ORIGINAL RESEARCH
`
`Efficacy, safety, and improved tolerability
`of travoprost BAK-free ophthalmic solution
`compared with prior prostaglandin therapy
`
`J Charles Henryl
`james H Peace2
`jeanette A Stewart3-4
`William C Stewart”
`
`'Little Rock Eye Clinic. Little Rock.
`AR, USA: zDialzietic Eye Medical
`Clinic. lnglewood.CA. USA13PRN
`Pharmaceutical Research Network.
`LLC, Dallas.TX. USA: ‘Carolina Eye
`Institute. University of South Carolina,
`School of Medicine,
`Columbia. SC. USA
`
`
`
`Correspondence: William C Stewart
`500i LBJ Freeway Suite 700, Dallas.
`TX 75244. USA
`Tel +l 843 762 6500
`Fax +l 843 762 7444
`Email into@pmorb.com
`
`Purpose: To evaluate the efficacy, safety and tolcrabilily of changing to travopmsl BAK-fi'ec
`from prior p-mstaglnndin therapy in patients Willi primary open-angle glaucoma or ocular
`hypertension.
`Dalgn: Prospective, multi-centcr, historical control study.
`Methods: Patients treated with latanoprost or himatoprost who needed alternative therapy
`due to tolerahility issues were enrolled. Patients were surveyed using the ( )cular Surlace Disease
`Index (OSDI) to evaluate OSD symptoms prior to changing to travoprost BAK-free dosed once
`every evening. Patients were rte-evaluated 3 months later.
`Results: In 691 patients, travoprost BAX-free demonstrated improved mean OSDI scores
`compared to either latanoprost or bimntoprost (p <1 0.0001). Patients having any bsselinc
`OSD symptoms (n = 235) demonstrated significant improvement after switching to tmvoprost
`BAK—frcc (p < 0.0001). in 70.2% of these patients, symptoms were reduced in severity by at
`least 1 level. After changing medications to travoprost BAR-lit», mean intraocular pressure
`( 10?] was significantly decreased ('p < 0.0001 ). Overall, 72.4% preferred travoprost BAK-frec
`(p < 0.0001, travoprost l.£AK-trec vs prior therapy). Travoprosa BAK-l‘ree demonstrated less
`conjunctiva] hypcremia than either prior therapy (p < 0.0001 1.
`Conclusions: Patients previously treated with a BAK-prcsen'cd prostaglundin analog who are
`changed to travoprost BAK-free have clinically and statistically significant improvement in their
`OSD symptoms, decreased hyperemia, and equal or better 101’ control.
`Keywords: glaucoma, prostaglandin analog. travoprost. latanopmst, himatoprost, preservative,
`benzalkonium chloride, ocular surface disease
`
`Introduction
`
`Symptoms of dry eye are reported in approximately 15% of the elderly according
`to a population-based study conducted by Schein et at (1997). However. it has
`recently been reported by Fechtner et a1 (2008') that prevalence of ocular surface
`
`disease (OSD) symptoms in glaucoma patients is 48.4% and the severity of OSD
`symptoms increases with the number of medications used. This increased occur—
`rence of dry eye symptoms in glaucoma patients is of particular interest. Glaucoma
`patients may be at an increased risk of developing dry eye symptoms due to the
`long-term use of intraocular pressure (lOPHowering medications. Many of these
`medications contain preservatives which have been associated with an increase
`in the prevalence of ocular signs and symptoms (Kuppcns ct a1 1995; Pisclla et a1
`2002: Jacnen et al 2007‘). Benzalkonium chloride (BAK), the. most commonly used
`preservative in ophthalmic preparations. has a high affinity for membrane proteins
`and may accumulate in ocular tissues. inducing cell toxicity and/or cell death in a
`dose-dependent manner (Yee 2007).
`
`Clinical Ophthalmology 2908:2(3) 6|3—62I
`© 2008 Henry et al. publisher and licensee Dove Medical Press Ltd.This is an Open Access article
`which permits unrestricted noncommercial use. provided the original work is properly cited.
`
`6 I 3
`
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
`
`ALCON 2133
`
`

`

`Henry et 3!
