Hindawi

Journal of Ophthalmology
Volume 2017, Article ID 1917570, 8 pages
https://doi.org/10.1155/2017/1917570

Clinical Study
Efficacy and Tolerability of Travoprost 0.004%/Timolol 0.5%
Fixed-Dose Combination for the Treatment of Primary
Open-Angle Glaucoma or Ocular Hypertension Inadequately
Controlled with Beta-Blocker Monotherapy

Simon Fabian Lerner,1,2 Ki Ho Park,3 Douglas A. Hubatsch,4 Valeriy Erichev,5

Jose A. Paczka,6,7 and Timothy V. Roberts8,9
1
Organización Medica de Investigación (OMI), Buenos Aires, Argentina
2
Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina
3
Seoul National University Hospital, Seoul, Republic of Korea
4
Alcon Research, Ltd., Fort Worth, TX, USA
5
Research Institute of Eye Diseases, Moscow, Russia
6
Instituto de Oftalmologia y Ciencias Visuales, CUCS, Universidad de Guadalajara, Guadalajara, JAL, Mexico
7
Unidad de Diagnostico Temprano del Glaucoma, Global Glaucoma Institute Occidente, Guadalajara, JAL, Mexico
8
Sydney Medical School, University of Sydney, Sydney, NSW, Australia
9
Vision Eye Institute, Sydney, NSW, Australia

Correspondence should be addressed to Simon Fabian Lerner; [email protected]

Received 21 September 2016; Revised 13 December 2016; Accepted 29 December 2016; Published 23 January 2017

Academic Editor: Tamer A. Macky

Copyright © 2017 Simon Fabian Lerner et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Objective. To evaluate the efficacy and tolerability of travoprost 0.004%/timolol 0.5% fixed-dose combination (TTFC) in patients
with open-angle glaucoma (OAG) or ocular hypertension (OHT) inadequately controlled on beta-blocker monotherapy. Methods.
In this phase IV, open-label study, 156 patients on beta-blocker monotherapy with mean intraocular pressure (IOP) between 18
and 32 mmHg were randomized (no washout period) to receive TTFC for 8 weeks (TTFC group) or to continue beta-blocker
monotherapy for 4 weeks followed by TTFC for the remaining 4 weeks (beta-blocker group). Results. The mean IOP (±standard
deviation) at baseline in the TTFC and beta-blocker groups was 22.5 ± 2.5 mmHg and 22.2 ± 2.3 mmHg, respectively, and at weeks
4 and 8, was 16.7 ± 3.1 mmHg and 16.1 ± 3.1 mmHg, respectively, in TTFC group and 21.1 ± 3.1 mmHg and 16.1 ± 2.8 mmHg,
respectively, in the beta-blocker group. There was a significant least squares mean difference between TTFC and beta-blocker in 8
a.m. IOP at week 4 (−4.6 mmHg; one-sided 95% confidence interval [−inf, −3.9]; 𝑝 < 0.0001 [primary endpoint]); the upper bound
of the 95% confidence interval was within the prespecified limit (<0). Both treatments were well tolerated. Conclusion. Superior
IOP control was achieved with TTFC in patients with OAG or OHT previously uncontrolled with beta-blockers. No new safety
findings were identified. This trial is registered with ClinicalTrials.gov NCT02003391.

1. Introduction reduction in IOP from baseline has been shown to substan-

tially reduce the risk of further loss of visual field in OAG
Elevated intraocular pressure (IOP) is the major and cur- patients as well as delay the progression to glaucoma in ocular
rently only modifiable risk factor for optic nerve damage hypertension (OHT) patients, the aim of treatment is to
in open-angle glaucoma (OAG) [1–9]. As a 20% to 30% reduce IOP to a target pressure [6, 8].
2 Journal of Ophthalmology

