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Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric glaucoma: A randomized clinical trial
Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol gel-forming solution 0.25% and 0.5% in pediatric glaucoma: A randomized clinical trial David A. Plager, MD,a Jess T. Whitson, MD,b Peter A. Netland, MD, PhD,c Lingam Vijaya, MD,d Parthasarathy Sathyan, MD,e Devindra Sood, MBBS,f S. R. Krishnadas, MD,g Alan L. Robin, MD,h,i Robert D. Gross, MD,b,j Sally A. Scheib, MS,j Haydn Scott, PhD,j Jaime E. Dickerson, PhD,j and the BETOPTICÒ S Pediatric Study Group* PURPOSE
To describe the safety profile and clinical response on elevated intraocular pressure (IOP) of betaxolol hydrochloride ophthalmic suspension 0.25% (betaxolol) and timolol maleate ophthalmic gel-forming solution (TGFS) (0.25% and 0.5%), in subjects under 6 years of age.
METHODS
Subjects were randomized to betaxolol 0.25% (twice daily) or TGFS (daily) (0.25% or 0.5%) in this double-masked study. IOPs were obtained at the same time of day (9 AM) at 2 baseline visits and weeks 2, 6, and 12. Mean change from baseline in IOP was the primary efficacy parameter. One hundred five subjects were randomized (34 to betaxolol, 35 to TGFS 0.25%, 36 to TGFS 0.5%). Betaxolol, TGFS 0.25%, and TGFS 0.5% produced statistically significant mean reductions in IOP; mean reductions after 12 weeks of treatment were 2.3, 2.9, and 3.7 mm Hg, respectively. In subjects who were not being treated with topical IOP-lowering medication at baseline, mean IOP reductions after 12 weeks of treatment were 3.1, 4.8, and 3.8 mm Hg, respectively. In patients discontinuing 1 or more topical IOP-lowering medications at baseline, mean IOP reductions at Week 12 were 1.8, 1.8, and 3.7 mm Hg, respectively. Responder rates ($15% reduction from baseline) for betaxolol, TGFS 0.25%, and TGFS 0.5% were 38.2, 45.7, and 47.2%, respectively. Adverse events were predominantly nonserious and did not interrupt patient continuation in the study.
RESULTS
CONCLUSIONS
Betaxolol ophthalmic suspension 0.25%, TGFS 0.25%, and TGFS 0.5% were well tolerated. Despite low responder rates, all 3 treatments produced statistically significant mean reductions in IOP in pediatric glaucoma subjects. ( J AAPOS 2009;13:384-390)
Introduction Author affiliations: aIndiana University School of Medicine, Indianapolis, IN; bUniversity of Texas Southwestern Medical Center, Dallas, TX; cHamilton Eye Institute, Memphis, TN; d Medical Research Foundation, Sankara Nethralaya, Chennai, India; eAravind Eye Hospital, Coimbatore, India; fGlaucoma Imaging Centre, New Delhi, India; gAravind Eye Hospital, Madurai, India; hWilmer Institute, Johns Hopkins University, Baltimore, MD; i University of Maryland, Baltimore, MD; jAlcon Research, Ltd., Fort Worth, TX * A complete list of study group participants is available as e-Supplement 1 at jaapos.org. This project was sponsored and financially supported by Alcon Research, Ltd., Fort Worth, TX. Presented in part at the 2007 Annual Meeting of the American Academy of Ophthalmology New Orleans, Louisiana, November 10-13. D. Plager, consultant (Alcon); J. Whitson, consultant (Alcon), speaker’s bureau (Alcon, Allergan, Merck, Pfizer); A. Robin, consultant (Alcon), equity owner (Alcon); Drs. Dickerson, Gross, and Scott and Ms. Scheib are employees and equity owners of Alcon Research, Ltd. Drs. Netland, Sathyan, Sood, Krishnadas, and Vijaya are not affiliated with Alcon. Submitted January 16, 2009. Revision accepted April 24, 2009. Reprint requests: Sally Scheib, MS, Alcon Research, Ltd., 6201 S. Freeway (TC-47), Fort Worth, TX 76134 (email: [email protected]). Copyright Ó 2009 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2009/$36.00 1 0 doi:10.1016/j.jaapos.2009.04.017
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laucoma in children is a relatively rare disease and is the result of a variety of distinct pathologies, congenital defects or anomalies, and various insults such as trauma or inflammation. Surgery is usually the first line of therapy for congenital glaucomas and for those glaucomas associated with ocular anomalies. Medical therapies are usually used to manage secondary glaucoma and as an adjunct to surgery.1 Medical therapies commonly used in children include prostaglandin analogues,2,3 miotics,1 carbonic anhydrase inhibitors,4-6 and beta-blockers.7-9 Of these drug classes, beta-blockers (ie, timolol) have been most frequently reported on, although published works were not, for the most part, randomized, masked clinical studies.7,8 Nevertheless, these studies indicate that timolol provided effective intraocular pressure (IOP) lowering in only a small portion (20%-31%) of the eyes treated with side effects occurring in approximately 10% of the subjects.7,8 Systemic
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Volume 13 Number 4 / August 2009 adverse effects occurring in 2% to 3% of the subjects included bradycardia, lightheadedness, asthmatic attack, and disassociated behavior. Ocular side effects reported included tearing (2%) and eye itching (4%).8 More recently, levobetaxolol, a selective beta-blocker, was evaluated in a randomized controlled study.9 The results of this study showed that levobetaxolol was well tolerated over the course of this study and provided clinically relevant IOP reduction (2.9 mm Hg at 12 weeks) in those subjects entering the study without a prior IOP-lowering medication. Controlled studies, such as this, provide useful safety and efficacy information to clinicians treating these subjects. The present study was designed to describe the safety profile and clinical response of betaxolol ophthalmic suspension 0.25% (marketed as BETOPTIC S 0.25% by Alcon Laboratories, Fort Worth, TX) and 2 concentrations of timolol gel-forming solution (TGFS 0.25% and 0.5%; Falcon Pharmaceuticals, Fort Worth, TX) in pediatric subjects with glaucoma or ocular hypertension.
