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Efficacy and tolerability of timolol maleate ophthalmic gel-forming solution versus timolol ophthalmic solution in adults with open-angle glaucoma or ocular hypertension: a six-month, double-masked, multicenter study
CLINICAL
THERAPEUTICSVVOL.
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Efficacy and Tolerability of Tim0101 Maleate Ophthalmic Gel-Forming Solution Versus Timolol Ophthalmic Solution in Adults with Open-Angle Glaucoma or Ocular Hypertension: A Six-Month, Double-Masked, Multicenter Study Arthur Shedden, MD, Jean Laurence, BS, and Robert Tipping, MS, for the Timoptic-XE@ 0.5% Study Group* Department of Ophthalmic Pennsylvania
Clinical Research, Merck Research Laboratories,
West Point,
ABSTRACT Background: Timolol has been formulated in a highly purified gellan gum to improve its duration of action. The efficacy of this formulation in short-term studies using oncedaily dosing has been reported. Objective: The purpose of this study was to evaluate the efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution (timolol GS) given once daily versus 0.5% timolol solution given twice daily in a long-term trial. Methods: This was a multicenter, double-masked, 6-month trial. After a washout of ocular hypotensive medication, 286 patients with open-angle glaucoma or ocular hypertension were randomly assigned in a 2: 1 ratio to receive 0.5% timolol GS in both eyes once daily or 0.5% timolol solution in both eyes twice daily. All patients received a morning (9 AM) and evening (9 PM) dose. For patients in the timolol GS group, the evening dose consisted of a vehicle only, whereas for patients in the timolol solution group, both doses consisted of active drug. Intraocular pressure (IOP) was measured at trough (before morning instillation) and peak (2 hours after instillation) at follow-up examinations at weeks 2, 4, 8, 12, and 24. Adverse events were monitored using patient reports. Results: Of the 286 patients randomized, 191 received timolol GS and 95 received timolol solution. Ninety-three percent of patients (265/286) completed the study. At the end of the treatment interval (week 24) the mean decrease in IOP at trough ranged from *Members of the Timoptic-XE@
0.5% Study Group are listed in the Acknowledgments.
Accepfed for publication Januafy 17, 2007. Printed in the USA. Reproduction in whole or part is not permitted.
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0149.2918/011$19.00
A. SHEDDEN
ET AL.
5.6 to 5.9 mm Hg in the timolol GS group and from 6.3 to 6.6 mm Hg in the timo101 solution group. Similar efficacy was observed, at 11 AM (peak). At week 24, the difference in mean IOP between treatments was -0.61 mm Hg (95% CI -1.44 to 0.22) at trough and -0.79 mm Hg (95% CI -1.77 to 0.20) at peak, indicating no significant difference between the 2 timolol formulations. The number of reports of blurred vision and tearing was significantly higher in the timolol GS group than in the timolol solution group (P = 0.04), whereas burning/stinging was reported more frequently in the timolol solution group than in the timolol GS group (P = 0.04). At week 12, the decrease in mean heart rate at trough (hour 0) was significantly less for patients in the timolol GS group than for those in the timolol solution group (-1.1 vs A.2 bpm; P = 0.024). At week 24 (hour 0), the decrease in mean heart rate was less for patients treated with timolol GS by 2.5 bpm (P = 0.051). The heart rate data at peak (hour 2) was similar to that observed at trough at week 12 (-2.7 vs -5.7 bpm; P = 0.006) and week 24 (-3.1 vs -4.7 bpm; P = 0.063). The mean change in blood pressure was not significantly different between treatments. There were no clinically significant differences between the groups in visual acuity, biomicroscopy and ophthalmoscopy results, or visual fields. Conclusions: TimololO.5% GS administered once daily was shown to be as effective in lowering IOP as the equivalent concentration of timololO.5% solution administered twice daily in patients with ocular hypertension or open-angle glaucoma. Key words: timolol, gellan gum, intraocular pressure, glaucoma. (Clin Thel: 2001;23:440-450)
INTRODUCTION Concerns about inadequate compliance’ and systemic side effects*-7 with ophthalmic solutions of beta-adrenoceptor antagonists for the treatment of glaucoma have led to the use of less frequent dosing schedules and active-drug concentrations <0.5%.st3 Standard ophthalmic solutions instilled in the conjunctival sac are cleared from the eye via dilution with tears and removal through the nasolacrimal duct into the nose and nasopharynx. Therefore, attempts have been made to improve the cornea1 contact time of ophthalmic solutions to increase the bioavailability of topical medications. Gels, ointments, and solid erodible and nonerodible inserts have been used to prolong drug contact time with the surface of the eye, thereby increasing penetration across the cornea. This may decrease the amount of drug required (ie, lower concentration or less frequent dosing) to achieve the same magnitude of effect. However, inserts and ointments are more difficult to administer.t4,15 In a continuation of these efforts, timo101 maleate has been formulated in 0.6% Gelrite@ (Merck & Co, Inc, West Point, Pennsylvania), a highly purified gellan gum that is an anionic heteropolysaccharide. The formulation is known as timolol maleate sterile ophthalmic gel-forming solution* (timolol GS). This formulation is a colorless, transparent solution that, on contact with monovalent and divalent cations in the precomeal tear film, forms a gel. 1&l7 In preclinical comparisons in albino and pigmented rabbits, timolol GS enhanced anterior segment bioavailability 4fold compared with the standard marketed *Trademark: Whitehouse
Timoptic-XE@ (Merck Station, New Jersey).
& Co, Inc,
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CLINICAL THERAPEUTICS@
timolol solution* or a hydroxyethylcellulose formulation.i8,i9 The ocular hypotensive efficacy and potency of timolol GS was evaluated in a l-drop, unilateral, doublemasked, crossover, placebo-controlled study in patients with ocular hypertension?O The treatments were 0.008% and 0.1% timolol GS, 0.008% and 0.1% timo101aqueous solution, and appropriate placebos. At each concentration, at several time points after instillation, timolol GS decreased intraocular pressure (IOP) 1 to 2 mm Hg more than did the timolol aqueous solution.20 In another study2t using oncedaily instillation for both medications and a l-week dosing period, 0.5% timolol GS produced a greater reduction in IOP from baseline compared with 0.5% timolol solution. The difference was statistically significant 2.5 hours after instillation.21 In the present study, we investigated the long-term (6 months) efficacy and tolerability of 0.5% timolol GS once daily versus 0.5% timolol solution twice daily using a randomized, double-masked study design.