Among the currently available treatment modalities, topi- The study was performed in accordance with the princi-
cal hypotensive medications are the preferred initial choice of ples of the Declaration of Helsinki and in compliance with the
treatment to lower IOP in glaucoma patients [2, 3]. Of the dif- Good Clinical Practices. The study protocol was approved by
ferent classes of topical hypotensives, prostaglandin analogs the appropriate independent ethics committee/institutional
(PGAs) and beta-blockers are commonly used worldwide as review board of the participating sites and patients provided
the first line of treatment for OAG and OHT [1, 10, 11]. signed informed consent.
DuoTrav (Alcon Laboratories, Inc., Fort Worth, Texas)
is a fixed-dose combination ophthalmic solution containing 2.2. Patients. Male or female patients, aged ≥18 years, with an
two topical hypotensives, a PGA travoprost 0.004% and existing clinical diagnosis of either OAG (presence of optic
a beta-blocker timolol 0.5% (TTFC). TTFC, through the nerve and visual field damage compatible with glaucoma
complementary mechanisms of action of its components, and not attributable to any other condition, in addition to
has been shown to lower IOP by 32% to 38% from baseline open angles in gonioscopy and elevated IOP values between
in patients with OAG or OHT [12–20]. TTFC is approved 18 and 32 mmHg) or OHT (open angles in gonioscopy
in Europe, Australia, Latin America, Canada, and several and elevated IOP values and absence of optic nerve and/or
countries in Asia for reducing IOP in adult patients with OAG visual field damage) were eligible if they were on beta-
or OHT who are insufficiently responsive to beta-blockers or blocker monotherapy for >30 days, with a mean baseline IOP
PGAs. >18 mmHg and <32 mmHg in at least one eye and in the
A head-to-head comparison of TTFC and beta-blocker opinion of the investigator would benefit from further IOP
treatment in patients with OAG or OHT with insufficient reduction.
IOP reduction with beta-blocker monotherapy has not been Exclusion criteria included any severe central visual field
investigated previously. The objective of this phase IV study loss (defined as a sensitivity of ≤10 dB in at least 2 of the
was to evaluate the efficacy and tolerability of TTFC com- 4 visual field test points closest to the point of fixation) in
pared with beta-blocker monotherapy in patients with OAG either eye within the last year; any chronic, recurrent, or
or OHT who were using a beta-blocker and needed further severe inflammatory eye disease (e.g., sclerotic, uveitis, or
IOP lowering. herpes keratitis); ocular trauma or surgery within the past
6 months; ocular infection or inflammation within the past
2. Methods 3 months; a best-corrected visual acuity (BCVA) score of
≤55 Early Treatment Diabetic Retinopathy Study (ETDRS)
2.1. Study Design. This 8-week, phase IV, prospective, multi- letters (equivalent to 20/80 Snellen score, 0.60 logarithm of
center, open-label, randomized, parallel-group, postmarket- the minimal angle of resolution [logMAR], or 0.25 decimal);
ing study was conducted across 14 sites in five countries any abnormality that would have prevented reliable mea-
(Argentina, Mexico, Australia, Russia, and Korea) between surement of IOP; other ocular pathologies (including severe
December 2013 and May 2015 (Clinicaltrials.gov identifier dry eye) that, in the opinion of the investigator, would have
NCT02003391). precluded the administration of study medication; conditions
Eligible patients were randomized (1 : 1) to receive either that would require the use of any additional topical or
TTFC (1 drop/affected eye, self-administered every evening at systemic ocular hypotensive medication during the study;
approximately 8 p.m.) or continued with their existing beta- and hypersensitivity to PGAs or any component of the
blocker monotherapy (1 drop/affected eye twice daily, self- study medications. Females who were pregnant, those who
administered at approximately 8 a.m. and 8 p.m.) for the first intended to become pregnant, those not willing to use a
4 weeks of the study. From week 5 to week 8, patients in both highly effective method of birth control during the study
treatment groups received TTFC (1 drop/affected eye, self- period, and those who were lactating were also excluded.
administered at approximately 8 p.m.). There was no washout
period between beta-blocker therapy and initiation of TTFC.
Patient randomization was stratified by site using a prestudy 2.3. Intervention. The approved formulation of TTFC in
generated randomization list that was provided to the sites Argentina, Australia, and Korea is DuoTrav PQ (with
in sealed envelopes. Each patient, upon informed consent, polyquad as preservative) and in Mexico and Russia is
was assigned a 7-digit study number consisting of a 4-digit DuoTrav BAK (with benzalkonium chloride as preserva-
sponsor-assigned number and a 3-digit sequential screening tive). Except for the preservative, both formulations are
number. Following verification of eligibility, patients were identical in composition. Previous studies have shown that
randomized by sequential assignment of numbers by the the formulations have similar efficacy and safety profiles [19].
designated staff at the investigational site. The proportion of
patients from the Latin American and Asian regions were 2.4. Assessments. IOP measurement, BCVA assessment, and
kept close to 1 : 1. an ocular examination of both eyes were conducted at every
Only one eye from each patient was chosen as the study visit (baseline, week 4, and week 8).
eye. If both eyes were diagnosed with OAG or OHT and IOP measurements were performed in both eyes using
dosed, the worse eye (defined as the eye with higher IOP at a Goldmann applanation tonometer with accuracy within
baseline) was selected as the study eye. If both eyes were equal ±2 mmHg. The fluorescein and anesthetic agents remained
at baseline, the right eye was selected as the study eye. The constant throughout the study, and all IOP measurements
study consisted of three visits: at baseline, week 4, and week 8. for any individual subject were preferably performed by the
Journal of Ophthalmology 3