Subjects and Methods This was a multicenter study conducted at 30 sites throughout the United States and India in accordance with the principles set forth in the Declaration of Helsinki. This was a double-masked, randomized, parallel group study. The study was registered on Clintrials.gov (NCT00061542). Each study site was approved by the appropriate Institutional Review Board or Institutional Ethics Committee. Prior to a child’s participation in the study, at least 1 parent or legal representative read, signed, and dated an Institutional Review Board/ Institutional Ethics Committee approved consent form. Additionally, this study was conducted in compliance with the Health Insurance Portability and Accountability Act at all of the U.S. study sites. Male and female subjects of any race who had not reached their sixth birthday at the time of the screening visit and who had a clinical diagnosis of glaucoma or ocular hypertension and required IOP-lowering in the opinion of the treating ophthalmologist were eligible. Subjects who had been under treatment with an ocular hypotensive medication(s) prior to the study and subjects who were not receiving ocular hypotensive treatment were eligible for enrollment. There was no washout of prior medications because it was felt that a washout period would expose subjects to an unacceptable risk. Because subjects with IOPs already controlled by an ocular hypotensive medication were eligible for enrollment, there was no minimum IOP requirement; however, subjects with IOPs exceeding 36 mm Hg were not eligible for enrollment. A substantial number of pediatric glaucoma subjects are aphakic and wear contact lenses; therefore, contact lens use was allowed during the study. All contact lens-wearing children were provided with new contact lenses at the time of enrollment and a second new set when they exited the study. Subjects were excluded from the study for any of the following reasons: 6 years of age or older at the time of screening; at or below the 5th percentile for body weight (applied to children \1 year of age only); intraocular surgery within the past 30 days in the study
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eye; clinically significant or progressive retinal disease in the study eye; ocular or systemic diseases precluding administration of a topical beta-blocker; any eye with a history of penetrating keratoplasty; any amount of congenital optic atrophy (as assessed by the investigator) in the study eye; fewer than 3 weeks stable dosing (prior to the screening visit) of current IOP-lowering medication(s); history of congenital cardiovascular anomalies or abnormalities that would preclude safe administration of a topical beta-blocker; any abnormality preventing reliable applanation tonometry; therapy with another investigational agent within 30 days of study start; use of any other topical or systemic ocular hypotensive medication during the study. Subject enrollment was divided into the 4 following age groups: 1 week to \1 year; 1 year to \2 years; 2 years to \4 years; and 4 years to \6 years. These age strata and the numbers enrolled in each are provided in Table 1. Subjects were randomized to treatment in a 1:1:1 ratio. Four distinct randomization series were generated for each investigator corresponding to the 4 age groups. The study was double-masked and all study medications were supplied in identical opaque dropper bottles identified by the subject randomization number. There were 2 scheduled prerandomization visits: the screening visit and the baseline visit, from 1 day to 14 days later. Subjects being treated with prestudy IOP-lowering medication(s) continued that medication(s) between the screening and baseline visits, receiving their final dose of prestudy medication(s) the day before the baseline visit. Subjects meeting inclusion and exclusion criteria at the screening and baseline visits were assigned a subject number; parents were given dosing instructions, and masked study drug was dispensed. Subjects were randomized in a 1:1:1 ratio to receive betaxolol 0.25% (twice daily, 8 AM and 8 PM) or TGFS 0.25% (daily, 8 AM) or TGFS 0.5% (daily, 8 AM). Subjects randomized to either of the TGFS groups were also dosed with vehicle (daily, 8 PM) for masking purposes. Regardless of whether subjects were randomized to betaxolol or 1 of the TGFS groups, all received a ‘‘morning’’ and an ‘‘evening’’ bottle of medication. Parents were instructed to instill a single drop in each study eye from the morning bottle at 8 AM (30 minutes) and dose 1 drop in each study eye from the evening bottle at 8 PM (30 minutes). Study subjects were scheduled for visits after 2, 6, and 12 weeks on study drug. Subjects exited the study at the week 12 visit. IOP was measured either with a Tono-Pen (Mentor O & O, Nowell, MA) handheld tonometer, or by Goldmann or Perkins applanation tonometry at all visits at approximately 9 AM before instilling the morning dose. Each eye was measured twice and the measurements were averaged. If the 2 measurements were different by more than 4 mm Hg, a third reading was taken and the 2 closest were averaged. Likewise, an additional Tono-Pen reading was taken in instances where a 5% confidence level was not obtained. The same tonometry method was used for any given subject throughout the study. If an examination under anesthesia was necessary to obtain IOPs, measurements were generally only obtained at the screening visit and at the exit visit. Additional examinations under anesthesia were performed at the discretion of the investigators. Visual acuity was measured at all visits using age-appropriate procedures. A single technique was used consistently for each
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Table 1. Subject demographics by treatment group Total Total Age 1 week to \1 year old 1 year to \2 years old 2 years to \4 years old 4 years to \6 years old Sex Male Female Race Asian Black or African American Caucasian Multi-racial Other Iris color Blue Brown Green Gray Hazel No irisy Diagnosis Primary congenital glaucoma Primary glaucoma associated with systemic or ocular abnormalities Glaucoma secondary to aphakia
Betaxolol 0.25%
TGFS 0.25%
TGFS 0.5%
N
%
N
%
N
%
N
%
p-value*
105
100.0
34
100.0
35
100.0
36
100.0
17 20 32 36
16.2 19.0 30.5 34.3
6 6 11 11
17.6 17.6 32.4 32.4
6 7 10 12
17.1 20.0 28.6 34.3
5 7 11 13
13.9 19.4 30.6 36.1
0.9989
61 44
58.1 41.9
17 17
50.0 50.0
26 9
74.3 25.7
18 18
50.0 50.0
0.0592
47 15 36 1 6
44.8 14.3 34.3 1.0 5.7
15 4 12 0 3
44.1 11.8 35.3 0.0 8.8
16 4 13 0 2
45.7 11.4 37.1 0.0 5.7
16 7 11 1 1
44.4 19.4 30.6 2.8 2.8
0.9075
14 77 1 2 8 3
13.3 73.3 1.0 1.9 7.6 2.9
5 25 0 1 3 0
14.7 73.5 0.0 2.9 8.8 0.0
6 25 1 1 1 1
17.1 71.4 2.9 2.9 2.9 2.9
3 27 0 0 4 2
8.3 75.0 0.0 0.0 11.1 5.6
0.6790
61 16
58.1 15.2
16 4
47.1 11.8
25 5
71.4 14.3
20 7
55.6 19.4
0.1241
28
26.7
14
41.1
5
14.3
9
25.0
2
*p-value from c or Fisher exact test. y Patients with aniridia. child. In addition to IOP and visual acuity, ocular signs (eyelids/ conjunctiva, cornea, iris/anterior chamber, lens), subject alertness, pulse, systolic and diastolic blood pressure, changes in concomitant medications, and adverse events were collected at all visits. Subject alertness was assessed using the Observer’s Assessment of Alertness Scale.10,11 A dilated fundus examination and measurement of corneal diameter were carried out prior to exposure to study drug and at the exit visit. The determination of the relationship of adverse events to study drug was made by the investigators.
Statistical Methods This study was designed to be in compliance with the terms of Food and Drug Administration Written Requests (for pediatric studies) for betaxolol hydrochloride and timolol maleate. Because of the low frequency of pediatric glaucoma, the study was descriptive and the sample size was not selected for statistical power considerations. The study was designed to collect, in a systematic way, adverse events that might be expected to occur with a frequency of approximately 3%, in addition to a description of the clinical response (IOP reduction) that could be expected when using these treatments. The primary efficacy parameter was an assessment of mean IOP change from baseline at 9 AM. Study visits were planned at weeks 2, 6, and 12. If only 1 of a subject’s eyes was dosed, the dosed eye was selected for analysis. If both eyes were dosed, the worse eye
was selected for analysis. The worse eye was defined as the eye with the higher IOP at 9 AM averaged across the screening and baseline visits. If both eyes were equal, then the right eye was selected for analysis. The primary analytic method consisted of describing the IOP data with means and 2-sided 95% confidence intervals. Repeated measures analysis of variance (ANOVA) was used to estimate the means and confidence intervals. Descriptive statistics were calculated for IOP, IOP change from baseline, and IOP percentage change from baseline. All subjects who received at least 1 dose of study medication were included in the safety data set. All subjects who received study medication, had at least 1 on-therapy visit, and met all inclusion/exclusion criteria were considered evaluable for the per-protocol data set. All subjects who received study medication and had at least 1 on-therapy visit were considered evaluable for intent-to-treat (ITT) analysis and included in the ITT data set. Evaluability for all subjects and visits was determined prior to breaking the code for masked treatment assignment. Results for the ITT and per-protocol analyses were similar; therefore, only the ITT results are presented here as it is the more inclusive data set. The statistical significance of response to treatment was assessed by comparing the baseline IOP with the week 12 IOP using t-tests for paired comparisons (1-tailed test used for those subjects on no prestudy therapy) with a significance level of 0.05. Clinical relevance of an IOP reduction was taken as a $2
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Table 2. Summary of study subject drop out Reason for discontinuing treatment Adverse event* Inadequate control of IOP Parent decisiony Noncompliance Total
Betaxolol 0.25%
TGFS 0.25%
TGFS 0.5%
1 2 1 1 5
0 5 1 1 7
0 3 0 0 3
*Unrelated to study drug. y Unrelated to adverse event. mm Hg IOP reduction from baseline. This is a commonly used measure of clinical relevance in controlled clinical studies.12 The statistical significance of differences in diagnostic category by treatment was assessed by using single-factor ANOVA. Subjects defined as responders were those that demonstrated a $15% reduction in IOP over the 12-week period. Note that ‘‘responder’’ refers to the response for an individual versus clinical relevance, which describes the overall mean reduction in IOP for the group.