PATIENTS AND METHODS Patients aged 21 to 90 years with ocular hypertension or open-angle glaucoma were considered for entry into this study. Those who were using ocular hypotensive therapy were required to undergo an unmedicated washout period-3 weeks for beta-adrenoceptor antagonists and 1 week for other ocular hypotensive medications. Exclusion criteria were contraindications to topical timolol (eg, asthma or significant bradycardia), dry eye syndrome, occludable iridocomeal angles, corrected visual acuity worse than 20/100 in either *Trademark: Timoptic@ (Merck & Co, Inc, Whitehouse Station, New Jersey).
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eye, intraocular or laser surgery within 2 months of study entry, or use of systemic medications that might affect IOP. Also excluded were premenopausal women who were not using a reliable method of contraception or those who were pregnant or breast-feeding. 22 Contact lens use was prohibited during the study. This study was approved by the governing institutional review board at each center, and all patients provided written informed consent. Up to 3 weeks before the start of the study, patients underwent a prestudy examination that included biomicroscopy, dilated ophthalmoscopy, a visual field examination, and measurement of IOP (using Goldmann applanation tonometry), visual acuity, heart rate, and blood pressure. At baseline, after appropriate washout of ocular hypotensive medication, IOP was measured at -9 AM. To continue in the study, patients were required to have an IOP of 922 mm Hg in at least 1 eye. Heart rate and blood pressure data were determined at the brachial artery using manual methods. The patient remained in the clinic, and measurements were repeated at 11 AM. Patients were randomly assigned to receive 0.5% timolol GS once daily or 0.5% timolol solution twice daily. To increase the number of patients exposed to the newer formulation, the randomization schema was designed to be unequal (2: 1 in favor of timolol GS). In addition, randomization was stratified by iris color to ensure equal balance of light and dark irides among the treatment groups. To maintain the doublemasked nature of the trial, each patient received a morning dose (9 AM) and evening dose (9 PM). For patients in the timolol GS group, the evening dose consisted of a gel vehicle only, whereas for patients in the timolol solution group, both doses contained active drug.
A. SHEDDEN ET AL.
After completion of the 11 AM baseline visit, patients had their study medication dispensed and were instructed to begin instillation with that evening’s dose. They were scheduled to return at weeks 2, 4, 8, 12, and 24 for follow-up examinations that included IOP measurements at 9 AM (trough, or before morning instillation) and 11 AM (peak, or -2 hours after instillation). At weeks 12 and 24, dilated ophthalmoscopy and a visual field examination were also performed.
Statistical Analysis The statistical null hypothesis evaluated in this study was that after 24 weeks of treatment, timolol GS once daily is not equivalent to timolol solution twice daily with regard to ocular hypotensive efficacy. The treatment groups were compared using a parametric 95% CI for the difference between the means. A 95% CI that contains 0 and has a width ~3 mm Hg was chosen a priori as the criterion for rejecting the null hypothesis in favor of the conclusion that timolol GS once daily is as effective in lowering IOP as timolol solution twice daily. The planned sample size (200 patients taking timolol GS, 100 patients taking timolol solution) provided >95% probability of meeting this criterion, assuming that the effect of both treatments was indeed equal (SD = 4.5 mm Hg). The primary analysis (intent-to-treat) included all patients who received treatment and had 21 posttreatment IOP evaluation. A secondary analysis excluded patients who had serious protocol violations. For all efficacy and safety profile analyses, a P value ~0.05 (2tailed) was set as the limit of statistical significance, and calculations were per-
formed using SAS@ version 6.04 (SAS Institute, Inc, Cary, North Carolina).
RESULTS A total of 286 patients (191 timolol GS, 95 timolol solution; age range, 28-88 years) were enrolled in the study (Table I). Approximately 75% (212/286) of the patients were white, and -69% (197/286) had a diagnosis of open-angle glaucoma. About 34% (98/286) of patients had systemic hypertension; 14% (41/286) had diabetes and 12% (35/286) had arthritis. Before entering the study, 43% (123/286) had been using timolol maleate solution and 28% (81/286) had been using another topical beta-blocker. There were no significant differences between groups in any prestudy characteristics. Ninety-three percent of patients (2651 286) completed the 24-week study. Three patients, all in the timolol GS group (31191, 2%), discontinued due to inadequately controlled IOP, and 7 patients (5 in the timo101GS group and 2 in the timolol solution group) discontinued for administrative reasons. Eleven patients (8 [4%] in the timo101 GS group and 3 [3%] in the timolol solution group) experienced adverse events that required cessation of treatment. In the timolol GS group, the following conditions were each reported in 1 patient: conjunctivitis, keratoconjunctivitis sicca, cornea1 erosion, dyspnea, “heart fluttering,” “flushed feeling,” otitis, and hepatic neoplasm. In the timolol solution group, 1 patient had dyspnea and paresthesia, another had a collection of symptoms (asthenia, syncope, bradycardia, and confusion), and 1 had pharyngeal cancer. With the exception of the 2 patients with cancer and 1 with a cornea1 erosion (lost to follow-up), all patients recovered.
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Ocular Hypotensive
Efjkacy
Mean IOP and mean change from baseline at weeks 2, 4, 8, 12, and 24 at trough and peak are shown in Table II and Figures 1 and 2. At 9 AM (trough), mean IOP at baseline was similar in both groups: 26.6 mm Hg in the timolol GS group and 26.7 mm Hg in the timolol solution group. The mean decrease at trough ranged from 5.6 to 5.9 mm Hg in the timolol GS group and 6.3 to 6.6 mm Hg in the timolol solution group. The difference between treatment effects was
Table I. Baseline demographic
icant differences between groups. Sex-bytreatment, race-by-treatment, and iris-bytreatment interaction terms were not significant at any time point (P > 0.10).
