No aggravations in the severity of telangiectasia, IGA or in- flammatory lesion counts were observed during either the
treatment or follow-up phase of either study.
Safety
The once-daily BT gel 0.5% was safe and well tolerated during 4
weeks of continuous application as demonstrated in both studies.
The incidence of AEs in the active treatment and vehicle
groups was 29.5% vs 25.2% in study A, and 33.8% vs 24.1%
in study B. In study A, the incidence of related AE was 11.6%
for the group of BT gel 0.5% and 5.3% for the group of vehicle
gel; while in study B, the incidence was similarly low for both
groups (9.5% and 9.7%). In both studies, the majority of related
AEs were cutaneous in nature, transient in duration, and mild
in intensity. The most frequent related AEs included worsening
of erythema and/or flushing (7 subjects in each study), pruritus
(4 and 1 subject in studies A and B, respectively), skin irritation
(3 subjects in study A), and worsening of rosacea (1 and 2
subjects, respectively). No serious related AEs occurred in any
study subjects. During the two studies, no abnormal changes in
blood pressure or heart rate were observed.
DISCUSSION
The results of these two pivotal studies of identical design confirm
the efficacy and safety of once-daily topical BT gel 0.5%
for the treatment of erythema of rosacea. The primary endpoint
was the 2-grade improvement on both CEA and PSA, which
is a very stringent criterion to evaluate the effectiveness of a
treatment. Efficacy was also evaluated based on the 1-grade
improvement on both CEA and PSA, which represents an effect
that is noticeable to both clinicians and patients, and thus
clinically relevant. In both studies, BT gel 0.5% provided significantly
greater efficacy compared with the vehicle gel in terms
of 2-grade and 1-grade improvement on both CEA and PSA,
with a good profile of safety and tolerability. Maximal drug
effects were typically observed 3 hours after application and
continued to about 6 hours after application, when about 70%
of subjects had an improvement based on the assessment by
the clinicians and the patients themselves.
Fast onset of action of the topical BT gel 0.5% was first observed
in the Phase II studies and confirmed in the present
two pivotal studies. Thirty minutes after the first application
on day 1, significantly greater effect was observed with BT
gel 0.5% compared with vehicle gel, with about 28% of subjects
having an improvement on both CEA and PSA. A single
application of BT gel 0.5% also resulted in a long duration
of effect, with more than 50% of subjects reporting 1-grade
improvement on both CEA and PSA 12 hours after the application.
The fast onset and long duration allow the condition
of erythema to be managed with a once-daily regimen, which
is considerably more convenient for patients compared to a
twice-daily regimen.
Tachyphylaxis (loss of previous noted effect) and rebound
(worsening of condition as compared to baseline) were
reported to be associated with nasal spray treatments containing
some but not all α-adrenergic receptor agonists.25 During a
1-year study on the treatment of glaucoma and ocular hypertension,
twice-daily usage of BT ophthalmic solution did not
lead to tachyphylaxis or rebound.26, 27 In the previous Phase IIb
study and the present two pivotal studies, where topical BT gel
was used once-daily for 4 weeks, no evidence of tachyphylaxis
was observed, as the efficacy remained similarly high at the
beginning and the end of the treatment phase in each study.24
Similarly, during the 4-week follow-up phase in all three studies,
no rebound or worsening of erythema was observed. In
the Phase IIb study, similarly low incidence of rebound was
reported between the active treatment and the vehicle groups;
24 In the present Phase III studies, the mean score of erythema
before treatment was same during the follow-up phase and
during the treatment phase, with only isolated cases of worsening
observed. Moreover, no aggravation of other disease
signs or symptoms was observed during any studies. Nevertheless,
the safety of topical BT gel 0.5% should be further
evaluated in a longer-term study.
In summary, there is currently no approved medication for the
effective treatment of the facial erythema of rosacea. Results
from these two Phase III pivotal studies demonstrate that oncedaily
BT gel 0.5% provides significantly greater efficacy and a
faster onset of action compared to the vehicle gel for the treatment
of the facial erythema of rosacea, without evidence of
tachyphylaxis, rebound, or aggravation of the other common
clinical signs of rosacea.
ACKNOWLEDGMENTS
The authors would like to thank other study investigators: William
Abramovits, MD, Dallas, TX; Kirk Barber, MD, Calgary, AB;
Leslie Baumann, MD, Miami Beach, FL; Robert Bissonnette,
MD, Montreal, QC; Fran Cook-Bolden, MD, New York, NY; Zoe
Draelos, MD, High Point, NC; Kimberly Grande, MD, Knoxville,
TN; Steven Grekin, DO, Warren, MI; Wayne Gulliver, MD, St.
John’s, NL; Robert Haber, MD, South Euclid, OH; Michael Heffernan,
MD, St. Louis, MO; Ian Landells, MD, St. John’s, NL;
Mark Ling, MD, Newnan, GA; Charles Lynde, MD., Markham,
ON; Robert Matheson, MD, Portland, OR; David Nieves, MD, East
