Topic Gel to Treat Facial Redness of Rosacea

05/12/2014

Mirvaso is the first and only FDA-approved topical treatment for persistent erythema of rosacea.

The FDA approved Mirvaso (brimonidine) Topical Gel, 0.33% in August 2013 as the first and only topical treatment indicated for the persistent (non-transient) facial erythema of rosacea in adults age 18 or older. The gel, marketed by Galderma Laboratories, L.P., is an alpha-2 adrenergic agonist that may work by constricting the dilated blood vessels to reduce the redness of rosacea. 

Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base. Brimonidine should be applied in a pea-sized amount, once-daily to each of the 5 regions of the face: the forehead, chin, nose and each cheek, avoiding the eyes and lips. Applied once daily, brimonidine works quickly to reduce the redness of rosacea up to 12 hours before the redness returns, according to the prescribing information.

The National Rosacea Society reports that rosacea, a chronic, inflammatory vascular disorder affecting the face, affects approximately 16 million Americans. Redness, visible blood vessels, bumps and blemishes typically appear in the middle of the face (forehead, nose and cheeks) after age 30 in men and women. Because of its red-faced, acne-like effects, rosacea can cause significant psychological, social and occupational problems if left untreated.

Surveys by the National Rosacea Society found that >76% of rosacea patients reported that their condition had lowered their self-confidence and self-esteem, and 41% said that it had caused them to avoid public contact or cancel social engagements. 

The FDA approved brimonidine based on data collected from more than 550 patients with moderate to severe facial erythema of rosacea enrolled in 2 Phase III clinical studies for a duration of 1 month. The results of the study were published in 2013 in the Journal of Drugs in Dermatology.1 Results of a long-term study of brimonidine were recently pulblished in the Journal of Drugs in Dermatology.2

The Dermatologist Product Spotlight provides a summary of the pivotal trials that evaluated the safety and efficacy of brimonidine for the treatment of persistent facial erythema of rosacea.

fig 1

Phase III Clinical Data

Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656.1

Study Objective

To assess the efficacy and safety of once-daily topical brimonidine tartrate (BT) gel 0.5% in the treatment of moderate to severe erythema of rosacea.

Method

The 2 Phase III, multicenter, randomized, double-blind, parallel-group, vehicle-controlled pivotal trials were conducted in the United States and Canada. Patients with moderate to severe erythema of rosacea were assigned in a 1:1 ratio to receive BT gel 0.5% or vehicle gel. During the first 4 weeks, patients were instructed to apply once daily a thin film of gel on the entire face. No medication was applied during the 4-week follow-up phase. 

There were 6 visits in each study: screening visit, days 1, 15 and 29 during the treatment phase, and weeks 6 and 8 during the follow-up phase. On days 1, 15 and 29, patients remained at the clinic for 12 hours, and erythema (Clinician’s Erythema Assessment [CEA] and Patient’s Self-Assessment [PSA]) was assessed prior to study drug application, and at 30 minutes, 3, 6, 9 and 12 hours after application. Telangiectasia, Investigator’s Global Assessment (IGA) of the lesion severity and inflammatory lesion counts were also evaluated on day 1 prior to study drug application at hour 12 on day 29. CEA, PSA, telangiectasia, IGA and inflammatory lesion counts were assessed at each follow-up visit.

The 2 studies were carried out from May 2011 to September 2011, and from May 2011 to November 2011, respectively. Periods of recruitment were May 2011 to July 2011 and May 2011 to September 2011.

Population

A total of 260 patients were enrolled in study A and 254 completed it normally. Among the 293 patients enrolled in study B, 283 reported normal study completion. Inclusion criteria included patients age 18 years or older, with a clinical diagnosis of rosacea, <3 facial inflammatory lesions and moderate to severe erythema according to both CEA and PSA at both the screening visit and the baseline visit. A wash-out period was mandatory for patients receiving prescription medications for inflammatory conditions, rosacea or acne. The groups of BT gel 0.5% and vehicle gel were comparable in terms of demographic characteristics in both studies.

Primary Endpoint

• Profile of success (defined as 2-grade improvement on both CEA and PSA) on days 1, 15 and 29, using the evaluations at hours 3, 6, 9 and 12 as representative time points for each day.

