Comparison of Latanoprost and Timolol in

Pediatric Glaucoma: A Phase 3, 12-Week,

Randomized, Double-Masked Multicenter
Study
Tomoko Maeda-Chubachi, MD, PhD,1 Katherine Chi-Burris, MPH,1 Brad D. Simons, MD, PhD,2
Sharon F. Freedman, MD,3 Peng T. Khaw, MD, PhD,4 Barbara Wirostko, MD,5 Eric Yan, PhD,6 for the
A6111137 Study Group*

Objective: To compare the efficacy and safety of latanoprost versus timolol in pediatric patients with
glaucoma.
Design: Prospective, randomized, double-masked, 12-week, multicenter study.
Participants: Individuals aged ⱕ18 years with glaucoma.
Methods: Stratified by age, diagnosis, and intraocular pressure (IOP) level, subjects were randomized (1:1) to
latanoprost vehicle at 8 AM and latanoprost 0.005% at 8 PM or timolol 0.5% (0.25% for those aged ⬍3 years) twice daily
(8 AM, 8 PM). At baseline and weeks 1, 4, and 12, IOP and ocular safety were assessed and adverse events were
recorded. Therapy was switched to open-label latanoprost PM and timolol AM and PM for uncontrolled IOP.
Main Outcome Measures: Mean IOP reduction from baseline to week 12. Latanoprost was considered
noninferior to timolol if the lower limit of the 95% confidence interval (CI) of the difference was ⬎⫺3 mmHg. A
proportion of responders (subjects with ⱖ15% IOP reduction at weeks 4 and 12) were evaluated. Analyses were
performed in diagnosis subgroups: primary congenital glaucoma (PCG) and non-PCG.
Results: In total, 137 subjects were treated (safety population; 12–18 years, n⫽48; 3–⬍12 years, n⫽55;
0 –⬍3 years, n⫽34). Mean age was 8.8⫾5.5 years, and mean baseline IOP was 27.7⫾6.17 mmHg; 125 subjects
completed the study, and 107 subjects were in the per protocol population. Mean IOP reductions for latanoprost
and timolol at week 12 were 7.2 and 5.7 mmHg, respectively, with a difference of 1.5 mmHg (95% CI, ⫺0.8 to
3.7; P⫽0.21). Responder rates were 60% for latanoprost and 52% for timolol (P⫽0.33). Between-treatment
differences in mean IOP reduction for PCG and non-PCG subgroups were 0.6 mmHg (95% CI, ⫺2.3 to 3.4) and
2.6 mmHg (95% CI, ⫺0.8 to 6.1), respectively. Responder rates for latanoprost versus timolol were 50% versus
46% for the PCG group and 72% versus 57% for the non-PCG group. Both therapies were well tolerated.
Conclusions: Latanoprost 0.005% is not inferior (i.e., is either more or similarly effective) to timolol and
produces clinically relevant IOP reductions across pediatric patients with and without PCG. Both latanoprost and
timolol had favorable safety profiles over the duration of this 3-month trial.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
Ophthalmology 2011;xx:xxx © 2011 by the American Academy of Ophthalmology.

*Group members listed online in Appendix 1 (available at http://aaojournal.org).

Pediatric glaucoma, which encompasses a collection of di-
verse pathophysiologic entities, is characterized by the pres-
ence of an abnormally elevated intraocular pressure (IOP)
that represents a risk factor for optic nerve damage and
subsequent visual field loss. Classification of the childhood
glaucomas into primary and secondary types provides a
framework for the evaluation and management of individual
patients.1,2 Primary glaucomas are those with isolated angle
malformations (trabeculodysgenesis) that have onset at birth
(congenital), in the first few years of life (primary infantile),
or later in childhood (juvenile). Secondary glaucomas are
either acquired (e.g., aphakic glaucoma) or related to a
clearly defined underlying ocular or systemic abnormality
that may occur at any age or be present at birth (e.g.,
Sturge–Weber syndrome).1,3
Depending on the cause and onset of pediatric glaucoma,
the disease course, initial treatment options, subsequent
treatment, and follow-up can vary. Although children with
primary congenital glaucoma (PCG) usually undergo sur-
gery soon after diagnosis,3–5 those with juvenile open-angle
glaucoma (JOAG) and certain secondary glaucomas such as
aphakic glaucoma usually receive initial pharmacologic
treatment.1,3
Reduction of IOP is the only proven and accepted
method of slowing disease progression, and optimal IOP
control is especially important given the long life expec-

© 2011 by the American Academy of Ophthalmology ISSN 0161-6420/11/$–see front matter 1

Published by Elsevier Inc. doi:10.1016/j.ophtha.2011.03.010
 Ophthalmology Volume xx, Number x, Month 2011
tancy (and therefore visual lifetime) of a pediatric patient
with glaucoma. The last 30 years have seen the introduction
of many effective agents for IOP management in adults,
including nonselective and selective ␤-blocking agents,
prostaglandin analogs, topical and oral carbonic anhydrase
inhibitor preparations, and ␣-agonists.6,7 Few of these med-
ications are approved for use in children. However, be-
cause of the clinical need to control IOP, medical treat-
ment of pediatric glaucoma often includes use of these
topical and oral IOP-lowering medications alone or fre-
quently in combination.8,9
Latanoprost, a prostaglandin F2␣ analog, was the first of
its class to be approved for the reduction of elevated IOP
associated with open-angle glaucoma or ocular hypertension.