Adverse Events Emergent and worsening ocular symptoms are reported in Table III. The number of reports of blurred vision was significantly higher in the timolol GS group (29% [56/191]) than in the timolol solution group (18% [ 17/95]; P = 0.04) as was the incidence of tearing (7% [13/191] in the timolol GS group vs 1% [l/95] in the timolol solution group; P = 0.04). Burning/ stinging was reported at a significantly higher rate in the timolol solution group than in the timolol GS group (22% [21/95] vs 12% [23/191]; P = 0.04). There were no statistically significant differences be-
and clinical characteristics Timolol GS
of patients.*
(n = 191)
Timolol Solution (n = 95)
Total (n = 286)
107 (56) 84 (44)
54 (57) 41 (43)
161 (56) 125 (44)
139 (73) 50 (26) 2 (1)
73 (77) 22 (23) 0 (0)
212 (74) 72 (25) 2 (
61.8 -c 12.4 28-88
61.1 + 12.9 29-84
61.6 + 12.6 28-88
Sex, no. (%)
Female Male Race, no. (%) White Black Other Age, Y Mean + SD Range Iris color, no. (%) Blue Dark brown Hazel Brown Green GS = gel-forming solution. *There were no significant differences
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62 48 38 35 8
(32) (25) (20) (18) (4)
between treatment
33 22 15 17 8
(35) (23) (16) (18) (8)
groups (P > 0.05).
95 (33) 70 (24) 53 (19) 52 (18) 16 (6)
A. SHEDDEN ET AL.
Table II. Mean + SD intraocular pressure (IOP) and mean + SD changes in IOP from timeadjusted baseline, in mm Hg.* Timolol Solution (n = 95)
Timolol GS (n = 191) Mean + SD Trough Baseline Week 2 Week 4 Week 8 Week 12 Week 24
Mean 2 SD Change
Mean f SD
Mean * SD Change
Treatment Difference? (95% CI)
26.6 20.9 20.7 20.6 20.8 20.9
+ f + + + +
3.3 3.5 3.5 3.5 3.6 3.5
-5.6 -5.8 -5.9 -5.7 -5.6
rt f -I f +
3.5 3.5 3.6 3.4 3.4
26.8 20.2 20.4 20.3 20.2 20.4
f f f + f ?
3.8 3.6 2.9 3.3 3.3 3.2
-6.5 -6.4 -6.5 -6.6 -6.3
+ f f f +
4.2 3.7 4.1 4.1 3.8
a.83 -0.41 a.47 -0.73 a.6 I
(-1.75 (-1.24 (-1.33 (-1.57 (-1.44
to to to to to
0.10) 0.42) 0.40) 0.12) 0.22)
25.6 19.5 19.6 19.2 19.5 19.5
+ + + f f +
4.0 3.1 3.3 3.3 3.2 3.1
-6.1 -6.0 -6.4 -6.1 -6.0
+ + + f f
4.0 3.9 3.6 4.1 3.9
26.5 19.3 19.5 19.6 19.5 19.6
+ * * 2 f +
4.5 3.5 3.0 3.3 3.5 3.3
-7.2 4.9 -6.8 -7.0 -6.9
f + + f f
4.6 4.4 4.1 4. I 4.4
-0.92 a.83 -0.35 -0.80 a.79
(-1.98 (-1.82 (-1.24 (-1.79 (-1.77
to to to to to
0.13) 0.16) 0.53) 0.18) 0.20)
Peak Baseline Week 2 Week 4 Week 8 Week 12 Week 24
*Mean changes from baseline and differences in mean changes from baseline have been rounded to the nearest 0.1 mm Hg. +Difference between treatments in mean change from baseline.
tween the 2 treatment groups in the incidence of ocular signs.
Heart Rate and Blood Pressure At week 12, the decrease in mean heart rate at trough (hour 0) was significantly less for patients in the timolol GS group than for those in the timolol solution group (-1.1 vs 4.2 bpm; P = 0.024) (Table IV). At week 24 (hour 0), the decrease in mean heart rate was less for patients treated with timolol GS but this difference was not significant (-1.1 vs -3.6 bpm; P = 0.051). The decrease in mean heart rate at peak (hour 2) was significantly less for patients in the timolol GS group than for those in the timolol solution group at week 12 (-2.7
vs -5.7 bpm; P = 0.006) but not at week 24 (-3.1 vs a.7 bpm; P = 0.063). The mean change in blood pressure in both groups ranged from -4.1 mm Hg to 0.8 mm Hg and was not significantly different between treatments (P> 0.05). No statistically significant differences between treatment groups in visual acuity, biomicroscopy, ophthalmoscopy, or visual fields were observed.
DISCUSSION In this double-masked, randomized trial, we found that timolol 0.5% GS administered once daily was as effective in lowering IOP as the equivalent concentration of timolol 0.5% solution administered
445
CLINICAL THERAPEUTICS@
35 -
u
Timolol gel-forming solution (n = 191)
-0
Timolol solution (n = 95)
30 - -
8 I 5
25-
B ----__
_-
20 15 ‘I 0
---
I 2
--____
I 4
I 6
I 0
____________-----
I
I 10
I 12
I 14
I 16
0
Y
I 18
I 20
1 22
I 24
Week
Figure 1. Mean + SD intraocular pressure (IOP) at trough (9 AM, 12 to 24 hours after the last active dose).
+
Timolol gel-forming solution (n = 191)
-u
15 ‘I 0
I 2
I 4
I 6
I 8
I 10
I 12
- Timolol solution (n = 95)
I 14
I 16
1 18
, 20
1 22
I 24
Week
Figure 2. Mean + SD intraocular active dose).
