ORIGINAL RESEARCH

24-Hour Efficacy of Travoprost/Timolol BAK-FreeVersus Latanoprost/Timolol Fixed Combinationsin Patients Insufficiently Controlled with Latanoprost

Anastasios G. P. Konstas • Irini C. Voudouragkaki • Kostantinos G. Boboridis •

Anna-Bettina Haidich • Eleni Paschalinou • Theodoros Giannopoulos •

Nikolaos D. Dragoumis • Alexandros K. Makridis • Malik Y. Kahook

To view enhanced content go to www.advancesintherapy.comReceived: April 7, 2014� Springer Healthcare 2014

ABSTRACT

Introduction: To compare the 24-h intraocular

pressure (IOP) control and tolerability of

travoprost/timolol benzalkonium chloride

(BAK)-free (TTFC) vs. latanoprost/timolol fixed

combination preserved with BAK (LTFC) in

open-angle glaucoma patients insufficiently

controlled with latanoprost 0.005%

monotherapy given once in the evening.

Methods: The authors have conducted a

prospective, observer-masked, active-

controlled, cross-over, comparison study.

Qualified open-angle glaucoma patients who

demonstrated a latanoprost-treated morning

IOP (10:00 ± 1 h) greater than 20 mmHg on

two separate visits were randomized for

3 months to receive either TTFC or LTFC.

Patients were then crossed over to the

opposite treatment for another 3 months. At

the end of the latanoprost run-in and after each

3-month therapy period patients underwent

24-h IOP monitoring in the habitual position

using Goldmann applanation tonometry in the

sitting position during the day (10:00, 14:00,

18:00 and 22:00) and Perkins tonometry in the

supine position at night (02:00 and 06:00).

Selected ocular surface parameters were

evaluated after each therapy period.

Results: Forty-two open-angle glaucoma

patients completed the study. The mean 24-h

baseline IOP on latanoprost was

21.5 ± 1.6 mmHg. Both fixed combinations

significantly reduced the IOP at each time

point, for the mean, peak and fluctuation of

Trial registration: ClinicalTrials.gov #NCT01779284.

Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-014-0125-9)contains supplementary material, which is available toauthorized users.

A. G. P. Konstas (&) � I. C. Voudouragkaki �K. G. Boboridis � E. Paschalinou � T. Giannopoulos �N. D. Dragoumis � A. K. Makridis1st University Department of Ophthalmology,Aristotle University of Thessaloniki, 1 KyriakidiStreet, 546 36 Thessaloniki, Greecee-mail: konstas@med.auth.gr

A. G. P. Konstas � K. G. Boboridis3rd University Department of Ophthalmology,Aristotle University of Thessaloniki, Thessaloniki,Greece

A.-B. HaidichDepartment of Hygiene, Aristotle University ofThessaloniki, Thessaloniki, Greece

M. Y. KahookDepartment of Ophthalmology, University ofColorado School of Medicine, Aurora, IL, USA

Adv Ther

DOI 10.1007/s12325-014-0125-9

24-h IOP compared with latanoprost

monotherapy (P\0.01). When the two fixed

combinations were compared directly, TTFC

provided significantly lower mean 24-h IOP

(18.9 ± 2.2 mmHg) vs. LTFC (19.3 ± 2.3 mmHg)

(P = 0.004) and significantly lower IOP at 18:00

(18.6 ± 2.5 vs. 19.5 ± 2.7 mmHg for LTFC)

(P\0.001). Further, TTFC demonstrated

significantly better tear film break-up time

(5.15 vs. 4.65 s), corneal stain (1.5 vs. 1.8) and

Schirmer I test (9.9 vs. 9.2 mm) compared with

LTFC after 3 months of therapy (P\0.01 for all

comparisons).

Conclusion: The mean 24-h IOP lowering of

TTFC was statistically more significant

compared to LTFC in patients insufficiently

controlled with latanoprost monotherapy.

Measurement of ocular surface health and tear

film status favored the BAK-free TTFC compared

to LTFC.