`
`introduced in 1996, the prostaglandin analog class of
`
`Methods
`
`lOP-lowering medications has become the most common
`
`Patients
`
`first-line therapy for the treatment of elevated 10? in the US
`
`generally because of its efficacy and systemic tolerability.
`
`However. prostaglandin analog preparations have tradition-
`
`ally been preserved with BAK and have been shown to
`damage ocular tissue by inducing apoptosis and increasing
`
`the concentrations of inflammatory markers (Noecker et al
`
`2004; Baudouin et al 2007).
`
`Travoprost BAK-free ophthalmic solution (TRAV-
`ATAN Z". Alcon Laboratories, Inc.. Fort Worth, TX,
`
`USA) was recently introduced as the first commercially
`
`available preparation of a prostaglandin analog preserved
`without BAK. Travoprost BAK-free contains an ionic
`
`buffered preservative system. soniaW. Recently, Lewis
`
`et al compared travoprost BAK-free with BAK-preserved
`
`travoprost (T RAVATAN“, Alcon Laboratories. Inc., Fort
`
`Worth. TX, USA) in a randomized, multi—center. paral-
`
`lel, double-masked trial (Lewis ct al 2007). IOP control
`
`was Statistically equivalent between treatment groups
`
`and less conjunctiva] hyperemia was observed with the
`
`BAK-free preparation, although it was not. statistically
`
`signi.icant.
`
`The toxicity of travoprost with and without BAK has been
`
`compared with the commercial preparation of iatanoprosr
`
`in several laboratory trials. Several investigators have used
`
`comeal and conjunctival cell cultures to demonstrate that
`
`travoprost BAK-free is associated with less apoptosis and
`
`cytotoxicity compared with latanoprost (preserved with
`
`0.02% BAK) (,Yee ct al 2006; Baudouin et a1 2007; Epstein
`
`etal 2008). Similarly. McCarey and Edclhauser (2007)
`
`reported that trctmcnt with ttcvoprest BAK-free had no
`
`negative effect on the integrity of corneal epithelial tight
`
`junctions, whereas latanoprost use was associated with
`
`significant loss of tight junctions (p < 0.0001). In addition,
`
`Eligible patients were adults with open-angle glaucoma
`
`or ocular hypertension treated with either latanoprost
`
`(Xaiatan‘i‘. Pfizer inc., New York, N '1', USA) or bimatoprost
`
`tLurnigan“, Allergan, irvine. CA, USA) monotherapy
`
`who demonstrated a need for greater tolerability and
`
`were judged by their physician to be a good candidate for
`
`travoprost BAK—free ophthalmic solution. The design was
`
`a multi-centcr, prospective, open-label, historical control
`
`study. Patients enrolled for this study were recruited from
`65 clinical sites across the US.
`
`Patients included in this study were at least 18 years
`
`of age: able to read and complete the OSDi questionnaire
`
`in English; had a clinical diagnosis of ocular hypertension
`
`or primary open—angle, pigment dispersion, or exfoliation
`
`glaucoma; treated with either latanoprost or bimatoprost
`
`monotherapy for at least 1 week, the last dose of which
`was instilled correctly so the patient was within the dos-
`
`ing cycle at Visit 1; best—corrected Snellen visual acuity
`
`of 20/200 or better in each eye; and IOP <30 mmHg in
`
`both eyes.
`
`Exclusion criteria included primary or secondary glau-
`
`coma not listed in inclusion criterion; untreated history of
`
`narrow angles in either eye; concurrent infectious/non-
`
`infectious conjunctivitis, keratitis. or uveitis in either eye:
`
`blepharitis (non-clinically significant. or prostaglandin-
`
`induced conjunctiva! injection was allowed); intraocular
`
`conventional surgery or laser surgery in study cyc(s) less
`
`than 3 months prior to Visit 1; risk of visual field or visual
`
`acuity worsening as a consequence of participation in the
`
`trial; anticipated use of ocular or oral corticosteroids for
`more than 2 weeks total during the trial; and contact lens
`
`use in the study eyets).