same operator using the same tonometer. IOP measurements Enrolled

were performed at 8 a.m. (±30 min), and two consecutive N = 157
Screening failure
measurements were recorded for each eye.
n=1
Slit lamp examination and BCVA testing preceded IOP Randomized
measurement. Safety parameters included evaluation of ocu- N = 156
lar signs (eyelids/conjunctiva, cornea, lens, and iris/anterior
chamber) in the right (oculus dextrus [OD]) and left (oculus TTFC group Beta-blocker group
sinister [OS]) eyes using slit lamp microscopy. BCVA was n = 81 n = 75
measured first in the right eye using an ETDRS chart at a
distance of 3 meters (10 feet) or 4 meters (13 feet). For patients Week 1 to week 4
Week 1 to week 8
Twice-daily dose
who could not read English letters, a numerical Tumbling E Once-daily TTFC of beta-blocker
or a Landolt C logMAR chart was used. Week 5 to week 8
Once-daily TTFC
Completed study
2.5. Study Endpoints. The primary endpoint of the study was n = 78
Completed study
the difference in 8 a.m. IOP between TTFC and beta-blocker Withdrew consent = 2
n = 73
monotherapy at week 4. The secondary endpoints were mean Adverse event = 1 Protocol deviation = 2
change from baseline and percentage change from baseline
in 8 a.m. IOP at week 4. Supportive endpoints included mean Included in Included in
change from baseline and percentage change from baseline safety population, safety population,
n = 81 (100%) n = 75 (100%)
in 8 a.m. IOP after 4 weeks of TTFC treatment using pooled
ITT population, ITT population,
data (data from baseline to week 4 for the TTFC group and n = 78 (96.3%) n = 73 (97.3%)
data from week 4 to week 8 for the beta-blocker group were
pooled), achievement of IOP ≤18 mmHg at week 4 and week Figure 1: Study design and patient disposition. ITT, intent-to-treat;
8, and the 8 a.m. IOP, the mean change from baseline and the TTFC, travoprost 0.004%/timolol 0.5% fixed-dose combination.
percentage change from baseline in 8 a.m. IOP at week 8 with
TTFC.
Safety assessments were performed at all study visits
and included monitoring and documentation of treatment-
emergent adverse events (TEAEs) and assessment of their between the two treatment groups. The secondary efficacy
severity, seriousness, and causal relationship to the treatment; endpoints were evaluated using the same ANCOVA model
determination of BCVA; and slit lamp examinations of the used for the primary analysis. A sensitivity analysis was
eyelids, conjunctiva, cornea, iris, and lens. also performed for the primary and secondary endpoints
using the ANCOVA model omitting the region effect. The
2.6. Statistical Analysis. Assuming a 10% drop-out rate, 156 supportive efficacy endpoints and safety endpoints were
patients were planned to be randomized (78 per region and summarized descriptively.
39 per treatment group in each region) to obtain 138 evaluable All efficacy analyses were based on the intent-to-treat
patients. This sample size had an estimated power of 80% to (ITT) population that included all patients who had received
detect differences between treatments in 8 a.m. IOP at week 4 study medication and had completed at least one on-therapy
(IOP in TTFC group lower than IOP in beta-blocker group) if study visit. Safety analyses were based on the safety pop-
the true difference was >1.5 mmHg between treatments based ulation that included all patients who received the study
on the assumption of a standard deviation (SD) of 3.5 mmHg medication.
and the use of a two-sample, one-sided 𝑡-test performed at 𝛼
= 0.05 level of significance. 3. Results
For the superiority hypothesis, TTFC treatment was
considered superior to beta-blocker monotherapy if the least A total of 157 patients were enrolled and 151 completed
squares means (LSM) difference in the mean 8 a.m. IOPs the study. One patient was not randomized due to failure
at week 4 between the treatment groups (TTFC and beta- to meet the IOP inclusion criteria, and the remaining 156
blocker) was significant (i.e., one-sided 𝑝 value was <0.05, patients were included in the safety population. The ITT
which corresponds to an upper bound of the one-sided 95% population included 151 patients; of the five excluded patients,
confidence interval [CI] of <0). The treatment difference two withdrew consent, one withdrew due to an adverse
for the primary endpoint was examined using a between- event (AE), and two did not meet the protocol-specified visit
treatment test based on the LSM derived from an analysis window (Figure 1).
of covariance (ANCOVA) model that included region (Latin The mean age of the study population was 63.3 years
America [Argentina and Mexico] or Asia [Australia, Russia, (range, 20–86 years); 70.2% of the patients were female, 72.8%
and Korea]) and treatment as fixed effects and baseline 8 were white, and the diagnosis at enrollment was OAG in
a.m. IOP as a covariate. No multiplicity adjustments were 78.8% patients. The baseline and demographic characteristics
necessary, as the outcome of the study was based solely were similar between the TTFC and beta-blocker groups
on the primary analysis comparing 8 a.m. IOP at week 4 (Table 1).
4 Journal of Ophthalmology