Results One hundred seven subjects were enrolled in the study and received study medication. Of these, 2 (1 each in the betaxolol 0.25% and TGFS 0.25% treatment groups) were discontinued from the study prior to collection of any on-therapy study visit data; therefore, 105 subjects were evaluable for and included in the ITT analysis. Of the 107 enrolled, 15 subjects (5 on betaxolol, 7 on TGFS 0.25%, and 3 on TGFS 0.5%), including the 2 noted above, discontinued the study prematurely. The most common reason for subject discontinuation was inadequate control of IOP (2 in the betaxolol 0.25% group, 5 in the TGFS 0.25% group, and 3 in the TGFS 0.5% group). Discontinuation rates and reasons for discontinuation were similar between all treatment groups (Table 2). Demographic data for the study population are given in Table 1. The age distribution was 12 days to 5 years (mean age for betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% was 2.5, 2.5, and 2.6 years, respectively). Treatment groups were similar with no statistically significant differences in the distribution of subjects regarding age category, race, iris color, or glaucoma diagnosis. There was a statistical trend for gender comparison (p 5 0.0592). Whereas the ratio of males to females was 1:1 in both the betaxolol 0.25% and the TGFS 0.5% groups, it was approximately 3:1 in the TGFS 0.25% group. Changes from Baseline Betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% produced statistically significant and clinically relevant mean reductions in IOP in pediatric subjects after 12 weeks of therapy (Figure 1). For betaxolol 0.25%, mean IOP decrease from baseline was 2.3 mm Hg (p 5 0.008); for TGFS 0.25% the reduction was 2.9 mm Hg (p 5 0.012),
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Mean IOP change (mm Hg)
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2 1 0 -1 -2 -3 -4 -5 -6
Betaxolol
Baseline average
TGFS 0.25%
Week 2 visit
TGFS 0.5%
Week 6 visit
Week 12 visit
FIG 1. Mean IOP change from baseline (mm Hg) and 95% confidence intervals.
and for TGFS 0.5% the reduction was 3.7 mm Hg (p 5 0.002). Baseline mean IOP was similar for all treatment groups when considering all of the subjects. Baseline IOP was also similar for the treatment groups subdivided into those subjects without a prestudy therapy and those on a prior treatment (Table 3). Because the study allowed enrollment of subjects either on or not on an IOP-lowering medication at the time of randomization, we analyzed the change in IOP from baseline in these 2 subpopulations. Fifty-nine percent of the betaxolol 0.25% subjects, 63% of the TGFS 0.25% subjects, and 78% of the TGFS 0.5% subjects were being treated with 1 or more IOP-lowering medications at the study start (Tables 3 and 4). These subjects discontinued their prestudy therapy or therapies at the time of enrollment, crossing over to the masked, monotherapy study drug. All 3 treatments demonstrated a reduction in mean IOP. Mean IOP reductions from baseline at week 12 in this subgroup were 1.8 mm Hg (p 5 0.15) for subjects treated with betaxolol 0.25%, 1.8 mm Hg (p 5 0.14) for subjects treated with TGFS 0.25%, and 3.7 mm Hg (p 5 0.01) for subjects treated with TGFS 0.5%. Prestudy treatment included all available classes of IOP-lowering drugs, with beta-adrenergic blockers being most commonly employed (Table 4). The mean number of prestudy IOPlowering medications per subject (for subjects on therapy) was 1.5 for the betaxolol 0.25% treatment group, 1.3 for TGFS 0.25%, and 1.5 for TGFS 0.5% treatment group. For subjects not on an IOP-lowering medication at the time of randomization, betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% produced statistically significant and clinically relevant mean reductions in IOP; mean IOP reductions after 12 weeks of treatment were 3.1 (p 5 0.008), 4.8 (p 5 0.01), and 3.8 (p 5 0.04) mm Hg, respectively. When a 15% reduction from baseline IOP is used as a threshold to define responders to therapy, 38.2% of the betaxolol group, 45.7% of the TGFS 0.25% group, and 47.2% of the TGFS 0.5% group could be classified as responders. The percentage of responders was similar when the groups were subdivided into those on prior IOP-lowering therapy and those that were not. Mean IOP reductions for responders were 7.5, 7.6, and 8.9 mm Hg for betaxolol, TGFS 0.25%, and TGFS 0.5%, respectively (p \ 0.0001).
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Table 3. Baseline IOP (mmHg) comparison
All patients Betaxolol 0.25% TGFS 0.25% TGFS 0.5% Prior IOP-lowering therapy Betaxolol 0.25% TGFS 0.25% TGFS 0.5% No prior therapy Betaxolol 0.25% TGFS 0.25% TGFS 0.5%
Table 4. Prestudy IOP-lowering therapy Baseline average*
Treatment group
N
Mean SD
Betaxolol TGFS TGFS 0.25% 0.25% 0.5%
34 35 36
24.6 5.5 23.2 5.5 24.4 5.7
20 22 28
23.7 5.8 21.5 5.2 23.8 5.6
14 13 8
26.1 4.8 26.2 4.8 26.4 6.1
SD, standard deviation. *Baseline average 5 average of the screening and baseline.
IOP-lowering efficacy of the 3 treatments may be analyzed in terms of subject diagnosis. Subjects are grouped by diagnosis into the 3 general categories: primary congenital glaucoma, glaucoma associated with systemic or ocular abnormalities, and glaucoma secondary to aphakia. These data are presented in Figure 2. Although there were no significant differences in response to therapy between diagnostic subgroups, differences approached significance within the TGFS 0.5% treatment (p 5 0.051, single-factor ANOVA). Safety Evaluation The evaluation of safety was based on all subjects (N 5 107) who were enrolled into the study and received at least 1 dose of study medication. Adverse events in the overall safety population were predominately nonserious and generally mild to moderate in intensity. No subject experienced a serious adverse event that was related to study drug. Adverse events judged to be related to treatment are tabulated in Table 5. Of these, 7 were associated with cardiovascular parameters and not unexpected in patients exposed to beta-blockers. The cardiovascular changes were mild in nature and did not require treatment or require discontinuation of the subjects from the study. Of the 107 enrolled subjects, 15 discontinued the study early (Table 2). The most frequent reason for discontinuation was inadequate control of IOP (2 betaxolol 0.25%, 5 TGFS 0.25%, 3 TGFS 0.5%). Other reasons for discontinuation were parent decision unrelated to an adverse event (2) and noncompliance (2). One subject in the betaxolol 0.25% group discontinued the study due to a nonserious adverse event (photophobia) unrelated to study drug.