`
`Whitson et al (2006) found little corneal toxicity in rabbits
`
`Procedures
`
`treated with travoprost BAK-free, whereas latanoprost caused
`
`superficial cell loss. Unfortunately, few data are available
`
`All patients signed an institutional Review Board-approved
`informed consent agreement and met the inclusion/exclu-
`
`that evaluate the clinical benefit of eliminating BAK from
`
`sion criteria before any procedures were performed. Eligible
`
`prostaglandin analog therapy.
`
`patients had an ocular and systemic history taken. Patients
`
`The purpose of the pres-hr study was to exam-
`
`then discontinued previous therapy and received l bottle of
`
`ine the safety, tolerability and efficacy of travoprost
`
`BAK-free ophthalmic solution compared to previous
`
`travoprost BAK—free ophthalmic solution (TRAVATAN Z“.
`Alcon Laboratories. Inc., Fort Worth, TX. USA) and a pre-
`
`use of either latanoprost or bimatoprost monotherapy.
`The Ocular Surface Disease index (OSDI), a validated
`
`English-language questionnaire, was used examine the
`
`scription for TRAVATAN Z", to be used once every evening
`
`in the study eye(s).
`Patients returned for Visit 2 at Week 12, which must
`
`prevalence of dry eye/08D complaints in glaucoma
`
`have been conducted at the same time of day (+ 1 hour) as
`
`patients (Schiffman et al 2000).
`
`Visit l. Patients who did not take their travoprost BAK-free
`
`
`
`6”
`
`Clinical Ophthalmology 2008:2(3)
`
`

`

`Travopmst BAK-free ophthalmic solution compared with prior prostaglandin therapy
`
`as prescribed the day before the visit were rescheduled.
`
`A one—way ANOVA test also was utilized to evaluate
`
`Patients may have been examined by the investigator at any
`time between Visits 1 and 2 but these were not considered
`
`differences in hyperemia grading (grade 0—3) and OSDI
`
`scores for both prior medications compared to travoprost
`
`study visits. However, if the patient was discontinued from
`
`BAK-free. The paired t-test within an ANOVA was used
`
`travoprost BAK-free before Visit 2, that visit was considered
`
`to evaluate differences among individual preparations.
`
`a study exit visit.
`
`A modified Bonfcrroni correction ((116) was used to adjust
`
`At Visits 1 and 2, Goldmann applanation tonomet. ',
`
`p-level for individual OSDI questions in order to declare
`
`conjunctival hyperemia grading (by a photographic scale),
`
`statistical significance.
`
`Snellen Visual acuity, and slit lamp biomicroscopy assess-
`
`ments were made. Patients completed the OSDI symptom
`
`Adverse events related to travoprost BAK-free therapy
`were not analyzed statistically because unsolicited adverse
`
`questionnaire at Visits 1 and 2 and provided a global prefer-
`
`ence response at Visit 2. Additionally. adverse events were
`recorded at Visit 2.
`
`event data related to bimatoprost or latanoprost therapy were
`not collected at Visit 1.
`
`Administration and calculation
`
`of OSDI score
`
`The OSDI is a validated questionnaire designed to measure
`
`the severity of symptoms associated with ocular surface
`
`disease (Schiffman et a1 2000). The OSDI questionnaire
`
`was handed to the patients and they were instructed to
`
`answer the questions on their own without any assistance.
`
`Patients were asked to answer all questions by placing a
`vuyyn Au |ll\« uuA ulu
`Aka. nl i” ska kn Flea
`corresponded to their symptoms. The
`
`individual answers corresponded to a specific value; all of
`the time = 4. most of the time = 3, half of the time = 2, some
`
`of the time = 1. and none of the time = 0. Those questions
`
`to which the patients responded not applicable (MA) and
`questions that were not answered were not factored into the
`score calculation.
`
`Total OSD] Score =
`
`Results
`
`Patients
`
`Enrolled in this study were 813 patients, of whom 17 were
`
`protocol violations. Of the 796 eligible patients, 105 (13%) did
`
`not complete the study. Therefore, 691 completed the study
`
`per protocol. The most common reasons for early discontinu-
`ation were related and unrelated adverse events (11 = 45; 6%),
`
`lost to follow-up (n: l 7; 2%), non-compliance (n = l 1 ; 1%),
`and withdrew consent (n — 10; 1%). The most common
`
`adverse events leading to discontinuation were conjunctival
`
`hyperemia ( n = 20; 3%), ocular irritation (In : 12; 2%). bum-
`ing (n-— 7; l 94;) and 5 each ('. 90) for reduced vision and itch-
`
`ing. No other ocular complaint was cited more than 2 times.