Keywords: 24-h intraocular pressure (IOP)

control; Benzalkonium chloride; Fixed

combinations; Latanoprost/timolol;

Ophthalmology; Polyquad; Travoprost/timolol;

Ocular surface; OSD

INTRODUCTION

Fixed combinations (FCs) minimize the number

of drops patients use and can enhance long-

term tolerability and adherence [1–3].

Prostaglandin/timolol fixed combinations

(PTFCs) are popular stepwise treatment

options for glaucoma patients insufficiently

controlled on prostaglandin monotherapies

and requiring additional lowering of

intraocular pressure (IOP) by 2–3 mmHg [2, 4,

5]. There is still uncertainty however as to the

precise role and value of PTFCs in the stepwise

therapy of glaucoma [2]. A 24-h IOP evaluation

allows a more complete assessment of the

efficacy of these adjunctive therapy options

[5–7]. At present, many glaucoma patients are

being treated with latanoprost as first-line

therapy. It is therefore of clinical importance

to clarify which PTFC provides optimal 24-h

IOP-lowering efficacy in those glaucoma

patients for whom monotherapy with

latanoprost was inadequate.

Glaucoma and ocular hypertension patients

are often committed to lifelong pressure

lowering therapies with roughly 50% of

patients requiring more than one medication

[8]. Chronic exposure to both active ingredient

and preservatives is known to cause significant

changes on the ocular surface [9, 10].

Benzalkonium chloride (BAK), a quaternary

ammonium, is the most common preservative

in glaucoma medications [11]. This highly

effective antimicrobial agent acts as a

detergent by denaturing proteins and

disrupting cytoplasmic membranes. It has

been convincingly demonstrated to adversely

affect corneal and conjunctival epithelium [12–

15]. Polyquaternium-1 is a less toxic

preservative with no detergent action, which

has been recently used in glaucoma topical

medications as an alternative to BAK [16].

Recent studies have recognized a high

prevalence of symptoms and signs of ocular

surface disease in chronically treated glaucoma

patients [13, 17]. Topical antiglaucoma

medications adversely impact tear film

synthesis and function, increase tear

osmolarity, reduce break-up time and decrease

Schirmer test [11]. These ocular adverse

reactions have subsequently been associated

with reduced treatment tolerability and

adherence, adversely impact quality of life and

may ultimately elicit a more unfavorable

surgical outcome [18–20].

Nevertheless, currently there is paucity of

clinical evidence documenting the comparative

Adv Ther

damage upon the ocular surface of FC therapies

with and without BAK. Published clinical

studies focus mainly on the hypotensive

efficacy and general safety profile without

investigating specific ocular surface

parameters. Beyond efficacy however long-

term tolerability can meaningfully impact

long-term adherence and success of therapy

[21]. The main objective of the current study

was to compare the 24-h IOP-lowering efficacy

and impact on the ocular surface of two popular

PTFCs (travoprost/timolol FC without BAK vs.

latanoprost/timolol FC containing BAK) in

open-angle glaucoma patients insufficiently

controlled on latanoprost monotherapy.

METHODS

Patients

This was a prospective, 3-month, observer-

masked, active-controlled, cross-over,

comparative study. The trial enrolled

consecutive patients at an academic glaucoma

service with early-to-moderate open-angle

glaucoma (primary open-angle, exfoliative, or

pigmentary glaucoma) who were insufficiently

controlled on branded latanoprost

monotherapy and demonstrated a latanoprost-

treated morning (10:00 ± 1 h) IOP greater than

20 mmHg at two separate visits.

All patients had to be treated with

latanoprost monotherapy for at least 3 months

to qualify. All study patients had to be older

than 29 years, and agreed to participate in this

trial and met the inclusion and exclusion

criteria. Enrolled patients exhibited typical

glaucomatous disc damage and visual field loss

(0.8 or better vertical cup-to-disc ratio and less

than 16 dB mean deviation visual field loss

attributed to glaucoma); visual acuity greater

than 0.1 in the study eye; corneal pachymetry

within the 550 ± 50 lm range; open anterior

chamber angles on gonioscopy. All patients

were treated in both eyes with the same

therapy regimen, if medical therapy was

indicated in both eyes.

