T. J. Phillips, MD
Boston University School of Medicine, Boston, MA, USA
Tazarotene (Tazorac®, Allergan) has been shown to be effective in reducing the effects of photoaging in short term studies. To determine its effectiveness in the longer term, a 24-week multicenter, double-blind, randomized, vehicle controlled intervention study of 563 patients with facial photodamage was carried out followed by a 28-week open label extension. Patients were treated with one daily application of tazarotene 0.1% cream or vehicle cream to the face for 24 weeks, then tazarotene 0.1% cream for another 28 weeks. At week 24, when compared to vehicle, tazarotene resulted in a significantly greater incidence of patients achieving treatment success (over 50% greater improvement) and at least a 1 grade improvement in fine wrinkling, mottled pigmentation, pore size, lentigines, elastosis, irregular depigmentation, tactile roughness, coarse wrinkling and overall integrated assessment of photodamage(p<.01). Additional clinical improvement occurred with continued tazarotene treatment and had not plateaued by week 52.
Key Words: photoaging, photodamage
The effects of photoaging can be seen clinically as wrinkling, dyspigmentation, laxity, roughness, sallowness and telangiectasia. In pilot studies, as well as larger double blind short term studies (6 months), tazarotene (Tazorac®, Allergan) was shown to improve photodamage when compared to placebo.1,2
The double-blind short term study was a multicenter, investigator masked study, daily topical application of tazarotene cream (0.01%, 0.025%, 0.05% and 0.1%) was compared with its vehicle and with 0.05% tretinoin emollient cream. Tazarotene cream and tretinoin cream significantly improved mottled hyperpigmentation and fine wrinkles. At week 24, treatment success rates based on global responses were:
• 67% (39 of 58 subjects) with 0.1% tazarotene
• 52% (30 of 58 subjects) with 0.05% tazarotene
• 36% (21 of 58 subjects) with 0.025% tazarotene
• 41% (24 of 59 subjects) with 0.01% tazarotene
• 55% (32 of 58 subjects) with 0.05% tretinoin
• 22% (13 of 58 subjects) with vehicle.
Local adverse events, although more frequent with tazarotene at higher concentrations, were generally mild-to-moderate.2
To further evaluate the long term efficacy and safety of 0.1% tazarotene cream in the treatment of photodamage, a 12-month study was performed.3 Male or female patients with facial photodamage were eligible for recruitment if they had at least mild severity of both fine wrinkling and mottled hyperpigmentation, and at least moderate severity of one of these. Patients were required to be older than 18 years of age and to have skin type I-IV. Women of childbearing potential were excluded if they were pregnant, nursing or planning a pregnancy during the study. Patients were randomized in a 1:1 ratio to receive 0.1% tazarotene cream or non-medicated vehicle cream in the 24-week double blind phase. All continuing patients received 0.1% tazarotene cream in the 28-week open label phase.
Patients were instructed to apply a pea size amount of study medication to lightly cover their entire face once daily in the evening. Patients were requested to avoid excessive exposure to UV light, to wear protective clothing when exposed to sunlight and to apply sunscreen of at least SPF 15 every morning.
Clinical evaluations were made at the screening visit (day -21 to -1 from baseline) and at weeks 0, 2, 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52. Primary efficacy was measured for fine wrinkling and mottled pigmentation. Other efficacy measures were lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, telangiectasia, actinic keratoses, overall integrated assessment of photodamage, global response to treatment and patients’ overall assessment of photodamage. A 5-point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe) was used to grade the parameters of photodamage above. Clinical improvement was defined as an improvement from baseline of at least one full grade. A one grade improvement was considered both noticeable and relevant to the patients as well as to the investigator. The overall integrated assessment of photodamage was assessed using a 6 point scale (0=none, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=very severe). For fine wrinkling and mottled pigmentation and overall integrated assessment of photodamage, photonumeric guidelines illustrating each grade were provided to each investigator in determining the grade. A total of 563 patients were enrolled for 15 investigator sites, which included both private and institutional practice. Enrollment was generally picked by investigators from their existing patients or from patients who responded to an advertisement.
Out of the 583 patients, 203 were treated with 0.1% tazarotene cream and 280 were treated with vehicle during the double-blind phase. Of the 563 patients, 511 (91%) completed the double-blind phase. A subgroup of the 511 patients continued into the open phase, and 482 (94%) completed treatment. The study population was generally at least middle-aged with 93% of the patients at least 40 years of age, and 22% older than 65 years of age. At baseline, most patients had at least moderate fine wrinkling and mottled hyperpigmentation. Improvement scores are shown in the graph below (see Figure 1).
Compared with vehicle, tazarotene treatment results in a significantly greater instance of patients achieving clinical improvement, at least a one grade improvement in both fine wrinkling (from weeks 8-24) and mottled hyperpigmentation (from weeks 2-24). Tazarotene treatments also resulted in a significantly greater instance of patients achieving clinical improvement in lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and overall integrated assessment of photodamage. During the open label period, patients previously treated with 0.1% tazarotene cream showed further clinical improvement with continued treatment in the following: fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, overall integrated assessment of photodamage, and treatment success.
Patients previously treated with the vehicle showed a similar magnitude in the speed of improvement in all variables, just as the other treatment group had shown in their first few months of tazarotene treatment. The patients’ self assessments showed that the patients who were treated with tazarotene during the double-blind prior continued to shift toward the much improved response during the open label study.
Incidence of adverse events was significantly higher in the tazarotene group than in the vehicle group. These were primarily signs and symptoms of local skin irritation. They were generally mild to moderate in severity.
The results of the study demonstrated that when compared to the vehicle, tazarotene cream can result in clinically and statistically significant improvements in multiple signs of photodamage. The pigmentary changes were the first to be evident with mottled hyperpigmentation and the overall integrated assessment showed statistically significant improvement over the vehicle group after only 2 weeks of therapy, and lentigines, irregular depigmentation and patient self-assessment significantly improved over the vehicle group by week 4. Fine wrinkling demonstrated significant improvement over the vehicle group by week 8 and elastosis, pore size, tactile roughness, and coarse wrinkling were significantly improved over the vehicle group by week 12. All of these parameters showed continually increasing improvement with the lengthened duration of therapy. Some improvement was seen in the vehicle treated group, which is attributable to the regular use of moisturizers and sunscreens.
Once daily application of 0.1% tazarotene cream to photodamaged facial skin for 6 months is significantly more effective than the vehicle in achieving clinically relevant reductions in fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and in overall integrated assessment of photodamage.