Discussion The use of medical therapy is common in treating children with elevated IOP. These therapies include beta-blockers, carbonic anhydrase inhibitors, and prostaglandin analogues. Despite the fact that physicians find these drugs
Monotherapy Beta-adrenergic antagonist Carbonic anhydrase inhibitor (CAI) Pilocarpine Prostaglandin analogue (PGA) Masked study medication Multiple medications Beta-adrenergic antagonist 1 CAI Beta-adrenergic antagonist 1 pilocarpine Beta-adrenergic antagonist 1 PGA PGA 1 CAI Beta-adrenergic antagonist 1 CAI 1 PGA Beta-adrenergic antagonist 1 CAI 1 alpha-adrenergic agonist Beta-adrenergic antagonist 1PGA 1 alpha-adrenergic agonist Total
11 0 0 1 1
14 0 1 0 0
13 2 1 1 0
0 4 1 0 1 0
2 1 2 2 0 0
4 3 1 0 2 1
1
0
0
20
22
28
7 6
Primary congenital Glaucoma secondary to aphakia Associated w/ systemic or ocular abnormalities
N = 20
N=5
IOP reduction (mm Hg)
388
N=4
5 4 3
N = 25 N = 16
2
N=5
N = 14
N=9
1 N=7
0 -1
p =
Betaxolol
TGFS 0.25%
TGFS 0.5%
0.551
0.632
0.051
FIG 2. Mean IOP reduction at week 12 (or early exit) by diagnosis; p-values calculated on the basis of single-factor analysis of variance (ANOVA).
useful, there has been limited safety and efficacy information available and pediatric use for many remains ‘‘offlabel.’’ There have been several studies of the treatment of pediatric glaucoma with timolol. In these, timolol was added as an adjunct to other pressure-reducing medications the children were already taking for their glaucoma.7,8,13,14 Boger and Walton13 demonstrated improvement in approximately 26.5% of the subjects and no clear benefit in 38% of the subjects when timolol was added to maximal medical therapy (which consisted of carbonic anhydrase inhibitors, cholinesterase inhibitors, epinephrine, and pilocarpine). Hoskins and colleagues7 retrospectively evaluated 67 subjects including subjects up to 18 years of age. In this group 31% were considered controlled after the addition of timolol. Few studies have evaluated the effect of timolol alone. Zimmerman and coworkers8 evaluated timolol monotherapy (N 5 11 subjects, 18 eyes) as part of a retrospective
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Table 5. Adverse events related to therapy (all patients)
Adverse event Ocular Hyperemia eye Discomfort eye Irritation eye Discharge eye Lid margin crusting Pruritus eye Sticky sensation Cardiovascular system Bradycardia Hypotension
Betaxolol 0.25% N 5 35
TGFS 0.25% N 5 36
N
%
N
%
N
%
2 2 1
5.7 5.7 2.9
1
2.8
2
5.6
1
2.8 2 1 1
5.6 2.8 2.8
1
2.8
1 1
2.9 2.9
study of timolol therapy in pediatric glaucoma (mean age, 7.2 years). Fifty percent of the eyes (N 5 9) were controlled with timolol alone. More recently, Whitson and colleagues9 published results on a cardioselective beta-blocker, levobetaxolol. Levobetaxolol (twice daily) was found to lower IOP in pediatric subjects. Subjects on prior therapy that were switched to levobetaxolol at the time of enrollment had a 1 to 3 mm Hg decrease in their IOP over all visits. Subjects entering the study without a prestudy therapy who were randomized to levobetaxolol demonstrated a 3 to 4 mm Hg drop in IOP over all visits. In the current study children with glaucoma were eligible whether or not they were already taking pressurereducing medication. Although the number of subjects entering the study without a prestudy therapy was small (33%), the effect of these drugs is readily apparent in this subgroup. Betaxolol 0.25% (N 5 14) lowered IOP 3.1 mm Hg; TGFS 0.25% (N 5 13) lowered IOP 4.8 mm Hg, and TGFS 0.5% (N 5 8) lowered IOP 3.8 mm Hg in these subjects. Results of all 3 treatments compare favorably with those seen in the adult studies (4.7, 5.0, and 4.8 mm Hg for betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5%, respectively).15-17 The majority of subjects enrolled (67%) were on a topical IOP-lowering medication(s) at study entry, most commonly beta-blockers resulting in lower baseline IOPs due to the absence of a washout phase, which would likely reduce the absolute response to study drug. Although many of the subjects entering the study were on more than 1 medication (average 1.4), evaluation of the exit IOPs demonstrated a reduction in mean IOP from baseline at trough (approximately 12 hours postdose for betaxolol and approximately 24 hours postdose for TGFS 0.25% and TGFS 0.5%) of 1.8, 1.8, and 3.7 mm Hg for betaxolol 0.25% (N 5 20), TGFS 0.25 (N 5 22), and TGFS 0.5% (N 5 28), respectively. An IOP reduction of 2 mm Hg is generally considered the smallest change of clinical relevance12; the mean reductions for the betaxolol and TGFS 0.25% groups approach but do not reach this threshold. However, maintenance of the prerandomization IOP by
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2 2
TGFS 0.5% N 5 36
5.6 5.6
these 2 treatments would imply that each was at least as efficacious as prior treatment, which in many instances was more than 1 medication. Different types of pediatric glaucoma may respond differently (or not at all) to different drug treatments.3,9 For example, levobetaxolol was found to be most efficacious in subjects with primary congenital glaucoma and least efficacious in secondary glaucomas (consisting primarily of aphakic glaucoma in that study).9 Brinzolamide was most effective in cases of glaucoma associated with systemic or ocular abnormalities (eg, Sturge-Weber) and slightly less effective in primary congenital or secondary glaucoma. In the current study all treatments showed efficacy in treating primary congenital glaucoma; this is consistent with the previous finding for levobetaxolol, also a beta-blocker.9 All 3 treatments showed less efficacy in glaucoma secondary to aphakia. There are a number of limitations to this study. These include the relatively small number of subjects when compared to adult studies, the short duration of treatment (12 weeks), and the variability in the study population. Subjects switched from prebaseline medications could have shown improvement due to Hawthorne effect or regression of IOP to the mean. Despite these limitations, it is clear from the data that betaxolol 0.25% (twice daily), TGFS 0.25% (daily), and TGFS 0.5% (daily) provided IOP-lowering benefits to subjects with pediatric glaucomas. In addition to IOP-lowering efficacy demonstrated by betaxolol and timolol, these medications appeared to be equally safe and well tolerated in the young children in this study.
References 1. Kanner EM, Netland PA. Medical therapy of pediatric glaucoma. Contemp Ophthalmol 2008;7:1-8. 2. Altuna JC, Greenfield DS, Wand M, Liebmann JM, Taglia DP, Kaufman PL, et al. Latanoprost in glaucoma associated with SturgeWeber syndrome. J Glaucoma 1999;8:199-203. 3. Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Surv Ophthalmol 2002;47(Suppl):S129-32. 4. Donohue EK, Wilensky JT. Dorzolamide: A review. Semin Ophthalmol 1997;12:119-26.
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5. Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS 1998;2: 43-7. 6. Ott EZ, Mills MD, Arango S, Getson AJ, Assaid CA, Adamsons IA, et al. A randomized trial assessing dorzolamide in patients with glaucoma who are younger than 6 years. Arch Ophthalmol 2005;123: 1177-86. 7. Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol 1985;103:1163-5. 8. Zimmerman TJ, Kooner KS, Morgan KS. Safety and efficacy of timolol in pediatric glaucoma. Surv Ophthalmol 1983;28(Suppl): S262-4. 9. Whitson JT, Roarty JD, Vijaya L, Robin AL, Gross RD, Landry TA, et al. Efficacy of brinzolamide and levobetaxolol in pediatric glaucomas: A randomized clinical trial. J AAPOS 2008;12:239-46. 10. Avramov MN, White PF. Methods for monitoring the level of sedation. Crit Care Clinics 1995;11:803-26. 11. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the Observer’s Assess-
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12.