446
pressure
(IOP) at peak (11 AM, 2 hours after the last
A. SHEDDEN ET AL.
twice daily. The ocular hypotensive efficacy of timolol solution is maximal 2 hours after instillation and lasts for 12 hours.23 In this study, observations were made at 9 AM, 12 hours after the last dose of timolol solution and 24 hours after the last dose of timolol GS, corresponding to the trough of the time-response curve of both treatments. Similarly, our observations at 11 AM, 2 hours after instillation, correspond to the peak of the time-response curve. At all visits (weeks 2, 4, 8, 12, and 24), at both peak and trough, the difference between the ocular hypotensive effect of timolol GS and timolol solution was cl.0 mm Hg and the 95% CIs included zero, indicating equal efficacy in lowering IOP The results suggest that a sample size of 286 patients almost achieves the power to detect differences in IOPlowering efficacy of
Symptom Total Blurred vision Burning Itching Tearing Foreign body sensation Crusting Grittiness Photophobia Dryness
relevant differences between timolol GS and timolol solution. A significantly greater number of patients treated with timolol GS reported blurred vision (29% vs 18% for timolol solution; P = 0.04) and tearing (7% vs 1% for timolol solution; P = 0.04), whereas significantly
multiple-dose study.2’ Other ophthalmic gel are associated with higher incidences of blurred vision than that associated with timolol GS. For example, blurring associated with containing hydroxyethylcel-
formulation, there is the potential for increased or decreased systemic absorption. In a separate study,25 6 healthy male subjects were randomized to receive either timolol GS 0.5% once daily or timolol maleate ophthalmic
ocular symptoms
with an incidence
Timolol GS (n = 191)
Timolol Solution (n = 95)
100 (52) 56 (29) 23 (12) 17 (9) 13 (7) 12 (6) 7 (4) 7 (4) 7 (4)
43 (45) 17 (18) 21 (22) 6 (6) 1 (1) 4 (4) 0 (0) 0 (0)
5 (3)
GS = gel-forming solution. *Reported as the number (%) of patients experiencing
I(1) l(1)
of s3%.* P
(Fisher exact test) 0.32 0.04 0.04 0.50 0.04 0.59 0.10 0.10 0.28 0.67
the symptom.
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CLINICAL THERAPEUTICS@
Table IV. Heart rate changes (bpm) from baseline.* Baseline (mean + SD)
Treatment (mean + SD)
Mean Change
Difference (P)
Hour 0 (trough) Week 12 Timolol GS Timolol solution Week 24 Timolol GS
72.7 + 9.6 74.6 k 8.7
71.6 f 10.7 70.4 + 8.8
-1.1 4.2
3.1 (0.024)
72.7 + 9.6
71.6 + 9.2
Timolol solution
74.6 + 8.7
71.1 * 8.3
-1.1 -3.6
2.5 (0.05 1)
Timolol GS Timolol solution Week 24
71.8 f 9.9 73.6 f 8.0
69.1 + 10.1 67.9 f 8.0
-2.7 -5.7
3.0 (0.006)
Timolol GS Timolol solution
71.8 f 9.9 73.6 * 8.0
68.7 + 9.5 68.9 + 7.9
-3.1 -4.7
1.6 (0.063)
Hour 2 (peak) Week 12
*Data are included for all patients treated, with last observation
solution 0.5% twice daily in both eyes for 8 days. For all subjects exposed to timo101GS, peak plasma concentrations of timo101 averaged ~0.3 ng/mL within 4 hours after the last dose. For all subjects exposed to timolol solution, peak plasma concentrations of timolol averaged -0.5 ng/mL and 0.3 ng/mL within 4 hours after the first and second dose, respectively, on day 8. In the present study, there was no evidence for increased systemic betaadrenergic receptor blockade with timolol GS compared with timolol solution. Indeed, treatment with timolol GS had less of an effect on heart rate in this study than did the timolol solution, both at peak and trough. Data from this study are also consistent with a previous study conducted in Scandinavia and Finland,26 which demonstrated that timolol GS has less effect than timolol solution on heart rate at trough.
448
carried forward.
However, both timolol GS and timolol solution are contraindicated in patients with asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, and second- and third-degree atrioventricular block.
CONCLUSIONS TimololO.5% GS administered once daily was shown to be as effective in lowering IOP as the equivalent concentration of timolol 0.5% solution administered twice daily in patients with ocular hypertension or open-angle glaucoma.
ACKNOWLEDGMENTS The authors acknowledge the writing assistance of Gary D. Novack, PhD; Myles Jaffe, PhD; and Sheila Logan-Wyner, MS.
A. SHEDDEN ET AL.
The members of the Timoptic-XE@ 0.5% Study Group are Mark B. Abelson, MD, Andover, Massachusetts; Robert C. Allen, MD, Charlottesville, Virginia; Reay H. Brown, MD, Emory University Clinic, Atlanta, Georgia; Leonard R. Capcioppo, MD, Brooksville, Florida; Marvin Greenberg, MD, Tamarac, Florida; Kevin C. Greenidge, MD, New York Eye & Ear Infirmary, New York, New York; Barrett G. Haik, MD, Tulane School of Medicine, New Orleans, Louisiana; David W. Karp, MD, Louisville, Kentucky; Melvyn M. Koby, MD, Louisville, Kentucky; Jean Laurence, BS, Merck Research Laboratories, West Point, Pennsylvania; Norman S. Levy, MD, Gainesville, Florida; Robert Rice, MD, Richmond, Virginia; Arthur Shedden, MD, Merck Research Laboratories, West Point, Pennsylvania; C. Eric Shrader, MD, Wichita, Kansas; Robert Tipping, MS, Merck Research Laboratories, West Point, Pennsylvania; Angela Vela-Thomas, MD, Atlanta, Georgia; Mark J. Weiss, MD, Tulsa, Oklahoma; H. Tom Youens, MD, Houston, Texas; and Thorn J. Zimmerman, MD, PhD, University of Kentucky, Louisville, Kentucky.