Exclusion criteria were history of less than

10% IOP decrease on any IOP-lowering

medication, evidence of concurrent

conjunctivitis, keratitis, or uveitis in either eye;

history of inadequate adherence; intolerance,

or contraindication to either prostaglandins,

b-blockers, or BAK; severe ocular surface

disease, intraocular conventional or laser

surgery in the study eye; previous history of

ocular trauma; use of corticosteroids (within

2 months before enrolment), history of dry eyes

on topical artificial tear drops or active

blepharitis; and use of contact lenses.

Evaluation and grading of dry eye and ocular

surface parameters were performed in accordance

with the recently published guidelines and

methodology proposed by the International Dry

Eye Workshop and Meibomian Gland

Dysfunction Workshop [22, 23].

Compliance with Ethics

All procedures followed were in accordance

with the ethical standards of the responsible

committee on human experimentation

(institutional and national) and with the

Helsinki Declaration of 1975, as revised in

2000 and 2008. Informed consent was

obtained from all patients for being included

in the study.

Procedures

Study patients first underwent ocular surface

evaluation and then habitual 24-h IOP

monitoring with branded latanoprost

Adv Ther

preserved with BAK (Xalatan�, Pfizer, New York,

NY, USA) administered in the evening (20:00).

Selected ocular surface signs (corneal stain, tear

film break-up time, Schirmer I test) were

recorded prior to IOP monitoring. The same

investigators measured the IOP using the same

calibrated instruments [Goldmann and Perkins

applanation tonometers (Haag Streit USA,

Mason, OH, USA)]. Patients were admitted to

the hospital in the morning and IOP

measurements were recorded with Goldmann

applanation tonometry at 06:00, 10:00, 14:00

and 18:00 in the seated position. The 02:00 and

06:00 h IOP measurements were performed

with a Perkins tonometer in the habitual

supine position after waking the patient. The

two night-time measurements were performed

5 min after wakening to avoid changes

associated with any startle response that might

occur. The investigators measuring the IOP were

masked from the treatment regimen. Any

potential side effect was recorded for each

period, separately.

Following the latanoprost-treated 24-h curve

all patients were randomized for 3 months

(±2 weeks) to either TTFC preserved with

polyquaternium-1 (DuoTrav�, Alcon

Laboratories Inc., Fort Worth, TX, USA)

administered each evening (20:00), or LTFC

drops preserved with BAK (Xalacom�, Pfizer,

New York, NY, USA) administered each evening

(20:00). A safety visit and a morning IOP

measurement (10:00 ± 1 h) were performed at

the end of week 2. At the end of both treatment

periods patients underwent ocular surface

assessment and a treated 24-h curve in the

habitual position as described above.

Ocular Surface Assessment

After recording any patient reported ocular

surface symptoms, the following tests were

performed in the following order to evaluate

tear film and ocular epithelium status. Tear

film break-up time (TFBUT) was recorded. A

small quantity of fluorescein was instilled into

the inferior fornix with the use of a

fluorescein impregnated paper strip soaked

with a drop of unpreserved normal saline.

After a few blinks the patient was instructed to

keep the eyelids open and the interval

between the last complete blink and the first

appearance of a dry spot, or disruption in the

tear film was recorded with the use of a cobalt

blue filter. A cut-off value of B5 s was required

for dry eye diagnosis. The authors then

conducted corneal fluorescein staining.

Following the previous test, the cornea was

examined for punctate epitheliopathy staining

with fluorescein. The pattern and density of

the spots were evaluated with the van

Bijsterveld grading method with a range of

0–3 [24]. Finally, a Schirmer I test (without

anesthesia) was carried out. This is an

estimation of reflex tear flow stimulated by

the insertion of a filter paper into the

conjunctival sac. The length of paper in mm

soaked by tears within 5 min was recorded in

each case. A value less than 5 mm was

considered pathognomonic for aqueous-

deficient dry eye.