13. 14. 15.
16.
17.
ment of Alertness Scale: Study with intravenous midazolam. J Clin Psychopharm 1990;10:244-51. DuBiner H, Cooke D, Dirks M, Stewart WC, VanDenburgh AM, Felix C, et al. Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: A 30-day comparison with latanoprost. Surv Ophthalmol 2001;45(Suppl):S353-60. Boger WP, Walton DS. Timolol in uncontrolled childhood glaucomas. Ophthalmology 1981;88:253-8. McMahon CD, Hetherington J Jr, Hoskins HD Jr, Shaffer RN. Timolol and pediatric glaucomas. Ophthalmology 1981;88:249-52. Weinreb RN, Caldwell DR, Goode SM, Horwitz BL, Laibowitz R, Shrader CE, et al. A double-masked three-month comparison between 0.25% betaxolol suspension and 0.5% betaxolol ophthalmic solution. Am J Ophthalmol 1990;110:189-92. Schenker HI, Silver LH. Long-term intraocular pressure-lowering efficacy and safety of timolol maleate gel-forming solution 0.5% compared with Timoptic XE 0.5% in a 12-month study. Am J Ophthalmol 2000;130:145-50. Timolol GFS [package insert]. Fort Worth (TX): Alcon Laboratories, Inc; 2007.
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To describe the safety profile and clinical response on elevated intraocular pressure (IOP) of betaxolol hydrochloride ophthalmic suspension 0.25% (betaxolol) and timolol maleate ophthalmic gel-forming solution (TGFS) (0.25% and 0.5%), in subjects under 6 years of age.
METHODS
Subjects were randomized to betaxolol 0.25% (twice daily) or TGFS (daily) (0.25% or 0.5%) in this double-masked study. IOPs were obtained at the same time of day (9 AM) at 2 baseline visits and weeks 2, 6, and 12. Mean change from baseline in IOP was the primary efficacy parameter. One hundred five subjects were randomized (34 to betaxolol, 35 to TGFS 0.25%, 36 to TGFS 0.5%). Betaxolol, TGFS 0.25%, and TGFS 0.5% produced statistically significant mean reductions in IOP; mean reductions after 12 weeks of treatment were 2.3, 2.9, and 3.7 mm Hg, respectively. In subjects who were not being treated with topical IOP-lowering medication at baseline, mean IOP reductions after 12 weeks of treatment were 3.1, 4.8, and 3.8 mm Hg, respectively. In patients discontinuing 1 or more topical IOP-lowering medications at baseline, mean IOP reductions at Week 12 were 1.8, 1.8, and 3.7 mm Hg, respectively. Responder rates ($15% reduction from baseline) for betaxolol, TGFS 0.25%, and TGFS 0.5% were 38.2, 45.7, and 47.2%, respectively. Adverse events were predominantly nonserious and did not interrupt patient continuation in the study.
RESULTS
CONCLUSIONS
Betaxolol ophthalmic suspension 0.25%, TGFS 0.25%, and TGFS 0.5% were well tolerated. Despite low responder rates, all 3 treatments produced statistically significant mean reductions in IOP in pediatric glaucoma subjects. ( J AAPOS 2009;13:384-390)
Introduction Author affiliations: aIndiana University School of Medicine, Indianapolis, IN; bUniversity of Texas Southwestern Medical Center, Dallas, TX; cHamilton Eye Institute, Memphis, TN; d Medical Research Foundation, Sankara Nethralaya, Chennai, India; eAravind Eye Hospital, Coimbatore, India; fGlaucoma Imaging Centre, New Delhi, India; gAravind Eye Hospital, Madurai, India; hWilmer Institute, Johns Hopkins University, Baltimore, MD; i University of Maryland, Baltimore, MD; jAlcon Research, Ltd., Fort Worth, TX * A complete list of study group participants is available as e-Supplement 1 at jaapos.org. This project was sponsored and financially supported by Alcon Research, Ltd., Fort Worth, TX. Presented in part at the 2007 Annual Meeting of the American Academy of Ophthalmology New Orleans, Louisiana, November 10-13. D. Plager, consultant (Alcon); J. Whitson, consultant (Alcon), speaker’s bureau (Alcon, Allergan, Merck, Pfizer); A. Robin, consultant (Alcon), equity owner (Alcon); Drs. Dickerson, Gross, and Scott and Ms. Scheib are employees and equity owners of Alcon Research, Ltd. Drs. Netland, Sathyan, Sood, Krishnadas, and Vijaya are not affiliated with Alcon. Submitted January 16, 2009. Revision accepted April 24, 2009. Reprint requests: Sally Scheib, MS, Alcon Research, Ltd., 6201 S. Freeway (TC-47), Fort Worth, TX 76134 (email: [email protected]). Copyright Ó 2009 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2009/$36.00 1 0 doi:10.1016/j.jaapos.2009.04.017
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laucoma in children is a relatively rare disease and is the result of a variety of distinct pathologies, congenital defects or anomalies, and various insults such as trauma or inflammation. Surgery is usually the first line of therapy for congenital glaucomas and for those glaucomas associated with ocular anomalies. Medical therapies are usually used to manage secondary glaucoma and as an adjunct to surgery.1 Medical therapies commonly used in children include prostaglandin analogues,2,3 miotics,1 carbonic anhydrase inhibitors,4-6 and beta-blockers.7-9 Of these drug classes, beta-blockers (ie, timolol) have been most frequently reported on, although published works were not, for the most part, randomized, masked clinical studies.7,8 Nevertheless, these studies indicate that timolol provided effective intraocular pressure (IOP) lowering in only a small portion (20%-31%) of the eyes treated with side effects occurring in approximately 10% of the subjects.7,8 Systemic
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Volume 13 Number 4 / August 2009 adverse effects occurring in 2% to 3% of the subjects included bradycardia, lightheadedness, asthmatic attack, and disassociated behavior. Ocular side effects reported included tearing (2%) and eye itching (4%).8 More recently, levobetaxolol, a selective beta-blocker, was evaluated in a randomized controlled study.9 The results of this study showed that levobetaxolol was well tolerated over the course of this study and provided clinically relevant IOP reduction (2.9 mm Hg at 12 weeks) in those subjects entering the study without a prior IOP-lowering medication. Controlled studies, such as this, provide useful safety and efficacy information to clinicians treating these subjects. The present study was designed to describe the safety profile and clinical response of betaxolol ophthalmic suspension 0.25% (marketed as BETOPTIC S 0.25% by Alcon Laboratories, Fort Worth, TX) and 2 concentrations of timolol gel-forming solution (TGFS 0.25% and 0.5%; Falcon Pharmaceuticals, Fort Worth, TX) in pediatric subjects with glaucoma or ocular hypertension.
