Download Betaxolol hydrochloride ophthalmic suspension 0.25% and timolol

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
384
G
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
Journal of AAPOS
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
Journal of AAPOS
Plager et al
385
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
386
Plager et al
Volume 13 Number 4 / August 2009
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
Journal of AAPOS
Plager et al
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),
Journal of AAPOS
Mean IOP change (mm Hg)
Volume 13 Number 4 / August 2009
387
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).
Plager et al
Volume 13 Number 4 / August 2009
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
Journal of AAPOS
Volume 13 Number 4 / August 2009
Plager et al
389
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
Journal of AAPOS
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.
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