`
`Patients may have had more than 1 complaint.
`
`Of 796 eligible patients, 61% were female and 77% were
`
`Caucasian (Table 1). The average age was 69.4 1r 1 1.8 years.
`
`Most patients (89%) had primary open-angle glaucoma. The
`
`most common associated ocular diagnoses at baseline were
`
`(Sum of Score for .A11
`
`nesting“; Angwered)__ (25)
`
`(m1)nnctiva! hvnr‘remia (11—— 3s; 4%) cataract (n: 20' 3%)
`
`(Total # of Questions Answered)
`
`and pseudophakia (n = 17; 2%); the most common systemic
`
`The classification of normal, mild, moderate. or
`severe OSD was determined on a scale from 0 to 100.
`
`OSD severity was classified as follows: normal (0—12),
`
`mild (13—22), moderate (23—32). and severe (33—100).
`
`Statistics
`
`diagnoses were systemic hypertension (n — 576; 72%), lipid
`
`disorder in = 254; 32%), and diabetes (11 = 220; 28%).
`
`Ocular surface disease symptoms
`In. a broad examination. of OSDI scores, travoprost
`
`BAK-free demonstrated improved mean global scores
`(8.7 i 11.3) compared with either latanoprost (12.0
`
`All data analyses were two—sided. An (l-leV’el of 0.05 was
`
`i l3.2, p < 0.000i) or bimatoprost therapy (13.2
`
`used to declare statistical significance. A per-protocol,
`average eye analysis was used. Intemet-based electronic data
`
`i 14.6, p < 00001; Figure 1). Use of travoprost
`
`BAK-free resulted in significantly improved scores
`
`capture was used for the trial.
`
`versus prior therapy whether latanoptost and bimato-
`
`The change in 101’ from previous prostaglandin analog
`
`prost were considered individually or were combined
`
`therapy (latanoprost orbimatoprost), to travoprost BAK-ftee
`
`(p < 0.0001). Individual questions which showed
`
`was analyzed by the paired t-test within each prior treatment
`
`significant improvement after travoprost BAKE-free ther-
`
`or the combined population (Book 1978).
`
`apy, following the Bonfcrroni correction, were sensitivity
`
`Clinical Ophthalmology 2008:2(3)
`
`6|5
`
`

`

`Henry et al
`
`Table i Patient demographics
`
`Age (mean years :i: SD)
`Gender
`
`Male
`Female
`Race
`
`Caucasian
`African-American
`Hispanic
`Asian
`Other
`
`Diagnosis
`Primary open-angle glaucoma
`Ocular hypertension
`Extoliative glaucoma
`Pigment dispersion glaucoma
`
`Eligible patients
`N = 796
`
`n (95)
`
`69.4 I I 1.8
`
`31 I (39)
`485 (61)
`
`6 IO (77)
`! 10 (14)
`39 (5)
`3| (4)
`6 (I)
`
`708 (89)
`77 (IO)
`8 (I)
`3 (0.4)
`
`and improved to a mean score of9.6 i 7.7 after travoprosr
`
`therapy: patients with moderate symptoms in = 59)
`
`improved from 27.1 i 2.1 to 19.2 i 13.5; and patients with
`
`severe symptoms (n = 64) improved from 45.8 i 10.9 to
`
`24.6 + 17.9. When symptomatic patients (those with mild.
`moderate or severe symptoms) were+pooled, their scores
`wera reduced from a mean of 27‘ _+13 5 to a mean of
`14 ..2 All changes from baseline in symptomatic
`
`patients were statistically significant (p < 0.0001 ). Regard-
`
`less of OSD severity, the use of travoprost BAK-free for
`
`3 months reduced the mean OSDI score by 1 category of
`
`severity: severe to moderate. moderate to mild. and mild
`to normal.