Subjects and Methods This was a multicenter study conducted at 30 sites throughout the United States and India in accordance with the principles set forth in the Declaration of Helsinki. This was a double-masked, randomized, parallel group study. The study was registered on Clintrials.gov (NCT00061542). Each study site was approved by the appropriate Institutional Review Board or Institutional Ethics Committee. Prior to a child’s participation in the study, at least 1 parent or legal representative read, signed, and dated an Institutional Review Board/ Institutional Ethics Committee approved consent form. Additionally, this study was conducted in compliance with the Health Insurance Portability and Accountability Act at all of the U.S. study sites. Male and female subjects of any race who had not reached their sixth birthday at the time of the screening visit and who had a clinical diagnosis of glaucoma or ocular hypertension and required IOP-lowering in the opinion of the treating ophthalmologist were eligible. Subjects who had been under treatment with an ocular hypotensive medication(s) prior to the study and subjects who were not receiving ocular hypotensive treatment were eligible for enrollment. There was no washout of prior medications because it was felt that a washout period would expose subjects to an unacceptable risk. Because subjects with IOPs already controlled by an ocular hypotensive medication were eligible for enrollment, there was no minimum IOP requirement; however, subjects with IOPs exceeding 36 mm Hg were not eligible for enrollment. A substantial number of pediatric glaucoma subjects are aphakic and wear contact lenses; therefore, contact lens use was allowed during the study. All contact lens-wearing children were provided with new contact lenses at the time of enrollment and a second new set when they exited the study. Subjects were excluded from the study for any of the following reasons: 6 years of age or older at the time of screening; at or below the 5th percentile for body weight (applied to children \1 year of age only); intraocular surgery within the past 30 days in the study
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eye; clinically significant or progressive retinal disease in the study eye; ocular or systemic diseases precluding administration of a topical beta-blocker; any eye with a history of penetrating keratoplasty; any amount of congenital optic atrophy (as assessed by the investigator) in the study eye; fewer than 3 weeks stable dosing (prior to the screening visit) of current IOP-lowering medication(s); history of congenital cardiovascular anomalies or abnormalities that would preclude safe administration of a topical beta-blocker; any abnormality preventing reliable applanation tonometry; therapy with another investigational agent within 30 days of study start; use of any other topical or systemic ocular hypotensive medication during the study. Subject enrollment was divided into the 4 following age groups: 1 week to \1 year; 1 year to \2 years; 2 years to \4 years; and 4 years to \6 years. These age strata and the numbers enrolled in each are provided in Table 1. Subjects were randomized to treatment in a 1:1:1 ratio. Four distinct randomization series were generated for each investigator corresponding to the 4 age groups. The study was double-masked and all study medications were supplied in identical opaque dropper bottles identified by the subject randomization number. There were 2 scheduled prerandomization visits: the screening visit and the baseline visit, from 1 day to 14 days later. Subjects being treated with prestudy IOP-lowering medication(s) continued that medication(s) between the screening and baseline visits, receiving their final dose of prestudy medication(s) the day before the baseline visit. Subjects meeting inclusion and exclusion criteria at the screening and baseline visits were assigned a subject number; parents were given dosing instructions, and masked study drug was dispensed. Subjects were randomized in a 1:1:1 ratio to receive betaxolol 0.25% (twice daily, 8 AM and 8 PM) or TGFS 0.25% (daily, 8 AM) or TGFS 0.5% (daily, 8 AM). Subjects randomized to either of the TGFS groups were also dosed with vehicle (daily, 8 PM) for masking purposes. Regardless of whether subjects were randomized to betaxolol or 1 of the TGFS groups, all received a ‘‘morning’’ and an ‘‘evening’’ bottle of medication. Parents were instructed to instill a single drop in each study eye from the morning bottle at 8 AM (30 minutes) and dose 1 drop in each study eye from the evening bottle at 8 PM (30 minutes). Study subjects were scheduled for visits after 2, 6, and 12 weeks on study drug. Subjects exited the study at the week 12 visit. IOP was measured either with a Tono-Pen (Mentor O & O, Nowell, MA) handheld tonometer, or by Goldmann or Perkins applanation tonometry at all visits at approximately 9 AM before instilling the morning dose. Each eye was measured twice and the measurements were averaged. If the 2 measurements were different by more than 4 mm Hg, a third reading was taken and the 2 closest were averaged. Likewise, an additional Tono-Pen reading was taken in instances where a 5% confidence level was not obtained. The same tonometry method was used for any given subject throughout the study. If an examination under anesthesia was necessary to obtain IOPs, measurements were generally only obtained at the screening visit and at the exit visit. Additional examinations under anesthesia were performed at the discretion of the investigators. Visual acuity was measured at all visits using age-appropriate procedures. A single technique was used consistently for each
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Table 1. Subject demographics by treatment group Total Total Age 1 week to \1 year old 1 year to \2 years old 2 years to \4 years old 4 years to \6 years old Sex Male Female Race Asian Black or African American Caucasian Multi-racial Other Iris color Blue Brown Green Gray Hazel No irisy Diagnosis Primary congenital glaucoma Primary glaucoma associated with systemic or ocular abnormalities Glaucoma secondary to aphakia
Betaxolol 0.25%
TGFS 0.25%
TGFS 0.5%
N
%
N
%
N
%
N
%
p-value*
105
100.0
34
100.0
35
100.0
36
100.0
17 20 32 36
16.2 19.0 30.5 34.3
6 6 11 11
17.6 17.6 32.4 32.4
6 7 10 12
17.1 20.0 28.6 34.3
5 7 11 13
13.9 19.4 30.6 36.1
0.9989
61 44
58.1 41.9
17 17
50.0 50.0
26 9
74.3 25.7
18 18
50.0 50.0
0.0592
47 15 36 1 6
44.8 14.3 34.3 1.0 5.7
15 4 12 0 3
44.1 11.8 35.3 0.0 8.8
16 4 13 0 2
45.7 11.4 37.1 0.0 5.7
16 7 11 1 1
44.4 19.4 30.6 2.8 2.8
0.9075
14 77 1 2 8 3
13.3 73.3 1.0 1.9 7.6 2.9
5 25 0 1 3 0
14.7 73.5 0.0 2.9 8.8 0.0
6 25 1 1 1 1
17.1 71.4 2.9 2.9 2.9 2.9
3 27 0 0 4 2
8.3 75.0 0.0 0.0 11.1 5.6
0.6790
61 16
58.1 15.2
16 4
47.1 11.8
25 5
71.4 14.3
20 7
55.6 19.4
0.1241
28
26.7
14
41.1
5
14.3
9
25.0
2
*p-value from c or Fisher exact test. y Patients with aniridia. child. In addition to IOP and visual acuity, ocular signs (eyelids/ conjunctiva, cornea, iris/anterior chamber, lens), subject alertness, pulse, systolic and diastolic blood pressure, changes in concomitant medications, and adverse events were collected at all visits. Subject alertness was assessed using the Observer’s Assessment of Alertness Scale.10,11 A dilated fundus examination and measurement of corneal diameter were carried out prior to exposure to study drug and at the exit visit. The determination of the relationship of adverse events to study drug was made by the investigators.
