Transcript A Prospective, Multi-center, Randomized Controlled Study of Loteprednol Initiation Therapy Followed by

A Prospective, Multi-center, Randomized
Controlled Study of Loteprednol
Initiation Therapy Followed by
Cyclosporine Maintenance for Dry Eye
John D. Sheppard, MD,1 Eric D. Donnenfeld, MD,2 Edward J. Holland, MD,
Charles B. Slonim, MD, Renée Solomon, MD, Kerry D. Solomon, MD,
Marguerite B. McDonald, MD, Henry D. Perry, MD, Stephen S. Lane, MD, and
Stephen C. Pflugfelder, MD.
1Virginia
Eye Consultants, Norfolk, VA, 23502, and 2Ophthalmic Consultants of Long island, Rockville
Center, NY, 11570
Financial Disclosures
• This study was supported by an unrestricted research grant from
Bausch & Lomb, Inc.
Abstract
Purpose: To evaluate the impact of loteprednol 0.5% as initiation
therapy, followed by topical cyclosporine (tCSA) maintenance therapy
in patients with dry eye disease (DED).
Methods: 121 patients with DED were enrolled in a multicenter,
randomized, controlled, masked, prospective clinical trial. Patients
received either initial loteprednol 0.5% or artificial tears for 2 weeks
prior to starting maintenance tCSA therapy.
Results: The loteprednol initiation group showed improved OSDI
scores (p<0.01) at Day 14, decreased cyclosporine stinging at Day 30
(p<0.04), and improved corneal staining at Day 30 (p<0.05) compared
to the placebo initiation group.
Conclusion: Loteprednol initiation followed by tCSA maintenance
improves patient compliance, reduces stinging and provides more rapid
relief of dry eye disease than tCSA therapy alone.
Introduction
•
Dry eye disease (DED) is an ocular surface disease that produces discomfort
and irritation.
•
Cyclosporine ophthalmic emulsion 0.05% (Restasis®) is indicated to increase
tear production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with keratoconjunctivitis
sicca. However, the relief of dry eye signs and symptoms with cyclosporine
therapy is often delayed by 1 to 6 months from the initiation of therapy, and
17% of patients experience burning and stinging leading to poor patient
compliance.1
•
Marsh & Pflugfelder2 showed that corticosteroid therapy in patients with
DED improved signs and symptoms, improved tear clearance, and
normalized mucus production, often having a sustained benefit after a 2
week pulse. In addition, corticosteroid treatment improved tear production by
controlling inflammation and decreased the irritation associated with the use
of cyclosporine by 75%.2,3
•
Loteprednol etabonate ophthalmic suspension 0.5% (Lotemax®) is indicated
for the treatment of steroid responsive inflammatory conditions associated
with the palpebral and bulbar conjunctiva, cornea, and anterior segment of
the globe.
Purpose
•
The purpose of this study was to evaluate the impact of loteprednol 0.5% as
initiation therapy in patients with DED.
Methods
•
A total of 121 patients with DED were enrolled in this multicenter,
randomized, controlled, masked, prospective clinical trial.
•
Patients received either initial loteprednol 0.5% or artificial tears for two
weeks (Day 1 to14) prior to starting maintenance tCSA therapy (Day 15 to
60). Additional use of artificial tears was allowed as needed.
•
Patients were evaluated by the Ocular Surface Disease Index (OSDI) for
symptoms and underwent full ophthalmic examination including BCVA,
biomicroscopy with fluorescein and lissamine green staining, applanation
IOP and Schirmer’s test without anesthesia on days 14, 30 and 60.
Results
•
•
Both treatments decreased central corneal staining over 60 days
(P<0.005).
Loteprednol etabonate/tCSA was more effective than artificial
tears/tCSA in reducing central corneal staining (P=0.003).
Table 1
Mean (± SEM) Central Fluorescein Corneal Staining
Baseline
14 Day
30 Day
60 Day
Loteprednol
0.30±0.05
0.21±0.04
0.25±0.04
0.0±0.0*†
Artificial
Tears
0.28±0.04
0.23±0.04
0.14±0.04
0.10±0.03*
Data compared with ANOVA after outliers were removed, with OS and OD pooled
* Significant change from baseline, P<0.005
† Significant difference between groups, P=0.003
Results (cont.)
•
Although both treatments decreased lissamine green staining grade,
loteprednol etabonate with tCSA was more effective in all cases (P<0.05).