Statistics

The primary efficacy endpoint of this trial was

the mean 24-h IOP (the average pressure for the

6 time points). The individual time points, the

peak, trough and fluctuation of 24-h IOP were

included as secondary endpoints. A mixed

model was used for the cross-over repeated

measures design to adjust for period and carry-

over effects. Period and sequence were included

in the model as fixed effects. Patients within a

sequence were included in the model as a

Adv Ther

random effect. A 95% confidence interval (CI)

was constructed for the adjusted difference in

means. An intention-to-treat approach was

adopted and the subjects were analyzed

according to their randomized group.

The current 24-h study had an 80% power to

identify a 1.25 mmHg difference between

individual time points and between mean

24-h pressure readings assuming a standard

deviation of 2.8 mmHg between treatments if

42 patients completed the trial. One eye was

randomly chosen for analysis. Mean 24-h

fluctuation (average of the highest time point

minus the lowest time point for each individual

patient) as well as the mean peak and trough

pressures was analyzed by a paired t test.

Ocular surface signs between agents were

compared with a paired t test. Adverse events

were evaluated by Cochran’s Q and McNemar’s

test. The Bonferroni-adjusted P values are

reported to correct the analyses for multiple

comparisons in secondary endpoints. All other

reported P values were two tailed with P\0.05

considered as significant. Analyses were

conducted using IBM/SPSS Statistics Release

(Version 20.0, IBM Corporation, Armonk, NY,

USA).

RESULTS

Patients

Forty-two open-angle glaucoma patients (22

female and 20 male) completed the study out

of 44 enrolled (Fig. 1). There were 23 with

primary open-angle glaucoma, 17 with

exfoliative glaucoma and 2 with pigmentary

glaucoma. The mean age of trial participants

was 65.3 years.

Intraocular Pressure

The mean untreated morning IOP of the study

cohort was 31.1 mmHg and the mean 24-h

baseline IOP on latanoprost was

21.5 ± 1.6 mmHg (Table 1). Both FCs

significantly reduced the IOP at each time

point, for the mean 24-h IOP, peak 24-h IOP

and 24-h fluctuation of IOP compared with

latanoprost monotherapy (P\0.01) (Table 1;

Figs. 2, 3). Specifically, LTFC further reduced

the mean 24-h IOP by 2.2 mmHg, whereas TTFC

further reduced 24-h IOP by 2.6 mmHg. The

difference in mean incremental IOP reduction

from latanoprost baseline between the two FCs

was significant (P = 0.004). When the two FCs

were compared directly, TTFC provided

significantly lower mean 24-h IOP

(18.9 ± 2.2 mmHg) compared with LTFC (19.3

± 2.3 mmHg) (P = 0.004) and significantly

lower IOP at 18:00 (18.6 ± 2.5 mmHg) vs.

LTFC (19.5 ± 2.7 mmHg) (P\0.001) (Table 2).

Test for carry-over effect (P = 0.526) and period

effect (P = 0.245) was not significant.

Ocular Surface Assessment

All three ocular surface signs investigated were

significantly worse with LTFC compared with

latanoprost monotherapy (P B 0.001), whereas

Fig. 1 Flow chart of the study. BAK benzalkoniumchloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK, OS ocularsurface evaluation, TTFC travoprost/timolol fixedcombination without benzalkonium chloride (BAK)

Adv Ther

TTFC demonstrated significantly more corneal

staining than latanoprost (1.53 vs. 1.3)

(P = 0.005), but no difference for the other

two signs of tear film break-up time and

Schirmer I test. When the two FCs were

compared directly, TTFC demonstrated

significantly better corneal staining (1.53 vs.

1.78), TFBUT (5.15 vs. 4.65), and Schirmer I test

(9.95 vs. 9.23) compared with LTFC (P\0.003

for all comparisons) at the end of treatment

period (Fig. 4; Table 3).

These findings indicate that both FCs impact

the corneal epithelium more than latanoprost

monotherapy, with the TTFC without BAK

causing the least epithelial damage. In

addition, LTFC worsened the quality and

quantity of tear film compared to latanoprost

alone, whereas TTFC was comparable to

latanoprost monotherapy and significantly

superior to LTFC on tear film changes possibly

due to the milder effect of polyquaternium-1

compared to BAK.