Latanoprost has become the most commonly prescribed first-
line glaucoma therapy in adults.10 The prostaglandin agonists
and timolol are the most effective IOP-lowering agents when
meta-analysis is carried out.11 The long-term safety and effi-
cacy of latanoprost in adult patients with elevated IOP are
supported by more than 13 years of clinical experience, in-
cluding two 5-year safety studies.12,13 Although latanoprost is
not approved for use in children, there have been several
publications that report the safety and effectiveness of its use in
pediatric patients with glaucoma.14 –19 A prospective, com-
passionate use study of 57 eyes of 48 children, of which 31
eyes had evaluable IOP data, showed that 32% of eyes had
an IOP reduction of more than 10% after the addition of
latanoprost and only 19% had a reduction of more than
15%.15 Responders were significantly more likely to have
JOAG.15 In a recently published retrospective chart review
by the same group,14 which included some of the same 48
children enrolled in the smaller prospective study, 115 chil-
dren had total latanoprost exposure of 2325 child-months. Of
these 115 children, 63 eyes (63 children) had interpretable
IOP data; 35% had an IOP reduction of ⱖ15% (mean
reduction, 27.7⫾8.4).14 Children with JOAG (n⫽19) had
the highest response (74%) followed by those with aphakic
(n⫽13) glaucoma (46%), whereas those with PCG (n⫽14)
or glaucoma associated with other diagnoses had a poor
response. Systemic and ocular side effects associated with
adult-dose latanoprost were infrequent and mild.14
Over the last few years, there has been an increased focus
by regulatory agencies and pediatric advocacy groups on the
need for the development and accessibility of medicinal
products for use in the pediatric population. In the European
Union (EU), new pediatric legislation was enforced in 2007
(Regulation [EC] No. 1901/200620) to improve the health of
children. In the United States, the Pediatric Research Equity
Act (Public Law No. 108-15521) was signed into law in
2003 to address the lack of pediatric drug use information in
product labeling. These legislations were designed to facil-
itate timely pediatric medicinal product development and
the generation of data on the appropriate use of agents
approved for the treatment of adult diseases in pediatric
patients. To date, there have been no well-controlled large
trials to prospectively assess the safety and efficacy of
latanoprost or any other prostaglandin analog in the pediat-
ric glaucoma population. Thus, the objective of this pro-
spective, randomized, controlled trial was to establish, over
3 months exposure, the relative safety and efficacy of the
2
adult dose of latanoprost ophthalmic solution (0.005%
dosed once daily) when compared with timolol in pediatric
patients with glaucoma.
Materials and Methods
Study Design
This was a 12-week, double-masked, parallel-group multicenter
study (NCT00716859, EudraCT2007-004543-30). The final pro-
tocol and informed consent documentation were reviewed and
approved by the institutional review boards or independent ethics
committees at each participating investigational center. The study
was conducted in compliance with the Declaration of Helsinki,
with all International Conference on Harmonisation Good Clinical
Practice guidelines, and, for sites in the United States, with the
Health Insurance Portability and Accountability Act. Each sub-
ject’s parent or legal guardian provided written informed consent
before study enrollment.