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Address correspondence to: Myles Jaffe, PhD, US Medical and Scientific Affairs, Merck & Co, Inc, UGl A-3.5, North Wales, PA 19454-1099. E-mail: [email protected]
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23, NO. 3,200l
Efficacy and Tolerability of Tim0101 Maleate Ophthalmic Gel-Forming Solution Versus Timolol Ophthalmic Solution in Adults with Open-Angle Glaucoma or Ocular Hypertension: A Six-Month, Double-Masked, Multicenter Study Arthur Shedden, MD, Jean Laurence, BS, and Robert Tipping, MS, for the Timoptic-XE@ 0.5% Study Group* Department of Ophthalmic Pennsylvania
Clinical Research, Merck Research Laboratories,
West Point,
ABSTRACT Background: Timolol has been formulated in a highly purified gellan gum to improve its duration of action. The efficacy of this formulation in short-term studies using oncedaily dosing has been reported. Objective: The purpose of this study was to evaluate the efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution (timolol GS) given once daily versus 0.5% timolol solution given twice daily in a long-term trial. Methods: This was a multicenter, double-masked, 6-month trial. After a washout of ocular hypotensive medication, 286 patients with open-angle glaucoma or ocular hypertension were randomly assigned in a 2: 1 ratio to receive 0.5% timolol GS in both eyes once daily or 0.5% timolol solution in both eyes twice daily. All patients received a morning (9 AM) and evening (9 PM) dose. For patients in the timolol GS group, the evening dose consisted of a vehicle only, whereas for patients in the timolol solution group, both doses consisted of active drug. Intraocular pressure (IOP) was measured at trough (before morning instillation) and peak (2 hours after instillation) at follow-up examinations at weeks 2, 4, 8, 12, and 24. Adverse events were monitored using patient reports. Results: Of the 286 patients randomized, 191 received timolol GS and 95 received timolol solution. Ninety-three percent of patients (265/286) completed the study. At the end of the treatment interval (week 24) the mean decrease in IOP at trough ranged from *Members of the Timoptic-XE@
0.5% Study Group are listed in the Acknowledgments.
Accepfed for publication Januafy 17, 2007. Printed in the USA. Reproduction in whole or part is not permitted.
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0149.2918/011$19.00
A. SHEDDEN
ET AL.
5.6 to 5.9 mm Hg in the timolol GS group and from 6.3 to 6.6 mm Hg in the timo101 solution group. Similar efficacy was observed, at 11 AM (peak). At week 24, the difference in mean IOP between treatments was -0.61 mm Hg (95% CI -1.44 to 0.22) at trough and -0.79 mm Hg (95% CI -1.77 to 0.20) at peak, indicating no significant difference between the 2 timolol formulations. The number of reports of blurred vision and tearing was significantly higher in the timolol GS group than in the timolol solution group (P = 0.04), whereas burning/stinging was reported more frequently in the timolol solution group than in the timolol GS group (P = 0.04). At week 12, the decrease in mean heart rate at trough (hour 0) was significantly less for patients in the timolol GS group than for those in the timolol solution group (-1.1 vs A.2 bpm; P = 0.024). At week 24 (hour 0), the decrease in mean heart rate was less for patients treated with timolol GS by 2.5 bpm (P = 0.051). The heart rate data at peak (hour 2) was similar to that observed at trough at week 12 (-2.7 vs -5.7 bpm; P = 0.006) and week 24 (-3.1 vs -4.7 bpm; P = 0.063). The mean change in blood pressure was not significantly different between treatments. There were no clinically significant differences between the groups in visual acuity, biomicroscopy and ophthalmoscopy results, or visual fields. Conclusions: TimololO.5% GS administered once daily was shown to be as effective in lowering IOP as the equivalent concentration of timololO.5% solution administered twice daily in patients with ocular hypertension or open-angle glaucoma. Key words: timolol, gellan gum, intraocular pressure, glaucoma. (Clin Thel: 2001;23:440-450)
INTRODUCTION Concerns about inadequate compliance’ and systemic side effects*-7 with ophthalmic solutions of beta-adrenoceptor antagonists for the treatment of glaucoma have led to the use of less frequent dosing schedules and active-drug concentrations <0.5%.st3 Standard ophthalmic solutions instilled in the conjunctival sac are cleared from the eye via dilution with tears and removal through the nasolacrimal duct into the nose and nasopharynx. Therefore, attempts have been made to improve the cornea1 contact time of ophthalmic solutions to increase the bioavailability of topical medications. Gels, ointments, and solid erodible and nonerodible inserts have been used to prolong drug contact time with the surface of the eye, thereby increasing penetration across the cornea. This may decrease the amount of drug required (ie, lower concentration or less frequent dosing) to achieve the same magnitude of effect. However, inserts and ointments are more difficult to administer.t4,15 In a continuation of these efforts, timo101 maleate has been formulated in 0.6% Gelrite@ (Merck & Co, Inc, West Point, Pennsylvania), a highly purified gellan gum that is an anionic heteropolysaccharide. The formulation is known as timolol maleate sterile ophthalmic gel-forming solution* (timolol GS). This formulation is a colorless, transparent solution that, on contact with monovalent and divalent cations in the precomeal tear film, forms a gel. 1&l7 In preclinical comparisons in albino and pigmented rabbits, timolol GS enhanced anterior segment bioavailability 4fold compared with the standard marketed *Trademark: Whitehouse
Timoptic-XE@ (Merck Station, New Jersey).
& Co, Inc,
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CLINICAL THERAPEUTICS@
timolol solution* or a hydroxyethylcellulose formulation.i8,i9 The ocular hypotensive efficacy and potency of timolol GS was evaluated in a l-drop, unilateral, doublemasked, crossover, placebo-controlled study in patients with ocular hypertension?O The treatments were 0.008% and 0.1% timolol GS, 0.008% and 0.1% timo101aqueous solution, and appropriate placebos. At each concentration, at several time points after instillation, timolol GS decreased intraocular pressure (IOP) 1 to 2 mm Hg more than did the timolol aqueous solution.20 In another study2t using oncedaily instillation for both medications and a l-week dosing period, 0.5% timolol GS produced a greater reduction in IOP from baseline compared with 0.5% timolol solution. The difference was statistically significant 2.5 hours after instillation.21 In the present study, we investigated the long-term (6 months) efficacy and tolerability of 0.5% timolol GS once daily versus 0.5% timolol solution twice daily using a randomized, double-masked study design.