Table 1 Statistical comparison in efficacy between latanoprost and TTFC (IOP values in mmHg)

Comparison time Latanoprost (mmHg) TTFC BAK-free (mmHg) P value

06:00 21.6 19.1 \0.001*

10:00 22.7 19.6 \0.001*

14:00 21.7 19.1 \0.001*

18:00 21.5 18.6 \0.001*

22:00 20.9 18.5 \0.001*

02:00 20.3 18.5 \0.001

Mean 24-h IOP 21.5 18.9 \0.001

Minimum 24-h 19.8 17.5 \0.001*

Peak 24-h 23.3 20.5 0.323

24-h fluctuation 3.52 2.98 0.014

BAK benzalkonium chloride, IOP intraocular pressure, TTFC BAK travoprost/timolol fixed combination without BAK* Bonferroni-adjusted P values

Fig. 2 IOP control with latanoprost vs. TTFC over 24 h(IOP values in mmHg). BAK benzalkonium chloride,IOP intraocular pressure, TTFC travoprost/timolol fixedcombination without benzalkonium chloride (BAK)

Fig. 3 24-h IOP efficacy with LTFC vs. TTFC (IOPvalues in mmHg). BAK benzalkonium chloride, IOPintraocular pressure, LTFC latanoprost/timolol fixedcombination preserved with BAK, TTFC travoprost/timolol fixed combination without BAK

Adv Ther

Adverse Events

All three treatments were well tolerated.

Patients reported significantly more stinging

with LTFC (19%) compared with latanoprost

(4.8%) (P = 0.031). When the two FC therapies

were compared directly the frequency of ocular

or systemic adverse effects did not differ

significantly between them (P[0.05).

DISCUSSION

To the best of the authors’ knowledge this study

is the first 24-h comparison between LTFC

preserved with BAK and TTFC preserved with

polyquaternium-1. Previous studies have

demonstrated that a 24-h IOP evaluation

allows a more complete assessment of the true

efficacy of available therapy options [25, 26].

There is limited published evidence evaluating

the complete diurnal–nocturnal efficacy of

PTFCs beyond 2–3 time points during the

daytime [1, 2]. Although PTFCs in regulatory

trials have demonstrated greater daytime

efficacy than each of their individual

components, the enhanced IOP reduction has

been less than was originally anticipated [2].

This may be due, at least in part, to the potency

of prostaglandin analogs, when used as

monotherapy, and the use of timolol only

once daily in PTFCs. Importantly, previously

published comparisons have generally

Table 2 Statistical comparison in efficacy between TTFC and LTFC (IOP values in mmHg)

Comparison time LTFC (mmHg) TTFC BAK-free (mmHg) P value

06:00 19.6 19.1 0.176*

10:00 19.4 19.6 1.000*

14:00 19.3 19.1 0.657*

18:00 19.5 18.6 \0.001*

22:00 19.1 18.5 0.084*

02:00 18.7 18.5 1.000*

Mean 24-h IOP 19.3 18.9 0.004

Minimum 24-h 17.7 17.5 0.229

Peak 24-h 20.7 20.5 0.323

24-h fluctuation 3.02 2.98 0.809

BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK,TTFC travoprost/timolol fixed combination without BAK* Bonferroni-adjusted P values

Fig. 4 Ocular surface parameters with LTFC vs. TTFC.BAK benzalkonium chloride, BUT break-up time, LTFClatanoprost/timolol fixed combination preserved withBAK, Stain corneal fluorescein staining, TTFCtravoprost/timolol fixed combination without BAK

Adv Ther

demonstrated greater efficacy for all PTFCs

compared with their prostaglandin

constituents over 24 h [27–30].