Statistical Methods This study was designed to be in compliance with the terms of Food and Drug Administration Written Requests (for pediatric studies) for betaxolol hydrochloride and timolol maleate. Because of the low frequency of pediatric glaucoma, the study was descriptive and the sample size was not selected for statistical power considerations. The study was designed to collect, in a systematic way, adverse events that might be expected to occur with a frequency of approximately 3%, in addition to a description of the clinical response (IOP reduction) that could be expected when using these treatments. The primary efficacy parameter was an assessment of mean IOP change from baseline at 9 AM. Study visits were planned at weeks 2, 6, and 12. If only 1 of a subject’s eyes was dosed, the dosed eye was selected for analysis. If both eyes were dosed, the worse eye
was selected for analysis. The worse eye was defined as the eye with the higher IOP at 9 AM averaged across the screening and baseline visits. If both eyes were equal, then the right eye was selected for analysis. The primary analytic method consisted of describing the IOP data with means and 2-sided 95% confidence intervals. Repeated measures analysis of variance (ANOVA) was used to estimate the means and confidence intervals. Descriptive statistics were calculated for IOP, IOP change from baseline, and IOP percentage change from baseline. All subjects who received at least 1 dose of study medication were included in the safety data set. All subjects who received study medication, had at least 1 on-therapy visit, and met all inclusion/exclusion criteria were considered evaluable for the per-protocol data set. All subjects who received study medication and had at least 1 on-therapy visit were considered evaluable for intent-to-treat (ITT) analysis and included in the ITT data set. Evaluability for all subjects and visits was determined prior to breaking the code for masked treatment assignment. Results for the ITT and per-protocol analyses were similar; therefore, only the ITT results are presented here as it is the more inclusive data set. The statistical significance of response to treatment was assessed by comparing the baseline IOP with the week 12 IOP using t-tests for paired comparisons (1-tailed test used for those subjects on no prestudy therapy) with a significance level of 0.05. Clinical relevance of an IOP reduction was taken as a $2
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Table 2. Summary of study subject drop out Reason for discontinuing treatment Adverse event* Inadequate control of IOP Parent decisiony Noncompliance Total
Betaxolol 0.25%
TGFS 0.25%
TGFS 0.5%
1 2 1 1 5
0 5 1 1 7
0 3 0 0 3
*Unrelated to study drug. y Unrelated to adverse event. mm Hg IOP reduction from baseline. This is a commonly used measure of clinical relevance in controlled clinical studies.12 The statistical significance of differences in diagnostic category by treatment was assessed by using single-factor ANOVA. Subjects defined as responders were those that demonstrated a $15% reduction in IOP over the 12-week period. Note that ‘‘responder’’ refers to the response for an individual versus clinical relevance, which describes the overall mean reduction in IOP for the group.
Results One hundred seven subjects were enrolled in the study and received study medication. Of these, 2 (1 each in the betaxolol 0.25% and TGFS 0.25% treatment groups) were discontinued from the study prior to collection of any on-therapy study visit data; therefore, 105 subjects were evaluable for and included in the ITT analysis. Of the 107 enrolled, 15 subjects (5 on betaxolol, 7 on TGFS 0.25%, and 3 on TGFS 0.5%), including the 2 noted above, discontinued the study prematurely. The most common reason for subject discontinuation was inadequate control of IOP (2 in the betaxolol 0.25% group, 5 in the TGFS 0.25% group, and 3 in the TGFS 0.5% group). Discontinuation rates and reasons for discontinuation were similar between all treatment groups (Table 2). Demographic data for the study population are given in Table 1. The age distribution was 12 days to 5 years (mean age for betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% was 2.5, 2.5, and 2.6 years, respectively). Treatment groups were similar with no statistically significant differences in the distribution of subjects regarding age category, race, iris color, or glaucoma diagnosis. There was a statistical trend for gender comparison (p 5 0.0592). Whereas the ratio of males to females was 1:1 in both the betaxolol 0.25% and the TGFS 0.5% groups, it was approximately 3:1 in the TGFS 0.25% group. Changes from Baseline Betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% produced statistically significant and clinically relevant mean reductions in IOP in pediatric subjects after 12 weeks of therapy (Figure 1). For betaxolol 0.25%, mean IOP decrease from baseline was 2.3 mm Hg (p 5 0.008); for TGFS 0.25% the reduction was 2.9 mm Hg (p 5 0.012),
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Mean IOP change (mm Hg)
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2 1 0 -1 -2 -3 -4 -5 -6
Betaxolol
Baseline average
TGFS 0.25%
Week 2 visit
TGFS 0.5%
Week 6 visit
Week 12 visit
FIG 1. Mean IOP change from baseline (mm Hg) and 95% confidence intervals.
and for TGFS 0.5% the reduction was 3.7 mm Hg (p 5 0.002). Baseline mean IOP was similar for all treatment groups when considering all of the subjects. Baseline IOP was also similar for the treatment groups subdivided into those subjects without a prestudy therapy and those on a prior treatment (Table 3). Because the study allowed enrollment of subjects either on or not on an IOP-lowering medication at the time of randomization, we analyzed the change in IOP from baseline in these 2 subpopulations. Fifty-nine percent of the betaxolol 0.25% subjects, 63% of the TGFS 0.25% subjects, and 78% of the TGFS 0.5% subjects were being treated with 1 or more IOP-lowering medications at the study start (Tables 3 and 4). These subjects discontinued their prestudy therapy or therapies at the time of enrollment, crossing over to the masked, monotherapy study drug. All 3 treatments demonstrated a reduction in mean IOP. Mean IOP reductions from baseline at week 12 in this subgroup were 1.8 mm Hg (p 5 0.15) for subjects treated with betaxolol 0.25%, 1.8 mm Hg (p 5 0.14) for subjects treated with TGFS 0.25%, and 3.7 mm Hg (p 5 0.01) for subjects treated with TGFS 0.5%. Prestudy treatment included all available classes of IOP-lowering drugs, with beta-adrenergic blockers being most commonly employed (Table 4). The mean number of prestudy IOPlowering medications per subject (for subjects on therapy) was 1.5 for the betaxolol 0.25% treatment group, 1.3 for TGFS 0.25%, and 1.5 for TGFS 0.5% treatment group. For subjects not on an IOP-lowering medication at the time of randomization, betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5% produced statistically significant and clinically relevant mean reductions in IOP; mean IOP reductions after 12 weeks of treatment were 3.1 (p 5 0.008), 4.8 (p 5 0.01), and 3.8 (p 5 0.04) mm Hg, respectively. When a 15% reduction from baseline IOP is used as a threshold to define responders to therapy, 38.2% of the betaxolol group, 45.7% of the TGFS 0.25% group, and 47.2% of the TGFS 0.5% group could be classified as responders. The percentage of responders was similar when the groups were subdivided into those on prior IOP-lowering therapy and those that were not. Mean IOP reductions for responders were 7.5, 7.6, and 8.9 mm Hg for betaxolol, TGFS 0.25%, and TGFS 0.5%, respectively (p \ 0.0001).
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Table 3. Baseline IOP (mmHg) comparison
All patients Betaxolol 0.25% TGFS 0.25% TGFS 0.5% Prior IOP-lowering therapy Betaxolol 0.25% TGFS 0.25% TGFS 0.5% No prior therapy Betaxolol 0.25% TGFS 0.25% TGFS 0.5%
Table 4. Prestudy IOP-lowering therapy Baseline average*
Treatment group
N
Mean SD
Betaxolol TGFS TGFS 0.25% 0.25% 0.5%
34 35 36
24.6 5.5 23.2 5.5 24.4 5.7
20 22 28
23.7 5.8 21.5 5.2 23.8 5.6
14 13 8
26.1 4.8 26.2 4.8 26.4 6.1
SD, standard deviation. *Baseline average 5 average of the screening and baseline.
IOP-lowering efficacy of the 3 treatments may be analyzed in terms of subject diagnosis. Subjects are grouped by diagnosis into the 3 general categories: primary congenital glaucoma, glaucoma associated with systemic or ocular abnormalities, and glaucoma secondary to aphakia. These data are presented in Figure 2. Although there were no significant differences in response to therapy between diagnostic subgroups, differences approached significance within the TGFS 0.5% treatment (p 5 0.051, single-factor ANOVA). Safety Evaluation The evaluation of safety was based on all subjects (N 5 107) who were enrolled into the study and received at least 1 dose of study medication. Adverse events in the overall safety population were predominately nonserious and generally mild to moderate in intensity. No subject experienced a serious adverse event that was related to study drug. Adverse events judged to be related to treatment are tabulated in Table 5. Of these, 7 were associated with cardiovascular parameters and not unexpected in patients exposed to beta-blockers. The cardiovascular changes were mild in nature and did not require treatment or require discontinuation of the subjects from the study. Of the 107 enrolled subjects, 15 discontinued the study early (Table 2). The most frequent reason for discontinuation was inadequate control of IOP (2 betaxolol 0.25%, 5 TGFS 0.25%, 3 TGFS 0.5%). Other reasons for discontinuation were parent decision unrelated to an adverse event (2) and noncompliance (2). One subject in the betaxolol 0.25% group discontinued the study due to a nonserious adverse event (photophobia) unrelated to study drug.