Subjects
Eligible subjects were aged ⱕ18 years, diagnosed with glaucoma
in 1 or both eyes, and had morning (before midday) IOP ⱖ22
mmHg in at least 1 eye at the baseline visit. The agreement
between the study sponsor and the European Medicines Agency
was to investigate the condition in the pediatric population, which
is defined as newborns, infants, infants and toddlers, children, and
adolescents. International Conference on Harmonisation/Commit-
tee for Medicinal Products for Human Use guideline E11 specifies
5 age categories for possible evaluation within a pediatric inves-
tigational plan: preterm newborn infants; term newborn infants
(0 –27 days); infants and toddlers (28 days to 23 months); children
(2–11 years); and adolescents (12 to 16 –18 years, depending on
region). Preterm (⬍37 weeks gestation) newborn infants were
excluded from the study.
Pharmacologic intervention with IOP-reducing therapy was
deemed clinically necessary in at least 1 eye. Prior glaucoma-
related surgery, including drainage implants, was allowed as long
as medical therapy was thought to be clinically indicated in this
situation. Exclusion criteria are summarized in Table 1 (available
at http://aaojournal.org).
To ensure a sufficient safety margin for systemic adverse
effects after instillation of latanoprost 0.005% ophthalmic solution
once per day to the eyes in this pediatric population, enrollment
was staged by age groups (12–18, 3–⬍12, and 0 –⬍3 years) after
examination of the results of the preceding pharmacokinetic study
(Invest Ophthamol Vis Sci, 51:E-abstract 210, 2010). In addition,
a Data Monitoring Committee conducted an interim safety analysis
and could have recommended stopping the trial if safety concerns
were identified.
Treatments and Assessments
Potentially eligible subjects were evaluated at a screening visit that
took place 0 to 28 days before the baseline visit. At screening,
ocular and medical histories were documented, a physical exami-
nation and biomicroscopy were performed, pupil diameter was
measured, and gonioscopy was performed if not done within the
preceding 6 months. In subjects able to cooperate, visual acuity
was measured and a visual field examination was conducted if
clinically possible and if not performed within the prior 6 months.
For visual acuity measurement, children who were familiar with
the letters of the alphabet were evaluated using Snellen visual
 Maeda-Chubachi et al 䡠 Latanoprost vs Timolol in Pediatric Glaucomas
acuity, and those who were unable or unfamiliar with the letters of
the alphabet were evaluated using charts made up of numbers,
pictures, E’s, Landolt’s broken rings, and other methods that were
equivalent to Snellen acuity. Intraocular pressure was measured in
both eyes, with the right eye first, using Goldmann applanation
tonometry (preferred method), Perkins tonometry, or a TonoPen
(Reichert, Inc., Depew, NY); the procedure was repeated for each
eye twice consecutively and a third time if the initial readings were
inconsistent. Intraocular pressure was measured after visual acuity
followed by biomicroscopy and finally pupil dilation. Subject
cooperation and any use of sedation during IOP measurements
were recorded.
After the screening visit, non-naive subjects (children who
were already receiving glaucoma medication) discontinued topical
ocular hypotensive medications for at least 24 hours before the
baseline visit with longer washout periods at the discretion of the
investigator. These subjects returned for IOP safety checks before
the baseline visit at the investigator’s discretion. The screening
visit could be used as the baseline visit for those naive to ocular
hypotensive medications.
At the baseline visit, any changes in medications were re-
corded; resting pulse and blood pressure were measured; alertness
was documented using a 5-point scale (5 ⫽ responds readily to
name spoken in normal tone; 4 ⫽ lethargic response to name
spoken in normal tone; 3 ⫽ responds only after name is called
loudly or repeatedly; 2 ⫽ responds only after mild prodding and
shaking; and 1 ⫽ does not respond to mild prodding and shaking);
refraction (cycloplegic where appropriate) was performed; hyper-
emia was assessed by slit-lamp examination and graded (0 ⫽ none,
1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe); pupil and corneal
diameters were measured; and ophthalmoscopy was performed.
Visual acuity, biomicroscopy, and IOP measurement were re-
peated using criteria and procedures established at screening.
Pachymetry was performed in subjects able to cooperate.
