STUDY Tazarotene Cream for the Treatment of Facial Photodamage A Multicenter, Investigator-Masked, Randomized, Vehicle-Controlled, Parallel Comparison of 0.01%, 0.025%, 0.05%, and 0.1% Tazarotene Creams With 0.05% Tretinoin Emollient Cream Applied Once Daily for 24 Weeks Sewon Kang, MD; James J. Leyden, MD; Nicholas J. Lowe, MD; Jean-Paul Ortonne, MD; Tania J. Phillips, MD; Gerald D. Weinstein, MD; Jag Bhawan, MD; Deborah A. Lew-Kaya, PharmD; Richard M. Matsumoto, PhD; John Sefton, PhD; Patricia S. Walker, MD, PhD; John R. Gibson, MD Objective: To assess the safety and efficacy of 4 con- Results: Tazarotenecreamandtretinoincreamsignificantly centrations of tazarotene cream in the treatment of improved mottled hyperpigmentation and fine wrinkles. facial photodamage. Atweek24,treatmentsuccessratesbasedonglobalresponses were 67% (39 of 58 subjects) with 0.1% tazarotene, 52% Design: Prospective weekly multicenter, investigator- (30 of 58 subjects) with 0.05% tazarotene, 36% (21 of 58 masked, randomized, parallel-group study. subjects) with 0.025% tazarotene, 41% (24 of 59 subjects) with 0.01% tazarotene, 55% (32 of 58 subjects) with 0.05% Setting: University hospitals and clinical research tretinoin, and 22% (13 of 58 subjects) with vehicle. Local centers. adverse events, although more frequent with tazarotene at higher concentrations, were generally mild to moderate. Patients: Three hundred forty-nine subjects with fa- cial photodamage. Conclusions: Tazarotene in a cream formulation is safe and is associated with positive changes in the treatment Intervention: Daily topical application of tazarotene of photodamaged facial skin. cream (0.01%, 0.025%, 0.05%, and 0.1%) compared with its vehicle and with 0.05% tretinoin emollient cream. Arch Dermatol. 2001;137:1597-1604 V IRRADIATION from the The topical retinoid tretinoin (all- sun causes premature trans-retinoic acid) has been shown to skin aging, also known as improve fine wrinkles, mottled hyperpig- photoaging. Photoaged mentation, and tactile roughness associ- skin is characterized by ated with photoaged skin.1,4 Histologi- Ucoarse and fine wrinkles, roughness, yel- cally, the improvement in appearance of lowness, laxity, uneven pigmentation, photoaged skin following topical treti- brown spots, and a leathery appearance.1 noin use is associated with compaction In contrast, chronologically aged skin that of the stratum corneum, thickening of has been protected from the sun is thin and the epidermis, reduced melanin content, has reduced elasticity but is otherwise and increased glycosaminoglycans.3,5 The smooth and unblemished.2 effacement of wrinkles correlates with a Histologically, photoaged skin dem- partial restoration of type I procollagen, onstrates an alteration in the dermal ma- which is typically reduced in photodam- trix. Abnormal elastin-containing mate- aged skin.6 rial and a disorganization of collagen fibrils Retinoids like tretinoin and tazaro- are the hallmark signs. In addition, the lev- tene mediate their responses primarily els of types I and III collagen precursors through activation of nuclear retinoid re- are reduced in photoaged skin compared ceptors. There are 2 families of nuclear reti- with sun-protected buttock skin.3 Changes noic acid receptors: the retinoic acid re- The affiliations of the authors in the epidermis can include a decrease in ceptor (RAR) family and the retinoid X appear in the acknowledgement epidermal polarity and an increase in ke- receptor family. Each receptor family con- section at the end of the article. ratinocytic atypia.2 tains 3 receptor subtypes: ␣, ␤, and ␥.7 (REPRINTED) ARCH DERMATOL / VOL 137, DEC 2001 WWW.ARCHDERMATOL.COM 1597 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 PARTICIPANTS AND METHODS centers were instructed not to apply the study medication on those evenings before blood sampling. Subjects were ad- STUDY POPULATION vised to avoid excessive sun exposure, to wear protective clothing when exposed to sunlight, and to use a daily sun- Male or female volunteers, 18 years or older, with skin types screen with a sun protective factor of at least 15. I (always burns easily and never tans), II (always burns eas- ily and tans minimally), III (burns moderately and tans gradu- CLINICAL EVALUATIONS ally), or IV (burns minimally and always tans well) and with at least moderate facial photodamage (but otherwise healthy) Evaluations were conducted at a pretreatment screening were eligible for recruitment into this 24-week multicenter visit, at weeks 0 (baseline), 2, 4, 8, 12, 16, 20, and 24, and study. The design was double blinded (with reference to taz- 2 weeks posttreatment (week 26). arotene creams vs vehicle), investigator masked (with ref- erence to the comparison vs