Discussion The use of medical therapy is common in treating children with elevated IOP. These therapies include beta-blockers, carbonic anhydrase inhibitors, and prostaglandin analogues. Despite the fact that physicians find these drugs
Monotherapy Beta-adrenergic antagonist Carbonic anhydrase inhibitor (CAI) Pilocarpine Prostaglandin analogue (PGA) Masked study medication Multiple medications Beta-adrenergic antagonist 1 CAI Beta-adrenergic antagonist 1 pilocarpine Beta-adrenergic antagonist 1 PGA PGA 1 CAI Beta-adrenergic antagonist 1 CAI 1 PGA Beta-adrenergic antagonist 1 CAI 1 alpha-adrenergic agonist Beta-adrenergic antagonist 1PGA 1 alpha-adrenergic agonist Total
11 0 0 1 1
14 0 1 0 0
13 2 1 1 0
0 4 1 0 1 0
2 1 2 2 0 0
4 3 1 0 2 1
1
0
0
20
22
28
7 6
Primary congenital Glaucoma secondary to aphakia Associated w/ systemic or ocular abnormalities
N = 20
N=5
IOP reduction (mm Hg)
388
N=4
5 4 3
N = 25 N = 16
2
N=5
N = 14
N=9
1 N=7
0 -1
p =
Betaxolol
TGFS 0.25%
TGFS 0.5%
0.551
0.632
0.051
FIG 2. Mean IOP reduction at week 12 (or early exit) by diagnosis; p-values calculated on the basis of single-factor analysis of variance (ANOVA).
useful, there has been limited safety and efficacy information available and pediatric use for many remains ‘‘offlabel.’’ There have been several studies of the treatment of pediatric glaucoma with timolol. In these, timolol was added as an adjunct to other pressure-reducing medications the children were already taking for their glaucoma.7,8,13,14 Boger and Walton13 demonstrated improvement in approximately 26.5% of the subjects and no clear benefit in 38% of the subjects when timolol was added to maximal medical therapy (which consisted of carbonic anhydrase inhibitors, cholinesterase inhibitors, epinephrine, and pilocarpine). Hoskins and colleagues7 retrospectively evaluated 67 subjects including subjects up to 18 years of age. In this group 31% were considered controlled after the addition of timolol. Few studies have evaluated the effect of timolol alone. Zimmerman and coworkers8 evaluated timolol monotherapy (N 5 11 subjects, 18 eyes) as part of a retrospective
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Table 5. Adverse events related to therapy (all patients)
Adverse event Ocular Hyperemia eye Discomfort eye Irritation eye Discharge eye Lid margin crusting Pruritus eye Sticky sensation Cardiovascular system Bradycardia Hypotension
Betaxolol 0.25% N 5 35
TGFS 0.25% N 5 36
N
%
N
%
N
%
2 2 1
5.7 5.7 2.9
1
2.8
2
5.6
1
2.8 2 1 1
5.6 2.8 2.8
1
2.8
1 1
2.9 2.9
study of timolol therapy in pediatric glaucoma (mean age, 7.2 years). Fifty percent of the eyes (N 5 9) were controlled with timolol alone. More recently, Whitson and colleagues9 published results on a cardioselective beta-blocker, levobetaxolol. Levobetaxolol (twice daily) was found to lower IOP in pediatric subjects. Subjects on prior therapy that were switched to levobetaxolol at the time of enrollment had a 1 to 3 mm Hg decrease in their IOP over all visits. Subjects entering the study without a prestudy therapy who were randomized to levobetaxolol demonstrated a 3 to 4 mm Hg drop in IOP over all visits. In the current study children with glaucoma were eligible whether or not they were already taking pressurereducing medication. Although the number of subjects entering the study without a prestudy therapy was small (33%), the effect of these drugs is readily apparent in this subgroup. Betaxolol 0.25% (N 5 14) lowered IOP 3.1 mm Hg; TGFS 0.25% (N 5 13) lowered IOP 4.8 mm Hg, and TGFS 0.5% (N 5 8) lowered IOP 3.8 mm Hg in these subjects. Results of all 3 treatments compare favorably with those seen in the adult studies (4.7, 5.0, and 4.8 mm Hg for betaxolol 0.25%, TGFS 0.25%, and TGFS 0.5%, respectively).15-17 The majority of subjects enrolled (67%) were on a topical IOP-lowering medication(s) at study entry, most commonly beta-blockers resulting in lower baseline IOPs due to the absence of a washout phase, which would likely reduce the absolute response to study drug. Although many of the subjects entering the study were on more than 1 medication (average 1.4), evaluation of the exit IOPs demonstrated a reduction in mean IOP from baseline at trough (approximately 12 hours postdose for betaxolol and approximately 24 hours postdose for TGFS 0.25% and TGFS 0.5%) of 1.8, 1.8, and 3.7 mm Hg for betaxolol 0.25% (N 5 20), TGFS 0.25 (N 5 22), and TGFS 0.5% (N 5 28), respectively. An IOP reduction of 2 mm Hg is generally considered the smallest change of clinical relevance12; the mean reductions for the betaxolol and TGFS 0.25% groups approach but do not reach this threshold. However, maintenance of the prerandomization IOP by
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2 2
TGFS 0.5% N 5 36
5.6 5.6
these 2 treatments would imply that each was at least as efficacious as prior treatment, which in many instances was more than 1 medication. Different types of pediatric glaucoma may respond differently (or not at all) to different drug treatments.3,9 For example, levobetaxolol was found to be most efficacious in subjects with primary congenital glaucoma and least efficacious in secondary glaucomas (consisting primarily of aphakic glaucoma in that study).9 Brinzolamide was most effective in cases of glaucoma associated with systemic or ocular abnormalities (eg, Sturge-Weber) and slightly less effective in primary congenital or secondary glaucoma. In the current study all treatments showed efficacy in treating primary congenital glaucoma; this is consistent with the previous finding for levobetaxolol, also a beta-blocker.9 All 3 treatments showed less efficacy in glaucoma secondary to aphakia. There are a number of limitations to this study. These include the relatively small number of subjects when compared to adult studies, the short duration of treatment (12 weeks), and the variability in the study population. Subjects switched from prebaseline medications could have shown improvement due to Hawthorne effect or regression of IOP to the mean. Despite these limitations, it is clear from the data that betaxolol 0.25% (twice daily), TGFS 0.25% (daily), and TGFS 0.5% (daily) provided IOP-lowering benefits to subjects with pediatric glaucomas. In addition to IOP-lowering efficacy demonstrated by betaxolol and timolol, these medications appeared to be equally safe and well tolerated in the young children in this study.
References 1. Kanner EM, Netland PA. Medical therapy of pediatric glaucoma. Contemp Ophthalmol 2008;7:1-8. 2. Altuna JC, Greenfield DS, Wand M, Liebmann JM, Taglia DP, Kaufman PL, et al. Latanoprost in glaucoma associated with SturgeWeber syndrome. J Glaucoma 1999;8:199-203. 3. Enyedi LB, Freedman SF. Latanoprost for the treatment of pediatric glaucoma. Surv Ophthalmol 2002;47(Suppl):S129-32. 4. Donohue EK, Wilensky JT. Dorzolamide: A review. Semin Ophthalmol 1997;12:119-26.
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