Before randomization, eligible subjects were stratified by age
(0 –⬍3, 3–⬍12, and 12–18 years), diagnosis (PCG or non-PCG,
including secondary glaucomas and JOAG), and baseline IOP
value of the study eye (⬍27, 27–31, and ⬎31 mmHg). If both eyes
qualified, the eye with the highest baseline IOP measurement was
designated as the study eye; if baseline IOP measurements were
the same in 2 qualified eyes, the right eye was designated as the
study eye. Within each stratum, subjects were randomized 1:1 to
latanoprost versus timolol using a centralized system administered
by a third party that maintained control of subject assignment
codes. Subjects assigned to the latanoprost group instilled 1 drop
of latanoprost 0.005% once daily at 8 PM (⫾30 minutes) and 1 drop
of the latanoprost vehicle (placebo) once daily at 8 AM (⫾30
minutes). Subjects assigned to receive timolol 0.5% (or optionally
0.25% for subjects aged ⬍3 years) twice daily instilled 1 drop at
8 AM (⫾30 minutes) and 1 drop at 8 PM (⫾30 minutes). The first
dose of study medication was to be administered at the baseline
visit in the morning after randomization, and the last dose was
instilled at 8 AM of the week 12/early discontinuation visit.
Follow-up visits were scheduled at weeks 1, 4, and 12. If at
weeks 1 or 4, the investigator determined that the IOP was not
controlled in a subject depending on each subject’s condition and
treatment history, the subject could be switched to open-label
concomitant therapy of latanoprost 0.005% at 8 PM (⫾30 minutes)
and timolol 0.5% (or optionally 0.25% for subjects aged ⬍3 years)
twice daily at 8 AM (⫾30 minutes) and 8 PM (⫾30 minutes). If such
a change was made, the subject returned for additional follow-up
at weeks 2 or 5; if the IOP remained uncontrolled, the subject
discontinued study participation. Intraocular pressure measure-
ments at each follow-up visit occurred at 10 AM (⫾1.5 hours).
Preferably, the same assessor, masked to subject assignment dur-
ing the entire study period, measured the IOP using the same
tonometer at each visit for a given subject.
At week 1 (and weeks 2 and 5, if needed), changes in medi-
cations were recorded, resting pulse and blood pressure were
measured, alertness was documented, hyperemia and visual acuity
were assessed, biomicroscopy was performed, and IOP was mea-
sured. At week 4, week 1 assessments were repeated, pupil and
corneal diameters were measured, and ophthalmoscopy was per-
formed. At weeks 12 and 13 or at the end of treatment, all baseline
assessments were repeated, visual field was evaluated, and gonios-
copy was performed.
Investigators monitored all observed or volunteered adverse
events throughout the study. Serious adverse events were those
that were life-threatening; required inpatient hospitalization or
prolonged hospitalization; caused persistent or significant disabil-
ity or incapacity; or resulted in congenital anomaly, birth defect, or
death. Adverse events were followed until they resolved or stabi-
lized, and investigators assessed causality for each such event.
Masking codes were broken in emergency situations for reasons of
subject safety, and the investigator was to contact Pfizer before
breaking the mask. If the masking code was broken, the reason was
fully documented.
Statistical Analyses
The primary efficacy end point was the mean IOP change from
baseline to week 12 in the study eye. At each visit, the median of
IOP measurements for the study eye represented the subject’s IOP.
For subjects who switched to open-label concomitant therapy or
who discontinued before week 12, the IOP measurement made at
the visit at which the investigator decided to switch/discontinue the
subject—a decision made after the IOP was measured—was used
to impute the week 12 IOP using the last observation carried
forward method.
For the primary end point, an analysis of covariance (ANCOVA)
model with treatment and baseline diagnosis as factors and
baseline IOP as a covariate was used to analyze the difference in
IOP reduction at week 12 between latanoprost and timolol. The
treatment difference (latanoprost – timolol) and its 95% confidence
interval (CI) were calculated, and latanoprost was considered
noninferior, was either more or similarly effective, to timolol if the
lower limit of the 95% CI of the difference was ⬎⫺3 mmHg
(noninferiority margin agreed to by the European Medicines
Agency Pediatric Committee as a component of the Pediatric
Investigator Plan). The analysis plan provided for an option of
switching to superiority in the event that the lower limit of the 95%
CI for the treatment difference not only lay above the noninferi-
ority margin (⫺3 mmHg) but also above zero.