PATIENTS AND METHODS Patients aged 21 to 90 years with ocular hypertension or open-angle glaucoma were considered for entry into this study. Those who were using ocular hypotensive therapy were required to undergo an unmedicated washout period-3 weeks for beta-adrenoceptor antagonists and 1 week for other ocular hypotensive medications. Exclusion criteria were contraindications to topical timolol (eg, asthma or significant bradycardia), dry eye syndrome, occludable iridocomeal angles, corrected visual acuity worse than 20/100 in either *Trademark: Timoptic@ (Merck & Co, Inc, Whitehouse Station, New Jersey).
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eye, intraocular or laser surgery within 2 months of study entry, or use of systemic medications that might affect IOP. Also excluded were premenopausal women who were not using a reliable method of contraception or those who were pregnant or breast-feeding. 22 Contact lens use was prohibited during the study. This study was approved by the governing institutional review board at each center, and all patients provided written informed consent. Up to 3 weeks before the start of the study, patients underwent a prestudy examination that included biomicroscopy, dilated ophthalmoscopy, a visual field examination, and measurement of IOP (using Goldmann applanation tonometry), visual acuity, heart rate, and blood pressure. At baseline, after appropriate washout of ocular hypotensive medication, IOP was measured at -9 AM. To continue in the study, patients were required to have an IOP of 922 mm Hg in at least 1 eye. Heart rate and blood pressure data were determined at the brachial artery using manual methods. The patient remained in the clinic, and measurements were repeated at 11 AM. Patients were randomly assigned to receive 0.5% timolol GS once daily or 0.5% timolol solution twice daily. To increase the number of patients exposed to the newer formulation, the randomization schema was designed to be unequal (2: 1 in favor of timolol GS). In addition, randomization was stratified by iris color to ensure equal balance of light and dark irides among the treatment groups. To maintain the doublemasked nature of the trial, each patient received a morning dose (9 AM) and evening dose (9 PM). For patients in the timolol GS group, the evening dose consisted of a gel vehicle only, whereas for patients in the timolol solution group, both doses contained active drug.
A. SHEDDEN ET AL.
After completion of the 11 AM baseline visit, patients had their study medication dispensed and were instructed to begin instillation with that evening’s dose. They were scheduled to return at weeks 2, 4, 8, 12, and 24 for follow-up examinations that included IOP measurements at 9 AM (trough, or before morning instillation) and 11 AM (peak, or -2 hours after instillation). At weeks 12 and 24, dilated ophthalmoscopy and a visual field examination were also performed.
Statistical Analysis The statistical null hypothesis evaluated in this study was that after 24 weeks of treatment, timolol GS once daily is not equivalent to timolol solution twice daily with regard to ocular hypotensive efficacy. The treatment groups were compared using a parametric 95% CI for the difference between the means. A 95% CI that contains 0 and has a width ~3 mm Hg was chosen a priori as the criterion for rejecting the null hypothesis in favor of the conclusion that timolol GS once daily is as effective in lowering IOP as timolol solution twice daily. The planned sample size (200 patients taking timolol GS, 100 patients taking timolol solution) provided >95% probability of meeting this criterion, assuming that the effect of both treatments was indeed equal (SD = 4.5 mm Hg). The primary analysis (intent-to-treat) included all patients who received treatment and had 21 posttreatment IOP evaluation. A secondary analysis excluded patients who had serious protocol violations. For all efficacy and safety profile analyses, a P value ~0.05 (2tailed) was set as the limit of statistical significance, and calculations were per-
formed using SAS@ version 6.04 (SAS Institute, Inc, Cary, North Carolina).
RESULTS A total of 286 patients (191 timolol GS, 95 timolol solution; age range, 28-88 years) were enrolled in the study (Table I). Approximately 75% (212/286) of the patients were white, and -69% (197/286) had a diagnosis of open-angle glaucoma. About 34% (98/286) of patients had systemic hypertension; 14% (41/286) had diabetes and 12% (35/286) had arthritis. Before entering the study, 43% (123/286) had been using timolol maleate solution and 28% (81/286) had been using another topical beta-blocker. There were no significant differences between groups in any prestudy characteristics. Ninety-three percent of patients (2651 286) completed the 24-week study. Three patients, all in the timolol GS group (31191, 2%), discontinued due to inadequately controlled IOP, and 7 patients (5 in the timo101GS group and 2 in the timolol solution group) discontinued for administrative reasons. Eleven patients (8 [4%] in the timo101 GS group and 3 [3%] in the timolol solution group) experienced adverse events that required cessation of treatment. In the timolol GS group, the following conditions were each reported in 1 patient: conjunctivitis, keratoconjunctivitis sicca, cornea1 erosion, dyspnea, “heart fluttering,” “flushed feeling,” otitis, and hepatic neoplasm. In the timolol solution group, 1 patient had dyspnea and paresthesia, another had a collection of symptoms (asthenia, syncope, bradycardia, and confusion), and 1 had pharyngeal cancer. With the exception of the 2 patients with cancer and 1 with a cornea1 erosion (lost to follow-up), all patients recovered.
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CLINICAL THERAPEUTIC6
Ocular Hypotensive
Efjkacy
Mean IOP and mean change from baseline at weeks 2, 4, 8, 12, and 24 at trough and peak are shown in Table II and Figures 1 and 2. At 9 AM (trough), mean IOP at baseline was similar in both groups: 26.6 mm Hg in the timolol GS group and 26.7 mm Hg in the timolol solution group. The mean decrease at trough ranged from 5.6 to 5.9 mm Hg in the timolol GS group and 6.3 to 6.6 mm Hg in the timolol solution group. The difference between treatment effects was
Table I. Baseline demographic
icant differences between groups. Sex-bytreatment, race-by-treatment, and iris-bytreatment interaction terms were not significant at any time point (P > 0.10).