`The use oftaimprost BAK-fr-e -or 3 merit. s r dHCPed
`the mean OSDI score by at least
`1 category of severity
`isevei'e to moderate, moderate to mild, or mild to normal)
`
`in 70.2% of the 235 patients with OSD symptoms at
`
`baseline (Table 2). Fifty-seven (46.3%) of 123 moderate
`
`or severe patients improved by a reduction in severity by
`
`to light, gritty feeling, painful eyes, blurred vision, poor
`
`at least 2 levels. Of the ()4 severe patients, 15 (23.4%)
`
`improved to normal, decreasing the level of severity by
`3 levels.
`u. n
`
`
`nunv .p nutfil'uary: AF not; nic- uri
`
`(D
`n.
`you. u
`n A u
`
`T
`
`
`
`w.
`tln
`
`”U uinni nan!
`”J unsunuvuu.
`
`vision, reading difficulties, driving difficulties at night,
`
`Working with the computer, windy conditions, and low
`hi In -< H nnfl'“
`. W tlolUVKII.
`
`In a subset examination of the data. patients were
`
`grouped according to seventy of their baseline visit (Visit 1 i
`
`OSDI score (normal, mild, moderate. or severe). Patients
`
`remained grouped according to baseline OSDI scores and
`
`were analyzed for changes at Visit 2. Those patients clas-
`sified as normal in = 456‘) had a baseline score of 4.7 i 3.8
`
`compared to 4.9 i 6.8 at Visit 2, which was not significantly
`
`differentt(p - 0.49; Figure 2'). The mean baseline score
`11.6
`W00
`.U
`'1;
`Ct‘i
`ftIsle-an:
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`11.1WILIAAUAAKAD’IAIIWAAS‘
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`\[
`
`reduction in OSD
`
`,ehdned as39 points or more, was
`_:
`also examined (Figure0r3) Ofthno 35 patients with mild to
`
`severe symptoms. 134 (57.0%) had a reduction of 9 points
`or more from their baseline OSDI score after 3 months of
`
`treatment with travoprost BAK-free, Approximately half
`
`of the patients with mild (49.1%) or moderate (49.2%)
`
`symptoms achieved clinically significant improvement,
`as did over three-quarters (78.1%) of patients with severe
`
`
`
`MeanOSDIscore
`
`
`
`Latanoprost
`N = 476
`
`Bimatoprost
`N = 215
`
`Combined
`N = 891
`
`Previous therapy
`
`u] LatanoprostlBimatoprost
`I Travoprost BAK-free
`
`Figure I Improvement in ocdar surlace disease index scores with travoprost BAK-lree according to previous prostaglandin analog use. *1) «J 0.0001.
`
`
`
`616
`
`Clinical Ophthalmology 1008:2(3)
`
`

`

`Travoprost BAK-lree ophthalmic solution compared with prior prostaglandin therapy
`
`Sev = >33
`
`_ _ _ _\
`
`j Mod = 23—32
`
`Mild = 13-22
`
`""""""
`
`.
`
`,
`
`.
`
`.
`
`.
`
`1
`
`-------- j
`
`Normal
`N=456
`
`Mild
`N=112
`
`Moderate
`N=59
`
`Severe
`N=64
`
`f Norm = 0—12
`
`i
`
`.
`Combined
`N=235
`
`Figure 2 Improvement in ocular suriace disease index scores with travoprost BAK-lree according to baseline severity. "p '5' 0.00m.
`
`OSDI baseline severity
`
`intraocular pressure
`After a change in medications from their previous prosta-
`
`glandinanalog to travoprost BAK-free. patients experienced
`
`a statistically significant reduction in IO? {17. 3 + 3 6 vs.
`llllllljb.1!
`x u. uuu r ,
`5m
`n AAvu AVA
`run
`15 5 + 3 8m mu.._ n z n nnm Fauna. 4} was“ mp "m
`
`analyzed by specific prior prostagiandin analog therapy, a
`
`significant decrease in IOP was observed after changing
`
`from latanoprost to travoprost (p < 0.0001), but not from
`
`bimatoprost to travoprost (p = 0.5245).
`
`prostaglandin analog use, also resulted in a statistically
`
`significant decrease in the hyperemia score. from
`0.8 i 0.8 to 0.5 i 0.6 (p < 0.0001).