The sample size of 120 subjects (60 subjects in each treatment
arm) was estimated to provide an 84% power to demonstrate that
latanoprost was not inferior to timolol within a margin of 3 mmHg,
assuming latanoprost had 1 mmHg reduction more than timolol in
mean IOP change from baseline, a common standard deviation
(SD) of 7 mmHg, and a 10% dropout rate. The same sample size
would provide an 84% power for a superiority test to detect a
difference of 4 mmHg between the latanoprost and timolol treat-
ment arms with the same assumption of a common SD of 7 mmHg
and a 10% dropout rate.
As recommended by the International Conference on Harmoni-
sation E9 guideline22 and the European Agency for the Evaluation
of Medicinal Products Points to Consider guidance document,23
the primary noninferiority efficacy analysis was based on the per
protocol (PP) population; a supporting analysis was based on the
intent-to-treat (ITT) population. The primary efficacy analysis
population for the determination of superiority would be based on
the ITT population. The PP population was restricted to subjects
3
 Ophthalmology Volume xx, Number x, Month 2011
Figure 1. Subject disposition.
with no major protocol violations who received at least 1 week of
study medication and who had an IOP measurement at week 1. The
ITT population was defined as all subjects randomized into the
study who received at least 1 dose of study medication.
Secondary efficacy end points included the mean change from
baseline in the study eye at each visit (weeks 1, 4, and 12), the
mean IOP level at each visit (baseline and weeks 1, 4, and 12), and
the proportion of subjects with at least a 15% IOP reduction from
baseline at both weeks 4 and 12 (responders). For analyses of
secondary end points, missing data were not imputed, and only
IOP levels measured while a subject was on masked monotherapy
were analyzed. An ANCOVA model with treatment and baseline
diagnosis as factors and baseline IOP as a covariate was used to
estimate the difference in IOP reduction at each visit between
latanoprost and timolol; corresponding 95% CIs also were calcu-
lated. The statistical significance of between-treatment differences
in proportion of responders was evaluated using the Cochran-
Mantel-Haenszel chi-square test stratified by baseline diagnosis
(PCG vs. non-PCG).
Efficacy analyses also were performed for the PCG and non-
PCG subgroups. For these analyses, the ANCOVA model included
only treatment as the factor and baseline IOP as a covariate. For
the responder analysis, a Pearson’s chi-square test was used to
evaluate the treatment difference.
Adverse events were classified by body system and preferred
term using the Medical Dictionary for Regulatory Activities
(MedDRA Version 12.1) coding system. Safety end points were
analyzed using the ITT population. The difference between the
4
baseline conjunctival hyperemia score and the highest score at
any post-baseline visit was calculated to reflect the maximum
shift in grade.
Results
A total of 139 subjects were randomized to study treatment at 42
centers (80 subjects at 24 EU centers and 59 subjects at 18 non-EU
centers; Fig 1). Although 69 subjects were assigned to receive
latanoprost and 70 subjects were assigned to receive timolol, 1
subject in each randomization group did not start study medication
because they were no longer willing to participate in the study.
Subjects discontinuing during the study included 4 of 68 (5.9%) in
the latanoprost-treated group versus 8 of 69 (11.6%) in the timolol-
treated group (not significant [NS]). Half (6/12) of the discontinu-
ations occurred in the youngest subjects (0 –⬍3 years); discontinu-
ations were noted for 3 subjects each in the age groups 3 to ⬍12
years and 12 to 18 years. All 137 treated subjects were included in
the ITT and safety populations, whereas 107 of 137 (78.1%)
subjects were included in the PP population.
Baseline demographic and diagnostic characteristics for the
ITT population are summarized in Table 2 (available at http://
aaojournal.org). More than three quarters of subjects in both treat-
ment groups were white, and approximately half were male. The
distribution across age groups was similar between treatments. The
primary diagnosis for approximately 45% of subjects in each
group was PCG. The most common non-PCG diagnosis was
 Maeda-Chubachi et al 䡠 Latanoprost vs Timolol in Pediatric Glaucomas
JOAG. Both eyes were treated in 33 of 62 (53.2%) subjects with
PCG, in 38 of 40 subjects (95.0%) with JOAG, and in 2 of 17
(11.8%) subjects with either aphakic or pseudophakic glaucoma.
The proportion of subjects in the latanoprost group who had
received ocular pharmacologic treatments for glaucoma before the
start of the study was 69% compared with 55% of subjects in the
timolol group (difference NS); these prior treatments most com-
monly included latanoprost, timolol, and brinzolamide. The latano-
prost- and timolol-treated subjects were similar with respect to
previous glaucoma-related surgery (reported for 17/68 [25.0%] vs.