Table 1: Demographics and baseline characteristics (ITT population).

TTFC Beta-blocker Overall

(𝑛 = 78) (𝑛 = 73) (𝑁 = 151)
Mean age ± SD (range), years 62.8 ± 12.8 (20–86) 63.8 ± 13.3 (22–86) 63.3 ± 13.0 (20–86)
Gender
Female, 𝑛 (%) 54 (69.2) 52 (71.2) 106 (70.2)
Race, 𝑛 (%)
White 58 (74.4) 52 (71.2) 110 (72.8)
Asian 12 (15.4) 10 (13.7) 22 (14.6)
Others 8 (10.3) 11 (15.1) 19 (12.6)
Underlying eye disease, 𝑛 (%)
OAG 61 (78.2) 58 (79.5) 119 (78.8)
OHT 17 (21.8) 15 (20.5) 32 (21.2)
ITT, intent-to-treat; OAG, open-angle glaucoma; OHT, ocular hypertension; SD, standard deviation; TTFC, travoprost 0.004%/timolol 0.5% fixed-dose
combination.

3.1. Efficacy Outcomes. The mean IOP (±SD) in the TTFC 30 −4.6∗ mmHg −4.6∗ mmHg −4.6∗ mmHg
and beta-blocker groups was 22.5 (±2.5) mmHg and 22.2 (−inf; −3.9) (−inf; −3.7) (−inf; −3.4)
25
(±2.3) mmHg, respectively, at baseline. At week 4, the mean
Mean IOP (mmHg),

