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

to abnormal, involuntary, and persistent dilation of facial blood vessels.^14-16 Therefore, agents with vasoconstrictive activity should be able to reduce erythema effectively.

Recent transcriptomic studies suggest that genes including adrenergic receptor are involved in the neurovascular regulation pathway.¹⁷ Adrenergic receptor agonists with vasoconstrictive activity may therefore be good candidates for the treatment of erythema. Topical and systemic agonists of α- and β-adrenergic receptors, such as oxymetazoline, nadolol, and propranolol, have been used in isolated cases for the treatment of flushing and/or erythema among rosacea patients.^18-20 Brimonidine tartrate (BT) is a highly selective α₂-adrenergic receptor agonist, with potent vasoconstrictive activity.²¹ It is currently approved for the treatment of open angle glaucoma, with well-documented efficacy and safety.^{22, 23} Topical BT gels of three concentrations (0.07%, 0.18% and 0.5%) were evaluated in the previous Phase IIa study, and a dose-dependent relationship was observed.²⁴ Three different dose regimens (0.18% once and twice-daily, and 0.5% once-daily) were further selected to be evaluated in the Phase IIb study, and BT gel 0.5% applied once-daily was determined to be the optimal dose regimen for the treatment of erythema of rosacea.²⁴ In the present two Phase III studies including a 4-week treatment phase and a 4-week follow-up phase, we aimed to assess the efficacy and safety of the once-daily topical BT gel 0.5% in the treatment of moderate to severe erythema of rosacea.

These two Phase III pivotal trials with identical design were multicenter, randomized, double-blind, parallel-group, and vehicle- controlled comparison studies carried out in the United States and Canada. The duration of the studies was 8 weeks, including a 4-week treatment phase, and a 4-week follow-up phase. Both studies were conducted in accordance with the ethical principles originating from the Declaration of Helsinki and Good Clinical Practices and in compliance with local regulatory requirements. The studies were reviewed and approved by institutional review boards. All subjects provided their written informed consent prior to entering the studies.

Eligible subjects were men and women, 18 years or older, with a clinical diagnosis of rosacea, less than 3 facial inflammatory lesions, and moderate to severe erythema according to both Clinician’s Erythema Assessment (CEA) and Patient’s Self-Assessment (PSA)²⁴ at both the screening visit and the baseline visit. A wash-out period was mandatory for subjects receiving prescription medications for inflammatory conditions, rosacea, or acne. Subjects were randomized in a 1:1 ratio to the groups of BT gel 0.5% and vehicle gel. During the first 4 weeks (treatment phase), subjects 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.

Randomization lists were generated prior to study initiation by an independent statistician using SAS Proc Plan procedure. The randomization lists were then sent to the clinical supply group, and only the personnel directly involved with labeling and packaging had access. The integrity of the blinding was ensured by packaging the topical gels in identical tubes and requiring a third party (designated study personnel) other than the investigator/ evaluator to dispense the medication. The labels of the study products identified only the randomization number. Treatment kit was assigned in ascending order to each subject intended to be treated, and no number was to be omitted or skipped.

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, subjects remained at the clinic in standard room temperature conditions for 12 hours, and erythema (CEA and PSA) was assessed prior to study drug application, and at 30 minutes, 3, 6, 9, and 12 hours after application; Telangiectasia [using a 5-point scale ranging from 0 (clear) to 4 (severe)], Investigator’s Global Assessment (IGA) of the lesion severity [using a 5-point scale ranging from 0 (clear) to 4 (severe)], and inflammatory lesion counts were also assessed on day 1 prior to study drug application and at Hour 12 on day 29. During the follow-up visits, CEA, PSA, telangiectasia, IGA, and inflammatory lesion counts were assessed at each visit. Safety was evaluated by physical exams and monitoring of adverse events (AEs) and vital signs throughout the study.

All efficacy variables were analyzed based on the intent-to-treat (ITT) population, which is defined as all subjects who were randomized and to whom study drug was administered. Primary analyses were also performed on the Per Protocol (PP) population, which is defined as the ITT subjects who had no major protocol deviations. All safety variables were analyzed based on the safety population, defined as all subjects who had applied the study drug at least once.

Primary efficacy endpoint was the 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. The primary analyses were to test treatment differences on success between the active and the vehicle groups using the Generalized Estimating Equation methodology in the ITT population. Multiple Imputation procedure was to be used to handle missing data at any time point. The 1-grade improvement on both CEA and PSA was analyzed using the same methodology. Secondary efficacy endpoint was the 30-minute effect, defined as 1-grade improvement from baseline on both CEA and PSA at 30 minutes on day 1. This variable was analyzed by Cochran-Mantel-Haenszel test stratified by analysis center, using general association statistics. The 1-grade and 2-grade improvements on CEA were also analyzed