`
`Visual acuity
`LogMAR visual acuity was significantly better with travo-
`
`prost BAK-free versus prior therapy (0.167 t 0.140 versus
`
`0174 i 0.151, p = 0.04).
`
`Hyperemia
`Physicians graded hyperemia for all patients on a 0 to 3
`
`Adverse events
`
`The most commonly reported unsolicited adverse events
`
`scale at both visits. The baseline hyperernia scores were
`A. “am.no Linn-mnan himnn
`
`(“name In 7 .L n "H on!r HI]uAAu
`nuns-Aw“) uhALAAAL upnnubull I‘llullV'lan‘ \u.
`
`with travoprost BAK-free were conjunctiva] hyperemia
`(«n .. An- £0/\
`\ml "Innnn-n in ._.innni
`rim-2+" {a ._ 00- 40/;
`(AA —— ‘fl. \t/u/ auu hlmllsb All vmuuA uwuu] \AA —- 4.0.
`
`birnatoprost (1.0 i 0.9; p< 00001; Figure 5). How-
`
`Table 3) There were 5 seriOus adverse events in 3 patients:
`
`ever, both groups experienced a significant decrease
`
`in hyperemia with travoprost BAK-free (0.5 i 0.6 and
`
`non-specific infection, vomiting and shortness of breath,
`aortic dissection, metastatic cancer of the liver. and
`
`0.6 i 0.7. respectively: p < 00001). An examination
`
`of hyperemia, irrespective of the patient’s previous
`
`abdominal rash. Investigators reported that none of these
`events were related to travoprost BAK-free.
`
`Table 2 Patients with an OSDI score that improved by at least one level of severity
`OSDI severity
`Patients improved
`Patients improved
`Patients Improved
`grouping (baseline)
`to normal [n (96)]
`to mild [n (96)]
`to moderate [n (96)]
`
`Patients Improved
`by at least I level [n (%)]
`
`Mild (n = I l2)
`Moderate (n = 59)
`
`79 (70.5%]
`2| (35.6%)
`
`Severe (n = 64)
`Mild + Moderate +
`Severe (n = 235)
`Abbreviations: OSDI. Ocular Surface Disease Index.
`
`I5 (23.4%)
`l is (48.9%)
`
`NIA
`18 (30.5%)
`
`2| (32.8%)
`39 ( l6.6%)
`
`N/A
`NIA
`
`|
`|
`
`I 07.2%)
`I (4.7%)
`
`79 (70.5%)
`39 (66.|%)
`
`47 (73.4%)
`I65 (70.2%)
`
`Clinical Ophthalmology 2008:2(3)
`
`6l7
`
`[DLatanOprostIBimatoprost
`iiTravoprost BAX-free
`
`|
`
`45
`4o
`36
`
`39 ......................
`
`_______________
`
`E 25 l
`
`(I)
`° 20
`
`15
`
`10
`
`5
`
`0
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`

`

`Henry et al
`
`100%
`
`E 80%
`. aE a. 60%
`Q E
`E '3
`3§.«m
`it ‘bAI
`
`é wn
`;
`
`0%
`
`
`
`Mild
`N = 112
`
`Moderate
`N = 59
`
`Severe
`N = 64
`
`Combined
`N = 235
`
`OSDI baseline severity
`
`Figure 3 Oinically significant improvement (29 points) in ocular surface disease index scores with travoprost BAK-lree according to baseline severity.
`
`Patient preference
`The results for the global patient preference survey
`
`found 500 of the 691 patients (72.4%) favored travo-
`
`solution compared with previous use of either iatarioprost or
`
`bimatoprost monotherapy in a typical clinical situation.
`
`The OSDI was the primary tool used to assess symptoms
`
`prost BAK—free while 191 (27.6%) preferred the prior
`
`related to ocular surface disease (Olcura et a1 2007). After
`
`prostaglandin analog (p < 0.0001; Table 4). An exami-
`
`the change to travoprost BAK-free. global mean OSDI
`
`nation based on specific prior prostaglandin analog use
`
`scores were significantly reduced from scores while taking
`
`demonstrated that 74.6% of the patients previously using
`
`latanoprost and bimatoprest. evaluated together or individu-
`
`latanoprost and 67.4% previously using bimatoprost pre-
`ferred travoprost BAK-free.