Adverse Events Emergent and worsening ocular symptoms are reported in Table III. The number of reports of blurred vision was significantly higher in the timolol GS group (29% [56/191]) than in the timolol solution group (18% [ 17/95]; P = 0.04) as was the incidence of tearing (7% [13/191] in the timolol GS group vs 1% [l/95] in the timolol solution group; P = 0.04). Burning/ stinging was reported at a significantly higher rate in the timolol solution group than in the timolol GS group (22% [21/95] vs 12% [23/191]; P = 0.04). There were no statistically significant differences be-
and clinical characteristics Timolol GS
of patients.*
(n = 191)
Timolol Solution (n = 95)
Total (n = 286)
107 (56) 84 (44)
54 (57) 41 (43)
161 (56) 125 (44)
139 (73) 50 (26) 2 (1)
73 (77) 22 (23) 0 (0)
212 (74) 72 (25) 2 (
61.8 -c 12.4 28-88
61.1 + 12.9 29-84
61.6 + 12.6 28-88
Sex, no. (%)
Female Male Race, no. (%) White Black Other Age, Y Mean + SD Range Iris color, no. (%) Blue Dark brown Hazel Brown Green GS = gel-forming solution. *There were no significant differences
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62 48 38 35 8
(32) (25) (20) (18) (4)
between treatment
33 22 15 17 8
(35) (23) (16) (18) (8)
groups (P > 0.05).
95 (33) 70 (24) 53 (19) 52 (18) 16 (6)
A. SHEDDEN ET AL.
Table II. Mean + SD intraocular pressure (IOP) and mean + SD changes in IOP from timeadjusted baseline, in mm Hg.* Timolol Solution (n = 95)
Timolol GS (n = 191) Mean + SD Trough Baseline Week 2 Week 4 Week 8 Week 12 Week 24
Mean 2 SD Change
Mean f SD
Mean * SD Change
Treatment Difference? (95% CI)
26.6 20.9 20.7 20.6 20.8 20.9
+ f + + + +
3.3 3.5 3.5 3.5 3.6 3.5
-5.6 -5.8 -5.9 -5.7 -5.6
rt f -I f +
3.5 3.5 3.6 3.4 3.4
26.8 20.2 20.4 20.3 20.2 20.4
f f f + f ?
3.8 3.6 2.9 3.3 3.3 3.2
-6.5 -6.4 -6.5 -6.6 -6.3
+ f f f +
4.2 3.7 4.1 4.1 3.8
a.83 -0.41 a.47 -0.73 a.6 I
(-1.75 (-1.24 (-1.33 (-1.57 (-1.44
to to to to to
0.10) 0.42) 0.40) 0.12) 0.22)
25.6 19.5 19.6 19.2 19.5 19.5
+ + + f f +
4.0 3.1 3.3 3.3 3.2 3.1
-6.1 -6.0 -6.4 -6.1 -6.0
+ + + f f
4.0 3.9 3.6 4.1 3.9
26.5 19.3 19.5 19.6 19.5 19.6
+ * * 2 f +
4.5 3.5 3.0 3.3 3.5 3.3
-7.2 4.9 -6.8 -7.0 -6.9
f + + f f
4.6 4.4 4.1 4. I 4.4
-0.92 a.83 -0.35 -0.80 a.79
(-1.98 (-1.82 (-1.24 (-1.79 (-1.77
to to to to to
0.13) 0.16) 0.53) 0.18) 0.20)
Peak Baseline Week 2 Week 4 Week 8 Week 12 Week 24
*Mean changes from baseline and differences in mean changes from baseline have been rounded to the nearest 0.1 mm Hg. +Difference between treatments in mean change from baseline.
tween the 2 treatment groups in the incidence of ocular signs.
Heart Rate and Blood Pressure At week 12, the decrease in mean heart rate at trough (hour 0) was significantly less for patients in the timolol GS group than for those in the timolol solution group (-1.1 vs 4.2 bpm; P = 0.024) (Table IV). At week 24 (hour 0), the decrease in mean heart rate was less for patients treated with timolol GS but this difference was not significant (-1.1 vs -3.6 bpm; P = 0.051). The decrease in mean heart rate at peak (hour 2) was significantly less for patients in the timolol GS group than for those in the timolol solution group at week 12 (-2.7
vs -5.7 bpm; P = 0.006) but not at week 24 (-3.1 vs a.7 bpm; P = 0.063). The mean change in blood pressure in both groups ranged from -4.1 mm Hg to 0.8 mm Hg and was not significantly different between treatments (P> 0.05). No statistically significant differences between treatment groups in visual acuity, biomicroscopy, ophthalmoscopy, or visual fields were observed.
DISCUSSION In this double-masked, randomized trial, we found that timolol 0.5% GS administered once daily was as effective in lowering IOP as the equivalent concentration of timolol 0.5% solution administered
445
CLINICAL THERAPEUTICS@
35 -
u
Timolol gel-forming solution (n = 191)
-0
Timolol solution (n = 95)
30 - -
8 I 5
25-
B ----__
_-
20 15 ‘I 0
---
I 2
--____
I 4
I 6
I 0
____________-----
I
I 10
I 12
I 14
I 16
0
Y
I 18
I 20
1 22
I 24
Week
Figure 1. Mean + SD intraocular pressure (IOP) at trough (9 AM, 12 to 24 hours after the last active dose).
+
Timolol gel-forming solution (n = 191)
-u
15 ‘I 0
I 2
I 4
I 6
I 8
I 10
I 12
- Timolol solution (n = 95)
I 14
I 16
1 18
, 20
1 22
I 24
Week
Figure 2. Mean + SD intraocular active dose).
