effective.5,6 In human beings and animal models, chronic therapy with topical tretinoin promotes remodeling of the collagen in the papillary and reticular dermis and decreases dermal inflammation.7,8 Retinoids also produce inhibitory effects on vascular endothelial growth factor production by cultured human skin keratinocytes.9 In fact, some studies have demonstrated positive effects of topical retinoids in the treatment of rosacea, not only in the papulopustular component but also in erythema.6 The clinical response to topical retinoids appears to be delayed, starting usually in 1-2 months of therapy. Retinoids also produce inhibitory effects on vascular endothelial growth factor production by cultured human skin keratinocytes.9
Clindamycin lotion has been compared favorably to oral tetracycline therapy in an investigator-blinded 12-week trial of 43 patients with acne vulgaris.10,11 Topical clindamycin (twice daily) produced clearance that was similar to oral tetracycline and is more effective than tetracycline for the eradication of pustules.10,11 The combination of clindamycin phosphate 1.2% and tretinoin 0.025% gel (CT gel) has been FDA approved for acne vulgaris. Acne vulgaris shares similarities with acne rosacea in that both consist of follicle-based inflammation clinically and histologically and therefore it might be predicted that papulopustular subtype might respond well to CT gel. In this study, we explore the possibility that CT gel may improve acne rosacea.
Objective
The objective of this study was to assess the safety and efficacy of CT versus placebo gel in subjects with papulopustular rosacea. The primary endpoint was the absolute change in inflammatory lesion counts (papules and pustules) from baseline to week 12 (end of treatment) as assessed by both physician and participant, both of whom are blinded to treatment. Secondary endpoints include percentage of participants in treated versus placebo groups with improvement in at least one symptom category after 12 weeks. Side effect incidence was compared as well between treated and placebo groups.
METHODS
Study Population and Procedures
A summary of the study design is shown in Figure 1. This was a randomized, double blind, placebo-controlled study at two academic centers, which consisted of one screening visit and four study visits. This study was conducted according to Declaration of Helsinki principles registered on www.clinicaltrials.gov. Following Institutional Review Board approval at both Massachusetts General Hospital and Stanford Hospital and Clinics, participants were recruited from advertisements in local newspapers, posters, and the internet. Following a preliminary telephone screen, potential study subjects underwent the informed consent process prior to all study procedures. Inclusion and exclusion criteria were reviewed, medical histories obtained, and their skin was examined by a board-certified dermatologist. Inclusion criteria included: ≥18 years of age, clinical diagnosis of papulopustular facial rosacea, 4 to 50 facial inflammatory lesions (papules plus pustules). The following exclusion criteria were used: acne conglobata, acne fulminans, secondary acne (chloracne, drug-induced acne, etc.) or severe acne requiring systemic treatment; history of regional enteritis or inflammatory bowel disease; use of topical rosacea treatments in the past two weeks; use of systemic antibiotics in the past four weeks; use of systemic retinoids within the past three months; use of laser or light-based rosacea treatments within the past two months; concomitant use of medications that are reported to exacerbate rosacea, such as topical and systemic steroids; current drug or alcohol abuse; other dermatologic conditions that require the use of interfering topical or systemic therapy or that might interfere with study assessments such as, but not limited to, atopic dermatitis, perioral dermatitis or acne vulgaris; pregnant or planning a pregnancy; use of any investigational therapy within the past four weeks; known hypersensitivity or previous allergic reaction to clindamycin or retinoids.
Qualifying subjects were randomized via a computerized random number generator to into two nearly equal populations and selected to receive either CT or placebo gel. The research staff member who randomized the study population was not involved with any study assessments. The CT gel and placebo gels were indistinguishable on visual inspection with respect to color, consistency and odor. The study subjects were instructed to apply the gel once daily for 12 weeks, and were given diaries to record usage and side effects. The weights of the gel tubes were taken at each visit to confirm compliance with CT and placebo gel usage.
Sample size was determined based on prior studies in the medical literature, with study subjects having a baseline papule or pustule count between 15 to 17 lesions. We estimated the CT group would experience a 50% improvement and that the placebo group would show a 35% improvement. Using a standard deviation of 3.5 lesions, a power of 80% and a 2-tailed alpha of 0.5, a sample size of 35 patients per group was needed to achieve statistical significance. To allow for a 15% to 20% dropout rate, 41 to 43 subjects for each group was needed. We used a modified intention-to-treat analysis (mITT) defined as the population that completed at least one follow-up visit defined as week 2, 6, or 12.
In addition to the screening visit, study subjects participated in four follow-up visits: baseline (day 1), interim assessments (at weeks 2, 6), and final assessments (at week 12). In all four visits, physician and patient rosacea assessment instruments derived from the National Rosacea Scoring System12,13 were administered. Optional photographs were taken.
Primary endpoints in the study included a statistically significant decrease in absolute count of papules/pustules on the face at week 12 compared to baseline, as well as percent decreased in papule/pustule count on the face at week 12 compared to