16/69 [23.2%] subjects, respectively) and any other prior ocular
surgery (reported for 23/68 [33.8%] vs. 22/69 [31.9%] subjects,
respectively).
In the ITT population, the median duration of treatment, in-
cluding open-label therapy, for both groups was 85.0 days (range:
latanoprost, 7–92 days; timolol, 2–105 days). The median duration
of masked monotherapy was 84.0 days in the latanoprost group
(range: 6 –92 days) and 85.0 days in the timolol group (range:
2–105 days). Similar durations of treatment were noted in the PP
population.
Both latanoprost and timolol reduced mean IOP levels in the
study eye from baseline to week 12 with least square mean
reductions of 7.2 and 5.7 mmHg, respectively (Table 3, available
at http://aaojournal.org). The least square mean difference was 1.5
mmHg in favor of latanoprost, and the 95% CI of the least square
mean difference was between ⫺0.81 mmHg (0.81 mmHg in favor
of timolol) and 3.74 mmHg (3.74 mmHg in favor of latanoprost;
P⫽0.21). The lower limit of the 95% CI of the difference (⫺0.81
mmHg) was ⬎⫺3 mmHg, which demonstrated that latanoprost
was not inferior (i.e., was either more or similarly effective) to
timolol (Fig 2). Mean IOP reductions in the latanoprost group were
numerically but not statistically significantly greater than in the
timolol group at weeks 1, 4, and 12 (Fig 3). In all, 60% of subjects
(32/53) treated with latanoprost and 52% of subjects (28/54)
treated with timolol were responders (ⱖ15% IOP reduction from
baseline at weeks 4 and 12; P⫽0.33; PP population).
Results of the analysis of the primary end point by diagnosis
(PCG vs. non-PCG) are summarized in Table 4 (available at
http://aaojournal.org). In general, non-PCG subjects had higher
mean baseline IOP levels and numerically greater IOP reductions
from baseline to week 12 than the PCG subjects in both treatment
Figure 2. Latanoprost noninferior to timolol. In this study, lower limit of
the CI of the difference was considered to indicate (A) inferiority if ⱕ⫺3,
(B) noninferiority if ⬎⫺3 and ⱕ0, or (C) superiority if ⬎0. CI ⫽
confidence interval; IOP ⫽ intraocular pressure; ITT ⫽ intent-to-treat;
PCG ⫽ primary congenital glaucoma; PP ⫽ per protocol.
Figure 3. Mean ⫾ standard error IOP reduction from baseline (mmHg) by
study visit, study eye, PP population excluding observations collected after
switching to open-label concomitant therapy. IOP ⫽ intraocular pressure;
PP ⫽ per protocol.
groups. Mean IOP reductions at week 12 were numerically greater
in the latanoprost group than in the timolol group, and this differ-
ence was more evident in the non-PCG subgroup compared with
the PCG subgroup. The lower bounds of the 95% CI of the
difference between the least square means in both diagnosis sub-
groups were ⬎⫺3 mmHg (Fig 2). Response rates in the PCG
subgroup were 50% (14/28) and 46% (12/26) for latanoprost- and
timolol-treated subjects, respectively (difference NS); in the non-
PCG groups, response rates were 72% (18/25) and 57% (16/28),
respectively (difference NS).
Both latanoprost and timolol were well tolerated. Greater pro-
portions of timolol- than latanoprost-treated subjects reported
treatment-related adverse events and serious adverse events and
discontinued treatment because of adverse events (Table 5). Seri-
ous adverse events considered by the investigator to be possibly
related to study drug treatment included uncontrolled developmen-
tal glaucoma and eye hemorrhage in 1 timolol-treated subject and
pneumonia in 1 timolol-treated subject. Treatment-related con-
junctival hyperemia judged to be an adverse event by an investi-
gator in the study eyes was reported as none in latanoprost-treated
subjects and 3 (4.3%) in timolol-treated subjects. Baseline hyper-
emia was noted in 10 and 17 study eyes in the latanoprost and
timolol groups, respectively; worsening from baseline, defined as
a 1 grade change on a hyperemia grading score at each visit,
occurred in 12 of 68 (17.6%) subjects in the latanoprost group and
in 10 of 69 (14.5%) subjects in the timolol group. In study eyes, 1
treatment-related case each of punctate keratitis, abnormal eye
sensation, and photophobia was reported in the timolol group, and
1 such case of installation site pain was reported in those treated
with latanoprost. No clinically relevant changes were noted in
other ocular safety measures (i.e., visual acuity, corneal thickness,
biomicroscopy, ophthalmoscopy, pachymetry, or gonioscopy) or
in systemic safety measures (i.e., vital signs, alertness, or physical
examination results).