Secondary Endpoint

• The 30-minute effect, defined as 1-grade improvement from baseline on both CEA and PSA at 30 minutes on day 1.

Results

The authors concluded that BT gel 0.5% was considerably more efficacious than vehicle gel throughout 12 hours on days 1, 15 and 29, with significant difference observed as early as 30 minutes after the application on day 1 (all P<.001). Significantly greater success was achieved with BT gel 0.5% versus vehicle gel in both studies on day 29. The success rate with BT gel 0.5% at hours 3, 6, 9 and 12 was 31.5%, 30.7%, 26.0% and 22.8%, respectively in study A, and 25.4%, 25.4%, 17.6% and 21.1%, respectively in study B versus 10.9%, 9.4%, 10.2% and 8.6% in study A, respectively, and 9.2%, 9.2%, 10.6% and 9.9%, respectively in study B for the vehicle gel.

Efficacy was also evaluated based on the 1-grade improvement on both CEA and PSA. The findings showed that the responder rate of BT gel 0.5% was significantly greater than that of vehicle gel in both study groups on day 29 (P<.001). Furthermore, no tachyphylaxis, rebound or aggravation of other disease signs were observed.

Safety Notes

Slightly higher incidence of adverse events (AEs) was observed for BT gel 0.5% versus the vehicle gel; however, most of the AEs were dermatological, mild and transient in nature. 

Long-Term Study

Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014;13(1):56-61.2

Study Objective

Evaluate the safety and efficacy BT gel 0.5% applied once daily for up to 12 months.

Method

The open-label, non-comparative study was carried out in 27 centers in the United States. The patients were instructed to apply a thin film of topical BT gel 0.5% once daily in the morning over the entire face for up to 12 months. Patients completed a questionnaire at baseline/day 1 and at months 3, 6, 9 and 12. The study included a total of 8 visits: screening, baseline/day 1, week 1 and months 3, 6, 9 and 12.  At each post-screening visit, the efficacy assessments included CEA, PSA, telangiectasia and inflammatory lesion count prior to study drug application, as well as CEA and PSA 3 hours after study drug application.

Population

A total of 586 patients were screened and 449 were enrolled in the study and included in the safety population.  Among them, 335 patients completed at least 6 months of treatment, and 279 patients completed the study (up to the 12- month visit). Inclusion criteria included patients age 18 years or older, with a clinical diagnosis of rosacea and moderate or severe erythema according to both CEA and PSA at both the screening visit and the baseline visit. There was no restriction on the number of inflammatory lesions of rosacea on the face of patients. The majority of the patients were female and Caucasian/white, with a mean age of 50.9 years. At baseline (prior to study drug application), the majority of patients had moderate erythema of rosacea according to either CEA or PSA, with a mean number of inflammatory lesions of 5.4. Patients were allowed to use other rosacea therapies (oral and topical) along with BT gel 0.5%.

Primary Endpoint

• Long-term safety and efficacy of BT gel 0.5%.

Results

Consistent with the results of previous trials, effect of BT gel 0.5% on erythema of rosacea was observed on day 1 after the first application, with mean CEA decreasing from 3.1 at hour 0 to 1.7 at hour 3. This improvement was observed throughout the 12 months. The results of PSA were similar to those of CEA. Over the course of the study, the mean PSA score at hour 0 reduced gradually from 3.1 on day 1 to 2.3 at month 3 and remained stable until month 12. In addition, no evidence of tachyphylaxis were reported.

Safety Notes

No new major safety findings were observed in this study as compared to the vehicle-controlled, pivotal studies. The incidence of AEs and AEs judged to be related to the study drug was higher at the beginning (90 days) and decreased over the course of the study. The related AEs observed most frequently in the study (≥2% of patients) were flushing (9.1%), worsening of erythema (6.5%), worsening of rosacea (3.6%), skin burning sensation (3.3%), skin irritation (3.1%), dermatitis contact (2.2%) and pruritus (2.0%). The majority of the related-AEs were dermatologic in nature and mild or moderate in intensity. n

Additional Resource

Prescribing information for Mirvaso: http://www.galdermausa.com/PI/MirvasoPI.pdf