A previous comparative 24-h study between

BAK-containing TTFC and LTFC in exfoliative

glaucoma patients demonstrated superior 24-h

efficacy for the TTFC containing BAK [6, 7]. It

should be noted, however, that a number of

parameters (time of administration,

methodology of IOP evaluation, baseline IOP,

etc.) influence 24-h comparisons. To remove

possible ambiguity with the new BAK-free

formulation of the TTFC it was considered

important to assess the therapeutic efficacy of

this new formulation vs. LTFC preserved with

BAK throughout the 24-h period. To better

reflect clinical practice worldwide, the authors

have included in the present trial open-angle

glaucoma patients insufficiently controlled on

latanoprost monotherapy. Currently,

latanoprost (branded or generic) is the

commonest initial monotherapy selected by

physicians in many countries.

Similarly, the authors believe the current

study is also the first to combine 24-h efficacy

evaluation and ocular surface health metrics.

Another novelty of the present study is the

inclusion of an easy-to-perform clinical

evaluation of three selected ocular surface

signs. These signs are seen as a credible

surrogate of ocular surface health and can be

used in clinical practice to detect and quantify

epithelial and tear film alterations caused by

topical antiglaucoma medications and their

preservatives [31].

In this study, both PTFCs provided significant

incremental 24-h IOP lowering compared with

branded latanoprost monotherapy in open-

angle glaucoma patients who needed further

IOP reduction. There was a clinically meaningful

and statistically significant 24-h IOP separation

between the two PTFCs (LTFC 2.2 mmHg and

TTFC 2.6 mmHg) and latanoprost. Thus, the

present investigation corroborates previous

evidence suggesting PTFCs can provide an

additional 2–3 mmHg of IOP lowering [5, 27–

30]. It is worth noting that, in this trial, TTFC

without BAK provided significantly better 24-h

efficacy than LTFC preserved with BAK. Hence,

the findings of this study consolidate evidence

from a previous trial with exfoliative glaucoma

patients, which also demonstrated superiority

over 24 h for TTFC vs. LTFC, both preserved with

BAK [6, 7].

There is convincing evidence in vitro and on

animal models [12, 32, 33] demonstrating the

milder profile of polyquaternium-1 compared to

BAK on the ocular surface. In addition, there is

some clinical evidence that travoprost BAK-free

formulation preserved with polyquaternium-1

is equally efficient and safe compared to BAK-

preserved travoprost [34]. In the same vein,

clinical evidence suggests that TTFC preserved

with polyquaternium-1 has comparable IOP-

lowering effect and better safety profile than

BAK-containing TTFC [35].

Table 3 Statistical comparison in ocular surface signs between LTFC and TTFC

Comparison LTFC TTFC BAK-free P value

BUT (s) 4.65 5.15 \0.001

Corneal stain (van Bijsterveld score) 1.78 1.53 0.003

Schirmer test (mm) 9.23 9.95 \0.001

BAK benzalkonium chloride, BUT break-up time, LTFC latanoprost/timolol fixed combination preserved with BAK,TTFC travoprost/timolol fixed combination without BAK

Adv Ther

A key consideration beyond efficacy for the

success of combined therapy is long-term

tolerability. Long-term tolerability may

influence the rate of adherence, persistence

and ultimately, the long-term efficacy and

success of combined therapy. It is therefore

important to consider the long-term ocular

surface health when selecting initial and

combined antiglaucoma therapy. In this study

the authors compared three commonly used

baseline ocular surface parameters (tear film

break-up time, corneal stain and Schirmer

I test). TTFC without BAK exhibited more

corneal stain than latanoprost monotherapy,

but there was no difference on the tear film

parameters despite the addition of timolol,

which has been demonstrated to adversely

affect ocular surface and break-up time, as it

happened with LTFC where all three ocular

surface parameters were worse than those with

latanoprost. When the two FCs were compared

directly, TTFC demonstrated better TFBUT,

corneal stain and Schirmer I test values than

LTFC possibly due to elimination of BAK and

the milder effect of polyquaternium-1 on the

ocular surface and tear film. This is also

highlighted by the superior tolerability profile

of TTFC preserved with polyquaternium-1 when

compared with BAK-preserved TTFC [35]. It is

logical to assume that while short-term

tolerability with latanoprost and the LTFC

may be superior the long-term tolerability and

ocular surface health between these

medications and travoprost/TTFC may differ

because latanoprost and LTFC contain the

highest concentration of BAK (0.02%), whereas

travoprost and TTFC now contain the

preservative polyquaternium-1. This

hypothesis requires further verification.