IOP (±SD) was 16.7 (±3.0) mmHg in the TTFC group and 21.4 20
LS means

(±3.0) mmHg in the beta-blocker group. At week 8, the mean

15
IOP (±SD) was 16.1 (±3.1) mmHg in the TTFC group and 16.1
(±2.8) mmHg in the beta-blocker group. 10

5
3.2. Primary Outcome. At week 4, the mean 8 a.m. IOP was 16.6 21.2 16.4 21 16.8 21.4
lower in the TTFC group (16.7 ± 3.1 mmHg) than in the 0
beta-blocker group (21.2 ± 3.1 mmHg). The LSM difference Overall Latin American Asian
in 8 a.m. IOP at week 4 between the treatment groups
was statistically significant (point estimate: −4.6 mmHg; one- TTFC
Beta-blocker
sided 95% CI [−inf, −3.9]; 𝑝 < 0.0001). The superiority of
TTFC over beta-blocker monotherapy was established as the Figure 2: Least squares mean 8 a.m. IOP at week 4 by treat-
upper bound of the one-sided 95% CI was <0 (Figure 2). ment groups (total population) and by region (ITT population).
∗
The results of the sensitivity analysis stratified by region ANCOVA results for LS mean difference (one-sided 95% CI)
were similar to those observed for the overall group between treatment groups (TTFC and beta-blocker); 𝑝 < 0.0001.
(Figure 2). Note. The 𝑝 values for regions (Latin America and Asia) are for
descriptive purposes only. ANCOVA, analysis of covariance; CI,
confidence interval; IOP, intraocular pressure; ITT, intent-to-treat;
3.3. Secondary and Supportive Outcomes. At week 4, the LSM LS, least squares; TTFC, travoprost 0.004%/timolol 0.5% fixed-dose
change and the percentage change from baseline in 8 a.m. combination.
IOP were greater in the TTFC group compared with the beta-
blocker group (𝑝 < 0.0001; Figures 3(a) and 3(b)).
Analysis of pooled data also showed a reduction in mean The exploratory sensitivity analysis stratified by region
change and percentage change from baseline in 8 a.m. IOP showed results similar to those of the overall group for
after 4 weeks of treatment with TTFC (mean change: −3.5 ± the LSM change from baseline and the percentage change
3.9 mmHg; percentage change: −15.3%±16.6%). As shown in from baseline in 8 a.m. IOP at week 4 (Figures 3(a) and
Figure 4, overall, a higher proportion of patients in the TTFC 3(b)). Similarly, at week 4, a higher proportion of patients
group compared with the beta-blocker group achieved IOP in the TTFC group achieved IOP ≤18 mmHg compared with
≤18 mmHg at week 4 (75.6% versus 13.9%). At week 8, the the beta-blocker group (Latin America: 77.5% versus 10.8%;
proportion of patients achieving IOP ≤18 mmHg increased in Asia: 73.7% versus 17.1%). In the TTFC group, at week 8, a
the beta-blocker group following a switch to TTFC after week higher proportion of Latin American patients achieved IOP
4 (Figure 4). ≤18 mmHg compared to Asian patients (97.5% versus 78.9%;
Among patients receiving TTFC treatment for 8 weeks, Figure 4). The mean change in 8 a.m. IOP from baseline at 8
the mean change in 8 a.m. IOP from baseline was −6.5 ± weeks among patients receiving TTFC treatment was −6.4 ±
3.3 mmHg, and the mean percentage change from baseline 2.5 mmHg and −6.5±3.9 mmHg in Latin American and Asian
in 8 a.m. IOP was −28.3% ± 12.6%. patients, respectively. The corresponding mean percentage
Journal of Ophthalmology 5

Total Latin American Asian

Overall Latin American Asian 0
0 −25.2 −4.9 −24.2 −4.6 −26.2 −6.3

Percentage age change from

−1.2 −0.8

baseline in IOP, LS means

Mean change from baseline in

−1 −5.8 −5.4 −6.2 −1.6 −5

IOP (mmHg), LS means

−2 −10
−3
−15
−4
−5 −20
−6 −25
−7
−4.6∗ mmHg −4.6∗ mmHg −4.6∗ mmHg −30 20.3 ∗ 20.6 ∗ 20.0 ∗
−8
(−inf; −3.9) (−inf; −3.7) (−inf; −3.4) (−inf; −16.8) (−inf; −16.3) (−inf; −14.4)

TTFC TTFC
Beta-blocker Beta-blocker
(a) (b)
a
Figure 3: (a) Least squares mean change from baseline in 8 a.m. IOP at week 4 by treatment groups (total population) and by region
(ITT population). a refers to beta-blocker-treated baseline; ∗ ANCOVA results for LS mean difference (one-sided 95% CI) between treatment
groups (TTFC and beta-blocker); 𝑝 < 0.0001. Note. The 𝑝 values for regions (Latin America and Asia) are for descriptive purposes only.
ANCOVA, analysis of covariance; CI, confidence interval; IOP, intraocular pressure; ITT, intent-to-treat; LS, least squares; TTFC, travoprost
0.004%/timolol 0.5% fixed-dose combination. (b) Least squares mean percentage change from baselinea in 8 a.m. IOP at week 4 by treatment
groups (total population) and by region (ITT population). a refers to beta-blocker-treated baseline; ∗ ANCOVA results for LS mean difference
(one-sided 95% CI) between treatment groups (TTFC and beta-blocker); 𝑝 < 0.0001. Note. The 𝑝 values for regions (Latin America and Asia)
are for descriptive purposes only. ANCOVA, analysis of covariance; CI, confidence interval; IOP, intraocular pressure; ITT, intent-to-treat;
LS, least squares; TTFC, travoprost 0.004%/timolol 0.5% fixed-dose combination.

100 97.5 Table 2: Treatment-emergent AEs with incidence ≥2% during the
Patients (%) with IOP ≤ 18 mmHg

88.5 study (safety population).