Table 2
Mean (±SEM) Lissamine Green Staining
Baseline
14 Day
30 Day
60 Day
Loteprednol
1.4 ± 0.1
1.0 ± 0.1
1.2 ± 0.1
0.9 ± 0.1*
Artificial tears
1.1 ± 0.1
1.0 ± 0.1
1.0 ± 0.1
1.0 ± 0.1
Loteprednol
1.4 ± 0.1
1.0 ± 0.1
1.1 ± 0.1
0.9 ± 0.1*
Artificial tears
1.3 ± 0.1
1.0 ± 0.1
1.3 ± 0.1
0.9 ± 0.1
Loteprednol
1.0 ± 0.1
0.8 ± 0.1
0.7 ± 0.1
0.6 ± 0.1*
Artificial tears
0.8 ± 0.1
0.7 ± 0.1
0.6 ± 0.1
0.5 ± 0.1
Loteprednol
1.1 ± 0.1
0.9 ± 0.1
0.9 ± 0.1
0.7 ± 0.1*
Artificial tears
0.9 ± 0.1
0.8 ± 0.1
0.8 ± 0.1
0.5 ± 0.1
Nasal OD
Nasal OS
Temporal OD
Temporal OS
Staining grade (0=no staining to 3=severe)
* Significant change from baseline (P<0.05)
Data compared with ANOVA
Results (cont.)
•
At baseline, tear production in both groups was similar (P=0.48).
Both treatments increased tear production from baseline (P=0.01 for
loteprednol etabonate with tCSA, P=0.05 for artificial tears with tCSA ).
When normalized to baseline, loteprednol etabonate with tCSA increased
tear production by 27% vs. 17% with artificial tears with tCSA over a 60 day
period (P<0.005).
Figure 2
Schirmer Test
12
*
10
*
Lotemax
Loteprednol
Artificial Tears
8
mm
•
•
6
4
2
0
Baseline
60 Days
* Significantly
greater
than
baseline,p<0.05
p<0.05
*Significant
change
from
baseline,
Data compared with ANOVA after outliers were removed. Data is pooled (OD and OS)
Results (cont.)
•
•
Both treatments decreased the frequency of adjunct tear use in patients.
After long term treatment (60 days), loteprednol etabonate/tCSA treatment
reduced the overall tear use in patients.
Table 3
Frequency of Adjunctive Artificial Tear Use
Frequency
Baseline
14 Day
30 Day
60 Day
Loteprednol
3/60 (5%)
3/60 (5%)
2/60 (3%)
0/60
Artificial tears
2/57 (4%)
1/57 (2%)
0/57
0/57
Loteprednol
21/60 (35%)
10/60 (17%)
8/60 (13%)
6/60 (10%)
Artificial tears
16/57 (28%)
9/57 (16%)
9/57 (16%)
8/57 (14%)
Loteprednol
26/60 (43%)
28/60 (47%)
21/60 (35%)
21/60 (35%)
Artificial tears
29/57 (51%)
27/57 (47%)
31/57 (54%)
21/57 (37%)
Loteprednol
10/60 (17%)
19/60 (32%)
29/60 (48%)
30/60 (50%)
Artificial tears
10/57 (18%)
20/57 (35%)
17/57 (30%)
27/57 (47%)
>6/Day
3-6/Day
1-2/Day
None
Results (cont.)
Baseline OSDI scores were not different between treatment groups.
Both treatments reduced OSDI scores over a period of 60 days (P<0.05).
Loteprednol etabonate with tCSA reduced OSDI scores significantly more
than artificial tears with tCSA (P<0.001).
Figure 3
Ocular Surface Disease Index (OSDI)
OSDI Score
•
•
•
40
35
30
25
20
15
10
5
0
Lotemax
Loteprednol
Artificial Tears
*†
*†
*†
Baseline
14
Days
Data compared with ANOVA after outliers were removed.
30
60
* Significantly reduced than baseline, p<0.05
† Significantly reduced than treatment B, p<0.05
Results (cont.)
With long term treatment (60 days), loteprednol etabonate/tCSA did not
affect IOP (P=0.22).
Figure 4
Intraocular Pressure
(pooled OD and OS)
Lotemax
Loteprednol
16
IOP mmHg
•
Artificial Tears
15
*†
*†
14
13
Baseline
14 Day
30 Day
60 Day
* *Significant
change
fromfrom
baseline,
p<0.006
Significantly
reduced
baseline,
p<0.006
†
Significant
difference
between
groups,
p<0.024
Significantly reduced, p<0.024
Data compared with ANOVA after outliers were removed. Data is pooled (OD and OS)
Data presented is the mean ± SEM
Conclusion
•
Loteprednol initiation followed by tCSA maintenance improves
patient compliance, reduces stinging and provides more rapid
relief of dry eye disease than tCSA therapy alone.
References:
•
Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies
of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to
severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology
2000;107:631-639.
•
Marsh P, Pflugfelder SC. Topical non-preserved methylprednisolone therapy for
keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology 1999;106:939-943.
•
Sheppard JD. Topical loteprednol pre-treatment reduces cyclosporine stinging.
ASCRS Presentation 39384, Washington DC, 2005.