tretinoin cream), randomized, EFFICACY MEASURES vehicle controlled, and a parallel comparison. Subjects had to have a baseline facial overall integrated assessment (OIA) Efficacy variables evaluated at all study visits included the of photodamage score of at least 3, on a 6-point scale (0 in- following: fine wrinkling, mottled hyperpigmentation, len- dicates no photodamage; 1, minimal photodamage; 2, mild tigines, irregular depigmentation, tactile roughness, coarse photodamage; 3, moderate photodamage; 4, severe pho- wrinkling, telangiectasia, pore size, elastosis, actinic kera- todamage; and 5, very severe photodamage). In addition, a toses, and OIA of photodamage. The OIA measure encom- baseline severity for either mottled hyperpigmentation or fine passed all the individual signs of photodamage. A pho- wrinkling of at least 3, on a 6-point scale, was required. Ex- tonumeric guideline illustrating the OIA grades of minimal, cluded were any volunteers who had used topical glycolic mild, moderate, and severe (3 examples per severity) was acid, ␣–hydroxy acid, salicylic acid, lactic acid, or ␤–hy- provided to assist the investigators in deriving an accurate droxy acid or vitamin A, ascorbic acid–, or vitamin E–con- and reproducible OIA score. Each of the efficacy variables taining products within 14 days before study enrollment and was evaluated on a 6-point scale (0 indicates none; 1, mini- those who had used topical or systemic retinoids within 6 mal; 2, mild; 3, moderate; 4, severe; and 5, very severe). months before study enrollment. Pregnant and nursing For these evaluations, evaluators did not have to remem- women were excluded, and women of childbearing poten- ber the status of the patient’s condition at baseline. tial were required to use a reliable form of contraception, have Global response to treatment, on the other hand, was a a normal menstrual cycle, and have a negative urine preg- measure that did involve memory. At each visit, evaluators nancy test result at baseline (week 0) and at weeks 4, 8, 12, compared the subject’s condition with that at baseline and 16, 20, and 24. Written informed consent was obtained from expressed the response on a 7-point scale (0 indicates com- all subjects, and the study was conducted in compliance with plete response [100% resolution of photodamage]; 1, al- Good Clinical Practices, Institutional Human Review Board most complete response [approximately 90% improve- Regulations, and the Declaration of Helsinki. Subjects were ment]; 2, marked response [approximately 75% randomly assigned to 1 of the 6 treatment groups using a improvement]; 3, moderate response [approximately 50% im- computerized randomization method. provement]; 4, slight response [approximately 25% improve- ment]; 5, no response; and 6, condition worsened). STUDY MEDICATIONS At the end of the study, subjects were asked for an evaluation of the cosmetic characteristics of the study medi- Study medications evaluated were 0.01%, 0.025%, 0.05%, cation and for a self-assessment of their overall response and 0.1% tazarotene creams, its inactive vehicle cream (Al- to treatment, compared with their condition at baseline, lergan, Inc, Irvine, Calif), and 0.05% tretinoin emollient using the following 5-point scale: 1 indicates much im- cream (Renova; Ortho Pharmaceutical Corp, Raritan, NJ). proved; 2, somewhat improved; 3, no change; 4, some- what worse; and 5, much worse. In addition, subjects were TREATMENTS asked to rate the cosmetic characteristics of the study medi- cation, to indicate whether they would continue to use the Subjects applied the study medication to the face every study medication, and to compare the study medication with evening for 24 weeks. They were instructed to wash and previously used products to treat photodamage. dry their faces before application, and to apply a thin layer of the study medication to lightly cover the face. Facial CRITERION FOR EFFECTIVENESS moisturizers, if used, were to be applied at least 1 hour be- fore or after application of the study medication. Those par- The effectiveness of the test products was deemed clini- ticipating in therapeutic drug monitoring at selected study cally significant if the difference in the proportion of Tretinoin and tazarotene display different receptor se- dermis is RAR ␥.9 It is unknown whether the receptor lectivities. Whereas tretinoin activates the RARs ␣, ␤, and selectivity of tazarotene has any particular clinical sig- ␥ directly, and the retinoid X receptors ␣, ␤, and ␥ in- nificance in the treatment of skin conditions such as pho- directly (through conversion of tretinoin to 9-cis- todamage. retinoic acid8), tazarotenic acid, the metabolite of taz- As an RAR agonist, tazarotene could be effective