`
`ally. This demonstrated statistically significant improvement
`
`in mean global scores on travoprost BAK-free (8.7 i 11.3)
`
`from eitherlatanoprosi (12.0 :‘c i3.2) or ‘oimatoprosi therapy
`
`Discussion
`
`(112i14ni
`
`The purpose of this study was to examine the safety.
`
`tolerability and efficacy of travoprost BAK—free ophthalmic
`
`In a subset examination of the data. patients were
`
`grouped according to baseline visit OSDl score.
`
`
`
`Meanintraocularpressure(mmHg)
`
`
`
`
`
`
`
`
`Latanoprost
`N = 476
`
`Bimatoprost
`N=215
`
`(:1 LatanoprostlBimatoprost
`I Travoprost BAK-free
`
`Figure 4 Change in mean lOP with rmmpmsr BAK-free armrding to previous pmsnglamin analog use. *p OOWI.
`
`
`
`6|8
`
`Clinical Ophthalmology 2008:2(3)
`
`

`

`Travoprost BAK-lree ophthalmic solution compared with prior prostaglandin therapy
`
`
`
`
`
`
`
`
`
`
`
`
`
`Meanhyperemiascore
`
`Latanoprost
`N = 478
`
`Bimatoprost
`N = 215
`F—‘—"_-—'""'—'_—-I
`
`Combined
`N = 691
`
`D Latanoprost/Bimatoprost
`I Travoprost BAK-l‘ree
`
`Figure 5 Change in mean hyperemia scores with trmprost BAK-free according to previous pmstaglandin analog use.*p 5' 0.000].
`
`Regardless ot‘the severity ot‘OSD symptoms, the use of
`travoprost BAK-free for 3 months significantly reduced
`
`improved comfort experienced by the study patients.
`Consequently, by using travoprost BAK-frec, a physi—
`
`the mean OSD] score in each group enough to reduce
`the category of severity to the next lower level (severe
`
`cian now has a way to prescribe chronic prostaglandin
`therapy while possibly helping improve a patient’s OSD
`
`to moderate, moderate to mild, and mild to normal).
`
`symptoms.
`
`Additionally. the shifts in mean OSD! scores for each of
`
`These findings may have clinical importance for
`
`the individual groups as well as for a group combining
`
`glaucoma patients beyond the lessening of OSD symp-
`
`mild, moderate. and severe scores was approximately 9
`
`toms. A consequence of a more comfortable ocular
`
`points or greater (range, 8.0—2 1 .2), confirmingthe clinical
`
`surface, as a remit of using travoprost BAK-free, may
`
`significance of this improvement (Miller et al 2006). The
`
`potentially be an improvement in patient adherence to
`
`data were also examined on a per patient basis to explore
`
`how individual patients responded. Over 70% of patients
`
`the lOP-lowering regimen, which could in turn improve
`lOP control.
`
`experienced a decrease in their OSD symptoms by at least
`
`This study demonstrated that [OP was significantly
`
`1 level of severity after 3 months on travoprost BAK—frce.
`
`Even more impressive is the fact that almost one quarter
`
`reduced afier the initiation of rravoprost BAK—frec therapy
`compared to prior prostaglandin analog therapy. The results
`
`of the patients with a severe baseline score improved to
`
`of this study are consistent with the travoprost BAK-free
`
`the normal range after 3 months. Furthermore. 57% of
`symptomatic patients had a clinically significant improve-
`
`regulatory trial. which demonstrated travoprost BAK-free
`
`was at least as efficacrous as the BAR-preserved preparation
`
`ment in their OSD symptoms. The absence of BAK in
`
`oftrav oprost (Lewis ct al 2007‘). Furthermore, a randomized,
`
`the travoprost preparation may have contributed to the
`
`double-masked study by Gross and colleagues demonstrated
`
`Table 3 Ophthalmic adverse events with travoprost BAK-free
`Description
`
`Hyperemia
`
`Change in visual acuity
`
`Burning
`Irritation
`
`Adverse events with an incidence of at least l%.