This trial further supports the need to

routinely assess ocular surface and tear film

parameters in glaucoma patients in addition to

IOP monitoring. The three ocular surface

parameters employed in the present study are

easy and relatively simple to perform in daily

practice. The authors deliberately did not assess

the more sensitive conjunctival epithelium

changes with the use of lissamine green

staining in order to avoid detection of earlier,

milder changes and rather focus on the more

established corneal epithelial changes. In the

future, it may be best to first evaluate patient

symptoms with a validated questionnaire (e.g.,

Ocular Surface Disease Index), then assess the

tear film quality and quantity, carry out an

osmolarity measurement and finally investigate

the ocular surface damage with lissamine green

and fluorescein staining. This should be

followed by an examination of meibomian

gland morphology and function [22, 23]. This

approach may improve the awareness and

understanding of all adverse effects induced by

glaucoma medications upon the ocular surface

and may clarify better its correlation with long-

term tolerability and adherence. Newer metrics

that can objectively assess the tear film and

perform in vivo imaging of the epithelium

might be of use in future studies once

validated in human trials [15, 36].

This trial did not evaluate the long-term 24-h

efficacy of TTFC without BAK vs. LTFC

containing BAK, or its individual components.

This study also did not compare the TTFC

without BAK to travoprost without BAK, or to

other fixed combinations. It should be noted

that when evaluating efficacy differences

between medications there might be a

difference between what is statistically

significant and what is clinically significant. As

with all similar studies, it remains unclear if the

detected IOP and ocular surface differences are

clinically significant. Nevertheless, a 24-h

efficacy difference may be of greater value

than a difference based on a single, or even a

Adv Ther

few IOP readings. More information is needed

on the specific role of 24-h parameters (e.g.,

peak 24-h IOP) upon glaucoma progression [30].

In addition, the use of three different metrics

for evaluation of the ocular surface bolsters the

findings and lends credence to the likelihood of

clinical significance. Evaluation with

questionnaires that focus on patient report

outcomes should be performed in future

studies as an additional metric that would be

of value. More research is needed to further

clarify the best FC therapy and to delineate the

optimal stepwise therapy to treat ocular

hypertension and open-angle glaucoma.

CONCLUSION

The present investigation established that in

open-angle glaucoma patients insufficiently

controlled on branded latanoprost TTFC

without BAK provided superior 24-h efficacy

compared with LTFC containing BAK. This

cross-over study also demonstrated statistically

better ocular surface parameters with TTFC

preserved with polyquaternium-1 compared

with BAK-containing LTFC.

ACKNOWLEDGMENTS

This study was supported in part by Alcon

(Alcon Laboratories Inc., Fort Worth, Texas,

USA). All named authors meet the ICMJE

criteria for authorship for this manuscript,

take responsibility for the integrity of the work

as a whole, and have given final approval for the

version to be published.

Conflict of interest. AG Konstas has received

research support from Alcon, Allergan and

consulting support from Alcon, Allergan,

Merck and Santen. KG Boboridis has received

consulting support from Allergan and Thea. MY

Kahook has received research support from

Alcon, Allergan, Bausch & Lomb and

consulting support from Alcon, Allergan, and

Aerie. He is stock shareholder in Shape

Ophthalmics, Shape Tech, and Clarvista. IC

Voudouragkaki, E Paschalinou, AB Haidich, T

Giannopoulos, ND Dragoumis and AK Makridis

declare no conflicts of interest.

Compliance with ethics guidelines. All

procedures followed were in accordance with

the ethical standards of the responsible

committee on human experimentation

(institutional and national) and with the

Helsinki Declaration of 1975, as revised in

2000 and 2008. Informed consent was

obtained from all patients for being included

in the study.

REFERENCES

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