Discussion
Because uncontrolled glaucoma in young children may lead
to a lifetime of blindness,24,25 it is important to find safe and
effective treatments for this condition. Our study demon-
strated that in pediatric patients with glaucoma, the adult
dose of latanoprost (0.005% ophthalmic solution once
5
 Ophthalmology Volume xx, Number x, Month 2011
Table 5. All Causality Treatment-Emergent Adverse Events, Intent-to-Treat Population
No. of adverse events
Subjects with adverse events, n (%)
No. of treatment-related adverse events
Subjects with treatment-related adverse events, n (%)
Subjects with serious adverse events, n (%)
Subjects discontinued because of adverse events, n (%)
Subjects discontinued because of treatment-related adverse
events, n (%)
Died during the study
n ⫽ number of subjects included in the assessment; N ⫽ number of subjects in the population.
daily) was not inferior (i.e., was either more or similarly
effective) to timolol 0.5% (or optionally 0.25% for those
aged ⬍3 years) administered twice daily in its ability to
reduce IOP. There was a trend favoring greater IOP reduc-
tion with latanoprost; however, latanoprost superiority was
not found on statistical analysis. There was no statistically
significant difference in responder rates (proportion of sub-
jects with a ⱖ15% IOP reduction) between latanoprost and
timolol, with approximately half of all patients having a
treatment response.
Results of previous retrospective studies suggested that
patients with PCG have little clinically relevant IOP-
lowering response with pharmacologic agents such as la-
tanoprost, brinzolamide, and levobetaxolol.14,26 In the pres-
ent study, the IOP-lowering effect of latanoprost was greater
in the non-PCG subjects than in the PCG subjects. Approx-
imately one half of the subset of non-PCG subjects had a
diagnosis of JOAG, with the remaining diagnoses including
unspecified secondary glaucomas, aphakic glaucoma, and
Sturge–Weber syndrome. In contrast with previously re-
ported results, in this study, latanoprost did demonstrate a
clinically relevant IOP-lowering effect in the PCG subgroup
(mean 5.9 mmHg; P⬍0.01), although the observed IOP
reductions suggest the magnitude of IOP-lowering effect
may be less than in the non-PCG subgroup (mean 8.4
mmHg; P⬍0.01) in general. The differences between these
findings in the PCG group in this present study and previous
smaller and retrospective studies may be explained by re-
gional practice differences. In particular, in the retrospective
studies conducted in the United States, latanoprost often
was added as an adjunctive therapy to patients with PCG
initially being managed with surgery. This may have se-
lected out refractory cases of glaucoma in which the uncon-
trolled IOP required additional medical therapy; thus, the
true efficacy of latanoprost was blunted because of the
underlying nature of the disease.
The reasons for a smaller IOP-lowering response in
patients with PCG overall are not entirely clear. Latanoprost
acts by increasing the uveoscleral outflow via relaxation of
the ciliary muscle27 and remodeling of connective tissue in
the trabecular meshwork between the outer longitudinal
muscle bundles.28 In eyes with PCG (or other forms of
glaucoma that predominate in children), the uveoscleral
outflow pathway may be anatomically abnormal in addition
6
Latanoprost (Nⴝ68) Timolol (Nⴝ69)
41 64
24 (35.3) 29 (42.0)
6 15
4 (5.9) 10 (14.5)
2 (2.9) 7 (10.1)
1 (1.5) 4 (5.8)
0 1 (1.5)
0 0
to the trabecular outflow pathway and, thus, slightly less
responsive to latanoprost.16
Although the effect of outflow modulating pharmacother-
apy in PCGs may not be straightforward, there may be value in
latanoprost being used as a “last resort” for cases that are
inadequately controlled with other drugs or before undergoing
surgical treatment.14 In the PCG subpopulation of the present
study, the IOP-lowering effect was 5.9⫾5.9 mmHg with la-
tanoprost compared with 5.3⫾4.2 mmHg with timolol.