80.8 81.6 80.0
80 75.6 77.5 73.7 78.9
TTFC Beta-blocker
MedDRA preferred term
(𝑁 = 81) (𝑁 = 75)
60
Total AEs, 𝑛 (%) 18 (22.2) 9 (12.0)
40 Ocular hyperemia 5 (6.2) 0
Dry eye 2 (2.5) 2 (2.7)
20 13.9 17.1
10.8 Eye pruritus 4 (4.9) 0 (0.0)
Nasopharyngitis 2 (2.5) 2 (2.7)
0
Total Latin Asian Total Latin Asian Influenza 0 2 (2.7)
American American A subject with more than one event in a specific category was only counted
Week 4 Week 8# once. Number of events based on MedDRA coding; due to splitting of terms,
number of MedDRA terms can be different from number of reported events.
TTFC MedDRA version 18.0.
Beta-blocker AEs, adverse events; MedDRA, Medical Dictionary for Regulatory Activities;
after switching from beta-blocker to TTFC TTFC, travoprost 0.004%/timolol 0.5% fixed-dose combination.

Figure 4: Percentage of patients achieving IOP ≤ 18 mmHg at week

4 and week 8 (total population) and by region (ITT population). (≥2%) TEAEs were ocular hyperemia, eye pruritus, dry
#
At week 8, both groups were receiving TTFC, as patients in the eye, and nasopharyngitis in the TTFC group and dry eye,
beta-blocker group had switched to TTFC between week 5 and week nasopharyngitis, and influenza in the beta-blocker group.
8. IOP, intraocular pressure; ITT, intent-to-treat; TTFC, travoprost
Treatment-related TEAEs were reported in 12 patients
0.004%/timolol 0.5% fixed-dose combination.
(14 AEs) in the TTFC group and in three patients (3 AEs)
in the beta-blocker group (after switching to TTFC). The
most frequently reported treatment-related AEs were ocular
change from baseline in 8 a.m. IOP was −29.9% ± 10.57% and hyperemia and eye pruritus in the TTFC group (Table 3).
−27.5% ± 14.7%, respectively. Three patients reported treatment-related AEs in the beta-
blocker group, between weeks 5 and 8 of the study, when
3.4. Safety Outcomes. Overall, 35 TEAEs were reported patients had received TTFC (Table 3).
during the 8-week study period: 22 TEAEs in 18 patients Two patients in the TTFC group discontinued the study
in the TTFC group and 13 TEAEs in nine patients in the due to treatment-related AEs. One patient withdrew due
beta-blocker group. As shown in Table 2, the most frequent to ocular hyperemia, 1 day after start of treatment. The
6 Journal of Ophthalmology