446
pressure
(IOP) at peak (11 AM, 2 hours after the last
A. SHEDDEN ET AL.
twice daily. The ocular hypotensive efficacy of timolol solution is maximal 2 hours after instillation and lasts for 12 hours.23 In this study, observations were made at 9 AM, 12 hours after the last dose of timolol solution and 24 hours after the last dose of timolol GS, corresponding to the trough of the time-response curve of both treatments. Similarly, our observations at 11 AM, 2 hours after instillation, correspond to the peak of the time-response curve. At all visits (weeks 2, 4, 8, 12, and 24), at both peak and trough, the difference between the ocular hypotensive effect of timolol GS and timolol solution was cl.0 mm Hg and the 95% CIs included zero, indicating equal efficacy in lowering IOP The results suggest that a sample size of 286 patients almost achieves the power to detect differences in IOPlowering efficacy of
Symptom Total Blurred vision Burning Itching Tearing Foreign body sensation Crusting Grittiness Photophobia Dryness
relevant differences between timolol GS and timolol solution. A significantly greater number of patients treated with timolol GS reported blurred vision (29% vs 18% for timolol solution; P = 0.04) and tearing (7% vs 1% for timolol solution; P = 0.04), whereas significantly
multiple-dose study.2’ Other ophthalmic gel are associated with higher incidences of blurred vision than that associated with timolol GS. For example, blurring associated with containing hydroxyethylcel-
formulation, there is the potential for increased or decreased systemic absorption. In a separate study,25 6 healthy male subjects were randomized to receive either timolol GS 0.5% once daily or timolol maleate ophthalmic
ocular symptoms
with an incidence
Timolol GS (n = 191)
Timolol Solution (n = 95)
100 (52) 56 (29) 23 (12) 17 (9) 13 (7) 12 (6) 7 (4) 7 (4) 7 (4)
43 (45) 17 (18) 21 (22) 6 (6) 1 (1) 4 (4) 0 (0) 0 (0)
5 (3)
GS = gel-forming solution. *Reported as the number (%) of patients experiencing
I(1) l(1)
of s3%.* P
(Fisher exact test) 0.32 0.04 0.04 0.50 0.04 0.59 0.10 0.10 0.28 0.67
the symptom.
447
CLINICAL THERAPEUTICS@
Table IV. Heart rate changes (bpm) from baseline.* Baseline (mean + SD)
Treatment (mean + SD)
Mean Change
Difference (P)
Hour 0 (trough) Week 12 Timolol GS Timolol solution Week 24 Timolol GS
72.7 + 9.6 74.6 k 8.7
71.6 f 10.7 70.4 + 8.8
-1.1 4.2
3.1 (0.024)
72.7 + 9.6
71.6 + 9.2
Timolol solution
74.6 + 8.7
71.1 * 8.3
-1.1 -3.6
2.5 (0.05 1)
Timolol GS Timolol solution Week 24
71.8 f 9.9 73.6 f 8.0
69.1 + 10.1 67.9 f 8.0
-2.7 -5.7
3.0 (0.006)
Timolol GS Timolol solution
71.8 f 9.9 73.6 * 8.0
68.7 + 9.5 68.9 + 7.9
-3.1 -4.7
1.6 (0.063)
Hour 2 (peak) Week 12
*Data are included for all patients treated, with last observation
solution 0.5% twice daily in both eyes for 8 days. For all subjects exposed to timo101GS, peak plasma concentrations of timo101 averaged ~0.3 ng/mL within 4 hours after the last dose. For all subjects exposed to timolol solution, peak plasma concentrations of timolol averaged -0.5 ng/mL and 0.3 ng/mL within 4 hours after the first and second dose, respectively, on day 8. In the present study, there was no evidence for increased systemic betaadrenergic receptor blockade with timolol GS compared with timolol solution. Indeed, treatment with timolol GS had less of an effect on heart rate in this study than did the timolol solution, both at peak and trough. Data from this study are also consistent with a previous study conducted in Scandinavia and Finland,26 which demonstrated that timolol GS has less effect than timolol solution on heart rate at trough.
448
carried forward.
However, both timolol GS and timolol solution are contraindicated in patients with asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, and second- and third-degree atrioventricular block.
CONCLUSIONS TimololO.5% GS administered once daily was shown to be as effective in lowering IOP as the equivalent concentration of timolol 0.5% solution administered twice daily in patients with ocular hypertension or open-angle glaucoma.
ACKNOWLEDGMENTS The authors acknowledge the writing assistance of Gary D. Novack, PhD; Myles Jaffe, PhD; and Sheila Logan-Wyner, MS.
A. SHEDDEN ET AL.
The members of the Timoptic-XE@ 0.5% Study Group are Mark B. Abelson, MD, Andover, Massachusetts; Robert C. Allen, MD, Charlottesville, Virginia; Reay H. Brown, MD, Emory University Clinic, Atlanta, Georgia; Leonard R. Capcioppo, MD, Brooksville, Florida; Marvin Greenberg, MD, Tamarac, Florida; Kevin C. Greenidge, MD, New York Eye & Ear Infirmary, New York, New York; Barrett G. Haik, MD, Tulane School of Medicine, New Orleans, Louisiana; David W. Karp, MD, Louisville, Kentucky; Melvyn M. Koby, MD, Louisville, Kentucky; Jean Laurence, BS, Merck Research Laboratories, West Point, Pennsylvania; Norman S. Levy, MD, Gainesville, Florida; Robert Rice, MD, Richmond, Virginia; Arthur Shedden, MD, Merck Research Laboratories, West Point, Pennsylvania; C. Eric Shrader, MD, Wichita, Kansas; Robert Tipping, MS, Merck Research Laboratories, West Point, Pennsylvania; Angela Vela-Thomas, MD, Atlanta, Georgia; Mark J. Weiss, MD, Tulsa, Oklahoma; H. Tom Youens, MD, Houston, Texas; and Thorn J. Zimmerman, MD, PhD, University of Kentucky, Louisville, Kentucky.
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Address correspondence to: Myles Jaffe, PhD, US Medical and Scientific Affairs, Merck & Co, Inc, UGl A-3.5, North Wales, PA 19454-1099. E-mail: [email protected]
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