Although 4 patients receiving latanoprost discontinued
the study, twice as many patient discontinuations occurred
in the timolol treatment group. There were no treatment-
related discontinuations due to latanoprost or its lack of
efficacy compared with 4% of patients receiving timolol.
Likewise, latanoprost was well tolerated with a low inci-
dence of adverse events over the 3 months of exposure. In
both treatment groups, the youngest subjects (0 –⬍3 years)
experienced a relatively higher frequency of adverse events
compared with the 2 older age groups (3–⬍12 years and
12–18 years), suggesting that the youngest children are
more likely to exhibit overt nonocular infection-related
symptoms such as rhinitis, pneumonia, and gastroenteritis.
The rates of conjunctival hyperemia were low in both
groups, but the proportion of patients or parents reporting a
worsening of the conjunctival hyperemia score was greater
in the latanoprost group. It seems most likely that cases of
conjunctival hyperemia were not considered by the inves-
tigators as being of clinical significance and were not re-
ported as adverse events.
Major limitations of this study were the recruitment
challenges and the conduct in this pediatric population. In
particular, the rarity of glaucoma in this age group made it
challenging to enroll patients. Consequently, statistical dif-
ferences in IOP reduction between latanoprost and timolol
were difficult to determine given the small numbers of
patients in the study, especially in the very young children.
This most likely also contributed to the lack of ability to
further explore the relative effects of latanoprost versus
timolol as monotherapy for pediatric glaucomas of different
causes or subtypes. Another limitation was the nonstandard-
ized method of identification of ocular structural changes in
terms of glaucomatous progression.
In conclusion, latanoprost seemed to be safe and effec-
tive for the subjects in this trial over a 3-month exposure
 Maeda-Chubachi et al 䡠 Latanoprost vs Timolol in Pediatric Glaucomas
period, supporting the use of this pharmacologic agent as a
treatment option for patients with pediatric glaucoma. Fur-
thermore, approximately half of the subjects with PCG had
a treatment response, suggesting that latanoprost also may
have a role in the treatment of PCG.
Acknowledgments. The authors thank Charles Bosworth, PhD,
for contributions to the conduct of the study, including its concep-
tion and design. Editorial support, including contributing to the
first draft of the article, revising after author comments, and styling
the article for journal submission, was provided by Jane G. Mur-
phy, PhD, of Zola Associates and was funded by Pfizer Inc.
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Footnotes and Financial Disclosures
Originally received: September 10, 2010.
Final revision: March 1, 2011.
Accepted: March 3, 2011.
Available online: ●●●. Manuscript no. 2010-1247.
1
Pfizer Inc, New London, Connecticut.
2 Germany; and in part at: the Annual Meeting of the 2010 American
Private Practice, Jupiter, Florida.
3
Duke Eye Center, Durham, North Carolina.
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4
NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye
Hospital and UCL Institute of Ophthalmology, London, United Kingdom.
5
University of Utah, Moran Eye Center, Salt Lake City, Utah.
6
Pfizer Inc, New York, New York.
Presented at: the World Ophthalmology Congress, June 5–9, 2010, Berlin,
Academy of Ophthalmology, October 16 –19, 2010, Chicago, Illinois.
Financial Disclosure(s):
7
 Ophthalmology Volume xx, Number x, Month 2011

The author(s) have made the following disclosure(s): TM-C, KC-B, and
EY are employees of Pfizer Inc. BW was an employee of Pfizer Inc at the
time the study was conducted and the article was developed. BW, BDS,
and SFF are currently consultants for Pfizer Inc. PTK is currently a
consultant for Pfizer Inc, Alcon, Allergan, Bausch & Lomb, and AstraZen-
eca.
Funding: This study was sponsored by Pfizer Inc, New York, New York.
The sponsor participated in the design of the study; in the management,
analysis, and interpretation of the data; and in the preparation, review, and
approval of the manuscript. Peng T. Khaw, MD, was funded by the NIHR
Biomedical Research Centre for Ophthalmology at Moorfields Eye Hos-
pital and UCL Institute of Ophthalmology.
Correspondence:
Tomoko Maeda-Chubachi, MD, PhD, MBA, Pfizer Inc, 50 Pequot Avenue,
B3240, New London, CT 06320. E-mail: tomoko.maeda@pfizer.com.