski for his contribution to our study design; and Andrea Kljajo, MSc, for her help in collecting and analyzing data.

Corresponding author: Susan Bershad, MD, 28 S Mountain Ave, Montclair, NJ 07042.

References
1.
Kligman  AMFulton  JEPlewig  G Topical vitamin A acid in acne vulgaris. Arch Dermatol. 1969;99469- 476Article
2.
Weinstein  GDKrueger  GGLowe  NJ  et al.  Tazarotene gel, a new retinoid for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol. 1997;3785- 92Article
3.
Peris  KFargnoli  MCChimenti  S Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma [letter]. N Engl J Med. 1999;3411767- 1768Article
4.
Sefton  JKligman  AMKopper  SCLue  JCGibson  JR Photodamage pilot study: a double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel. J Am Acad Dermatol. 2000;43656- 663Article
5.
Hofmann  BStege  HRuzicka  TLehmann  P Effect of topical tazarotene in the treatment of congenital ichthyoses. Br J Dermatol. 1999;141642- 646Article
6.
Petkovich  MBrand  NJKrust  AChambon  P A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987;330444- 450Article
7.
Giguere  VOng  ESSegui  PEvans  RM Identification of a receptor for the morphogen retinoic acid. Nature. 1987;330624- 629Article
8.
Brand  NPetkovich  MKrust  A  et al.  Identification of a second human retinoic acid receptor. Nature. 1988;332850- 853Article
9.
Krust  AKastner  PPetkovich  MZelent  AChambon  P A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989;865410- 5414Article
10.
Chandraratna  RA Tazarotene: the first receptor-selective topical retinoid for the treatment of psoriasis. J Am Acad Dermatol. 1997;37 (suppl 2, pt 3) S12- S17Article
11.
Shroot  B Pharmacodynamics and pharmacokinetics of topical adapalene. J Am Acad Dermatol. 1998;39 (suppl 2, pt 3) S17- S24Article
12.
Nagpal  SAthanikar  JChandraratna  RAS Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. J Biol Chem. 1995;270923- 927Article
13.
Elder  JTFisher  GJZhang  O  et al.  Retinoic acid receptor gene expression in human skin. J Invest Dermatol. 1991;96425- 433Article
14.
Chen  SOstrowski  JWhiting  G  et al.  Retinoic acid receptor gamma mediates topical retinoid efficacy and irritation in animal models. J Invest Dermatol. 1995;104779- 783Article
15.
Esgleyes-Ribot  TChandraratna  RALew-Kaya  DASefton  JDuvic  M Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol. 1994;30581- 590Article
16.
Nagpal  SPatel  SAsano  ATJohnson  ATDuvic  MChandraratna  RAS Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor–responsive gene in skin. J Invest Dermatol. 1996;106269- 274Article
17.
Nagpal  SThacher  SMPatel  S  et al.  Negative regulation of two hyperproliferative keratinocyte differentiation markers by an RAR-selective retinoid: insight into the mechanism of retinoid action in psoriasis. Cell Growth Differ. 1996;71783- 1791
18.
Leyden  JJ Topical treatment of acne vulgaris: retinoids and cutaneous irritation. J Am Acad Dermatol. 1998;38 (suppl) S1- S4Article
19.
Bershad  S Developments in topical retinoid therapy for acne. Semin Cutan Med Surg. 2001;20154- 161Article
20.
Shalita  ARChalker  DKGriffith  RF  et al.  Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis. 1999;63349- 354
21.
Webster  GFBerson  DStein  LF  et al.  Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis. 2001;67 (suppl 6) 4- 9
22.
Leyden  JLowe  NKakita  LDraelos  Z Comparison of treatment of acne vulgaris with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene gel: a randomized trial. Cutis. 2001;67 (suppl 6) 10- 16
23.
Shalita  AWeiss  JSChalker  DK  et al.  A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34482- 485Article
24.
Ellis  CNMillikan  LESmith  EB  et al.  Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol. 1998;139 (suppl 52) 41- 47Article
25.
Rougier  ADupuis  DLotte  CRoquet  RSchaefer  H In vivo correlation between stratum corneum reservoir function and percutaneous absorption. J Invest Dermatol. 1983;81275- 278Article
26.
Rougier  ADupuis  DLotte  CRoquet  R The measurement of the stratum corneum reservoir: a predictive method for in vivo percutaneous absorption studies: influence of application time. J Invest Dermatol. 1985;8466- 68Article
27.
Rougier  ALotte  CMaibach  HI In vivo percutaneous penetration of some organic compounds related to anatomic site in humans: predictive assessment by the stripping method. J Pharm Sci. 1987;76451- 454Article
28.
Marks  R Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol. 1998;39 (suppl) S134- S138Article
29.
Lammer  EJChen  DTHoar  RM  et al.  Retinoic acid embryopathy. N Engl J Med. 1985;313837- 841Article
30.
Eckhoff  CNau  H Identification and quantification of all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res. 1990;311445- 1454
31.
Tang-Liu  DDMatsumoto  RMUsansky  JI Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet. 1999;37273- 287Article
32.
Franz  TJLehman  PAFranz  S  et al.  Percutaneous absorption of AGN 190168, a new synthetic retinoid, through human skin in vivo [abstract]. Clin Res. 1992;40533
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