`
`Table 4 Patient preference (per patient analysis)
`
`7-
`
`49
`
`28
`
`I 4
`9
`
`Baseline
`proshglandin
`analog
`
`La'uu IUPI cost
`
`Bimatoprost
`Combined
`
`n
`
`476
`
`2| 5
`69 |
`
`Preferred
`previous
`therapy
`
`Preferred
`travoprost
`BAK-free
`
`25.4%
`
`32.6%
`27.6%
`
`74.6%
`
`67.4%
`72.4%
`
`pavaiue
`
`<0.000 i
`
`<0.000|
`<0.000l
`
`Clinical Ophthalmology 2008:2(3)
`
`6 l 9
`
`

`

`Henry et al
`
`that the two formulations oftravoprost (travoprost with BAK
`
`trial to confirm the findings noted in this study. in addition,
`
`and travoprost BAK-free) had similar efficacy, including a
`
`this study was not designed to address the long-term clinical
`
`prolonged duration of action showing >6 mml-lg reduction in
`IOP 60 hours after final dose ofeither drug (Gross et a] 2008).
`
`outcomes of travoprost BAK—free therapy. Further research
`
`with prostaglandin analogs will clarify the best therapeutic
`
`However, physicians must interpret the efficacy data from the.
`
`approach with this class of medicine for patients with
`
`cumth trial with caution because of its open-label design.
`
`glaucoma or ocular hypertension.
`
`which may have introduced bias into the results for lOP.
`
`Additionally, the reduction in conjunctival hyperemia
`
`experienced by patients after the initiation of travoprost
`
`BAK-free correlated well with reports that BAK has been
`
`shown to worsen conj unctival inflammation (Noecker et a1
`
`2004; Yce et al 2006; Kahook et al 2008'). BAK might
`
`further worsen conjunctival hyperemia already present due
`tn nrngtaglandin arming therany whichre nsgncriatcrj with
`
`nitric oxide synthesis within the conjunctiva] vessels (Astin
`et al 1994). Removing the BAK from lOP-lowering medi-
`
`cations might reduce inflammation and assist in reducing
`
`conjunctiva! vessel dilation; this hypothesis is supported
`
`by the lessened hyperemia observed in the study.
`
`Overall, the incidence of patients discontinuing due to
`
`an adverse event related to travoprost BAK-free therapy was
`
`very low. Conjunctival hypcrernia was the most commonly
`n mnfl r‘nmmnn
`v lll\lul vvunuuu
`
`adverse event leading to discontinuation (3%). However,
`
`this must be mentioned in the context that 4% of patients
`
`were diagnosed with conj unctival hyperemia at the baseline
`visit.
`
`Visual acuity was also slightly improved after 3
`
`months of travoprost BAK-free therapy. The change was
`
`small and may have been by chance However if corneal
`
`tear film stability is improved by remmal of the BAK
`n
`nI nnv‘.
`a \LUUJ}, VIBUOI
`(“a II .7
`.n '1
`{AA L" kl a
`at
`lIWnI\C\
`'v nu
`5/: h:
`have improved a result of changing to a BAK-free
`
`preparation.
`
`This study suggests that patients previously treated
`
`with BAK-preserved prostaglandin analog therapy and
`
`subsequently changed to travoprost BAK-free had, on
`average, similar to slightly better IOP control while
`
`experiencing reduced anterior segment symptoms and
`lessened hyperemia.
`
`The study did he evaluate differences
`
`in enricacy and
`
`safety between BAK—free travoprost anddothcr prostaglandin
`
`therapy in a parallel, randomized, masked fashion. The
`
`change in therapeutic regimen may have fostered the expecta-
`
`tion in some patients ofa superior therapy, possibly resulting
`
`in more favorable subjective outcomes than may have been
`observed in a randomi'led. double-masked study. More
`
`research is needed in an adequately controlled prospective
`
`Acknowledgments
`This clr.nical trial was supported by an unrestricted grant from
`-n rand:
`nnnnn
`1b., FUIL ‘VVrUlLll. TCAGD
`
`Disclosures
`
`None of the authors has any conflicts of interest to disclose.
`- ‘
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`Clinical Ophthalmology 2008:2(3)
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`