Table 3: Incidence of treatment-related TEAEs during the study TTFC in patients inadequately controlled on beta-blocker
(safety population). monotherapy has been reported in previous observational
TTFC Beta-blocker
and open-label, noncomparator studies [15–17, 20]. Similarly,
MedDRA preferred term effective improvements in IOP have also been reported
(𝑁 = 81) (𝑁 = 75)
Eye disorders, n (%) 12 (14.8) 3 (4.0) with TTFC in patients having an insufficient IOP reduction
Ocular hyperemia 5 (6.2) 0 with PGA monotherapy [15, 16, 21]. Further, studies have
Ocular pruritus 3 (3.7) 0 shown that TTFC provides greater IOP reduction than its
Conjunctivitis allergic 1 (1.2) 1 (1.3) components travoprost and timolol, used separately as single
Dry eye 1 (1.2) 1 (1.3) agents [12, 13]. The long-term IOP-lowering efficacy of TTFC
Ocular surface disease 1 (1.2) 1 (1.3) has been proven in studies with up to 12 months of follow-up
Eyelid-pigmentation 1 (1.2) 0 [18, 22].
Eye irritation 1 (1.2) 0
It has been observed that approximately 40% to 50% of
Eye pain 1 (1.2) 0
glaucoma patients invariably require more than one medi-
Eyelids pruritus 1 (1.2) 0
cation to achieve their target IOP and therefore have to be
Immune system disorders, n switched to a more powerful therapy or need an add-on
1 (1.2) medication to their existing therapy [2, 6]. At present, treat-
(%)
Hypersensitivity 1 (1.2) 0 ment with topical hypotensives follows a step-wise approach,
wherein if appropriate response to initial monotherapy is not
A subject with more than one event in a specific category was only counted
once. MedDRA coding; due to splitting of terms, number of MedDRA terms achieved, patients are transitioned to another antiglaucoma
can be different from number of reported events. MedDRA version 18.0. agent of the same or different class. PGA and beta-blocker
MedDRA, Medical Dictionary for Regulatory Activities; TEAEs, treatment- fixed-dose combinations are more effective in reducing IOP
emergent adverse events; TTFC, travoprost 0.004%/timolol 0.5% fixed-dose compared with timolol monotherapy [23]. A meta-analysis
combination.
including 40 randomized clinical trials showed that treatment
with fixed-dose combinations containing timolol can result
in an IOP percentage reduction of >30% from baseline [24].
other patient withdrew due to moderate eye pruritus and Fixed-dose combination therapies also provide additional
hypersensitivity to treatment, 15 days after start of treatment. advantages of longer-lasting effect, simple dosing regimen,
No serious adverse events (SAEs) or deaths were reported and better compliance as well as a lower risk of ocular surface
during the study. disease in patients due to reduced exposure to preservatives,
There were no changes from baseline in BCVA at week when compared to concomitant administration of their
4 and week 8 in either treatment group. No clinically components [25]. Hence, the results from this study and
relevant changes were observed on slit lamp examination over previous studies suggest that transitioning to a fixed-dose
the 8-week period, except for conjunctival abnormality in combination such as TTFC can be considered to reach target
approximately 10% of patients in both groups (TTFC, 10.3% IOP faster, in patients with inadequate response to their
OD/10.3% OS; beta-blocker, 9.6% OD/11.0% OS). existing monotherapy treatment [15–17, 20].
Interestingly, nearly 20% more Latin American patients
4. Discussion achieved IOP ≤18 mmHg at week 8 compared with Asian
patients. The clinical relevance of this finding is not known,
This study demonstrated the superior efficacy of once-daily as the mean IOP-lowering efficacy of TTFC was similar in the
dosing of TTFC in lowering the IOP in patients with two regional groups. It should also be noted that the study
OAG and OHT with an insufficient response to existing was not powered to analyze the difference between the two
beta-blocker monotherapy. There was an additional 25% regional groups.
(−5.8 mmHg) mean reduction in IOP levels at week 4 with Both treatments were generally well tolerated, with
TTFC as compared with a 4.7% (−1.1 mmHg) mean reduc- overall low rates of AEs reported in this study. Only two
tion observed with beta-blocker therapy. The higher IOP patients withdrew from the study due to ocular AEs in the
lowering with TTFC gains significance considering that this TTFC group. The most commonly reported drug-related
was additional reduction achieved from the beta-blocker- AE with TTFC was hyperemia, which is attributable to the
treated baseline (i.e., in treatment-exposed patients) without PGA component of the combination. Higher AE rates have
any washout period between prior and current treatments, generally been reported with fixed combination therapies,
mimicking everyday practice. The IOP reduction observed in likely due to the presence of two components. Consistent with
the beta-blocker group at week 4 may be attributable to the this observation, the incidence of AEs and treatment-related
Hawthorne effect, which is often observed in switch studies. AEs in the study were higher in the TTFC group than in
Overall, 8-week treatment with TTFC resulted in a net 28% or the beta-blocker group. No SAEs or new safety findings were
6.5 mmHg mean reduction in IOP. These mean reductions in reported with TTFC during the 8-week study period, and the
IOP with TTFC are clinically relevant, as a 1 mmHg reduction safety profile of TTFC in this study was consistent with that
in IOP is reported to be associated with a 10% lowering in the reported in previous studies [12–20].
risk of disease progression in glaucoma patients [9]. This phase IV study had both strengths and limitations.
Significant IOP control (an additional 5.0 to 5.7 mmHg The lack of washout period before switching therapies, which
mean reduction in IOP over a 4- to 16-week period) with ensured that patients received continuous medical care for
Journal of Ophthalmology 7

controlling IOP, is similar to actual clinical practice and adds [4] Collaborative Normal-Tension Glaucoma Study Group, “The
strength to the present findings. Limitations of the study effectiveness of intraocular pressure reduction in the treatment
include the open-label design, lack of long-term follow-up, of normal-tension glaucoma,” American Journal of Ophthalmol-
and a lack of adjustment for multiplicity. ogy, vol. 126, no. 4, pp. 498–505, 1998.
European Glaucoma Society guidelines recommend that [5] A. Heijl, M. C. Leske, B. Bengtsson, L. Hyman, B. Bengtsson,
aggressive treatment could be required in some glaucoma and M. Hussein, “Reduction of intraocular pressure and glau-
cases, such as in young patients or those with severe disease, coma progression: results from the Early Manifest Glaucoma
to ensure that the quality of life is sustained by minimizing Trial,” Archives of Ophthalmology, vol. 120, no. 10, pp. 1268–1279,
2002.
loss to visual function [1]. The results from this study suggest
that patients with glaucoma whose IOP is inadequately [6] M. A. Kass, D. K. Heuer, E. J. Higginbotham et al., “The
Ocular Hypertension Treatment Study: a randomized trial
controlled with beta-blockers may derive clinical benefit from
determines that topical ocular hypotensive medication delays or
earlier transition to TTFC.
prevents the onset of primary open-angle glaucoma,” Archives of
Ophthalmology, vol. 120, no. 6, pp. 701–713, 2002.
5. Conclusion [7] M. C. Leske, S.-Y. Wu, A. Hennis, R. Honkanen, and B.
Nemesure, “Risk factors for incident open-angle glaucoma: the
Travoprost 0.004%/timolol 0.5% fixed-dose combination was Barbados Eye Studies,” Ophthalmology, vol. 115, no. 1, pp. 85–93,
superior to beta-blocker monotherapy in lowering IOP in 2008.
patients with OAG or OHT inadequately controlled on beta- [8] P. R. Lichter, D. C. Musch, B. W. Gillespie et al., “Interim clinical
blocker monotherapy. Both treatments were well tolerated, outcomes in the collaborative initial glaucoma treatment study
and no new safety findings were identified. comparing initial treatment randomized to medications or
surgery,” Ophthalmology, vol. 108, no. 11, pp. 1943–1953, 2001.
Competing Interests [9] M. C. Leske, A. Heijl, M. Hussein, B. Bengtsson, L. Hyman,
and E. Komaroff, “Factors for glaucoma progression and the
Dr. Simon Fabian Lerner has conducted clinical trials for effect of treatment: the early manifest glaucoma trial,” Archives
Alcon and Allergan, has received honoraria for speaking of Ophthalmology, vol. 121, no. 1, pp. 48–56, 2003.
events from Alcon and Sidus, is an advisory board member [10] B. E. Prum, L. F. Rosenberg, S. J. Gedde et al., “Primary open-
for Alcon, and has received travel support from Glaukos. Dr. angle glaucoma,” Ophthalmology, vol. 123, no. 1, pp. P41–P111,
Ki Ho Park conducted the clinical trial for Alcon. Douglas 2016.
Hubatsch is an employee of Alcon Research Ltd. Dr. Jose A. [11] R. L. Stamper, S. A. Wigginton, and E. J. Higginbotham,
Paczka has acted as a consultant for Alcon, Allergan, Lab- “Primary drug treatment for glaucoma: beta-blockers versus
oratorios Sophia, Mundipharma, and Zeiss; has conducted other medications,” Survey of Ophthalmology, vol. 47, no. 1, pp.
63–67, 2002.
clinical trials for Alcon, Allergan, and Laboratorios Sophia;
and has received honorarium for lectures from Alcon. Dr. [12] H. S. Barnebey, S. Orengo-Nania, B. E. Flowers et al., “The safety
and efficacy of travoprost 0.004%/timolol 0.5% fixed combina-
Valeriy Erichev has no conflict of interests or competing
tion ophthalmic solution,” American Journal of Ophthalmology,
financial interests with regard to the publication of this paper. vol. 140, no. 1, pp. 1–7, 2005.
Dr. Timothy V. Roberts has conducted clinical trials and
[13] J. S. Schuman, G. J. Katz, R. A. Lewis et al., “Efficacy and
received honoraria for speaking events from Alcon, Pfizer,
safety of a fixed combination of travoprost 0.004%/timolol 0.5%
and Allergan. ophthalmic solution once daily for open-angle glaucoma or
ocular hypertension,” American Journal of Ophthalmology, vol.
Acknowledgments 140, no. 2, pp. 242.e1–242.e11, 2005.
[14] R. J. Noecker, N. S. Awadallah, and M. Y. Kahook, “Travoprost
Manuscript writing assistance was provided by Shivani Vada- 0.004%/timolol 0.5% fixed combination,” Drugs of Today, vol.
palli and Lakshmi Venkatraman (Novartis Healthcare Pvt. 43, no. 2, pp. 77–83, 2007.
Ltd., Hyderabad, India). This study was sponsored by Alcon [15] K.-O. Arend and T. Raber, “Observational study results in
Research, Ltd., Fort Worth, Texas, USA. glaucoma patients undergoing a regimen replacement to fixed
combination travoprost 0.004%/timolol 0.5% in Germany,”
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