Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials

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Clinical Oph halmology 2016:10 445–454 Clinical Oph halmology Do ep ess submi you manusc ip | www.do ep ess.com Do ep ess 445 O iginal esea Ch open access o scien i ic and medical esea ch Open access Full Tex a icle h p://dx.doi.o g/10.2147/OPTH.S91402 Bene i s o swi ching om la anop os o p ese a i e- ee a lup os eye d ops: a me a-analysis o wo Phase IIIb clinical ials hannu Uusi alo1 e geniy ego o 2 Kai Kaa ni an a3 Yu i as akho 4 auli opo5 On behal o he Swi ch S udy Ta lup os S udy g oups 1Depa men o Oph halmology, SILK, Uni e si y o Tampe e, Tampe e Uni e si y Hospi al, Tampe e, Finland; 2Depa men o Oph halmology, The ussian na ional esea ch Medical Uni e si y, Moscow, Russia; 3Depa men o Oph halmology, Uni e si y o Eas e n Finland, Kuopio Uni e si y Hospi al, Kuopio, Finland, 4Depa men o Oph halmology, Fi s Pa lo S a e Medical Uni e si y o S Pe e sbu g, Sain Pe e sbu g, Russia, 5Global Medical A ai s, San en Oy, Tampe e, Finland In oduc ion: Glaucoma pa ien s equen ly exhibi ocula su ace side e ec s du ing ea men wi h p os aglandin eye d ops. The p esen wo k in es iga ed whe he glaucoma pa ien s su e - ing om signs and symp oms o ocula su ace disease while using p ese ed la anop os eye d ops bene i ed om swi ching o p ese a i e- ee a lup os eye d ops. Pa ien s and me hods: The analysis was based on 339 glaucoma pa ien s en olled in wo Phase IIIb ials. The pa ien s we e equi ed o ha e wo symp oms, o one sign and one symp om o ocula su ace disease a baseline, and a leas 6 mon hs p eceding ea men wi h la anop os eye d ops p ese ed wi h benzalkonium chlo ide. All eligible pa ien s we e swi ched om la anop os o p ese a i e- ee a lup os o a o al o 12 weeks. Ocula symp oms and ocula signs we e e alua ed a baseline and a 2 weeks, 6 weeks, and 12 weeks a e commencing ea men wi h a lup os . In aocula p essu e (IOP), d op discom o , and ea men p e e ence we e e alua ed o in es iga e he clinical e icacy and pa ien - ela ed ou comes. Resul s: A e 12 weeks o ea men wi h p ese a i e- ee a lup os , he incidences o i i a ion/bu ning/s inging, o eign body sensa ion, ea ing, i ching, and d y eye sensa ion had diminished o one- hi d o hose epo ed o p ese ed la anop os a baseline. The incidences o blepha i is and co neal/conjunc i al luo escein s aining had in u n dec eased o one-hal o hose epo ed o p ese ed la anop os . Se e i y o conjunc i al hype emia was hal ed du ing ea men wi h p ese a i e- ee a lup os , and he e was signi ican imp o emen in ea b eak-up ime and ea p oduc ion. A u he educ ion in IOP (~1 mmHg) was seen wi h p ese a i e- ee a lup os compa ed wi h p ese ed la anop os . D op discom o was alle i- a ed du ing p ese a i e- ee a lup os ea men , and an ou s anding majo i y o pa ien s (72%) p e e ed p ese a i e- ee a lup os o e p ese ed la anop os . Conclusion: This me a-analysis con i med ha IOP emained a he same le el a e eplacing benzalkonium chlo ide-p ese ed la anop os eye d ops wi h p ese a i e- ee a lup os eye d ops. P ese a i e- ee a lup os signi ican ly dec eased he symp oms and signs o ocula su ace disease and ou a ed la anop os in d op com o and ea men p e e ence. Keywo ds: Ta lo an®, p ese ed la anop os , Xala an®, ocula su ace disease, ocula symp oms and signs, IOP, pa ien - ela ed ou come In oduc ion Se e al s udies ha e ecen ly illus a ed ha a la ge numbe o glaucoma pa ien s using opical d ugs su e om concomi an ocula su ace disease.1–3 Acco ding o hose s ud- ies, as much as hal o hese pa ien s appea o encoun e d y eye symp oms. I has u he been demons a ed ha he p ese a i e – mos ly benzalkonium chlo ide (BAC) – is he causa i e agen leading o he symp oms o d y eye. Thus, he ad e se p ese a i e e ec s cons i u e a signi ican clinical p oblem in he ea men o glaucoma. Co espondence: hannu Uusi alo Depa men o Oph halmology, SILK, Uni e si y o Tampe e, ARVO B229, Tampe e 33014, Finland Tel +358 40 190 1214 email [email p o ec ed] Jou nal name: Clinical Oph halmology A icle Designa ion: O iginal Resea ch Yea : 2016 Volume: 10 Running head e so: Uusi alo e al Running head ec o: F om p ese ed la anop os o p ese a i e- ee a lup os eye d ops DOI: h p://dx.doi.o g/10.2147/OPTH.S91402 Numbe o imes his a icle has been iewed This a icle was published in he ollowing Do e P ess jou nal: Clinical Oph halmology 15 Ma ch 2016 Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 446 Uusi alo e al BAC is mos commonly used wi h concen a ions anging om 0.004% o 0.02% in he an iglaucoma medica ions; wi hin his ange, i is oxic in a dose-dependen manne . BAC has been shown o ha e di ec oxici y o a ious issues o he ocula su ace and causes ad e se e ec s, such as conjunc i al hype emia, punc a e ke a opa hy, and epi helial e osions. In addi ion, accumula ion o signs and symp oms, such as i i a ion/bu ning/s inging, i ching, o - eign body sensa ion, ea ing, and d y eye sensa ion, has been epo ed.4,5 Glaucoma d ugs ha con ain a p ese a i e ha e been inc imina ed in educing he numbe o goble cells, inc easing he subepi helial collagen deposi ion, expanding he subs an ia p op ia wi h an in il a e o ch onic in lamma- o y cells, and e en exhibi ing a p oapop o ic e ec in he conjunc i a.6–11 The use o an iglaucoma d ugs in gene al and BAC-con aining d ugs pa icula ly has been di ec ly linked o he ailu e o glaucoma su ge y.9,12 Ta lup os 0.0015% oph halmic solu ion (Ta lo an®, Sa lu an®; San en, Osaka, Japan) was he i s p ese a i e- ee p os aglandin medica- ion de eloped o he ea men o glaucoma; i has a p o en p eclinical and clinical in aocula p essu e (IOP)-lowe ing e icacy.13–19 Ta lup os is a p od ug o syn he ic analog o p os aglandin F2α and ac s on p os aglandin F p os anoid ecep o s wi h high a ini y and selec i i y. The pha ma- cological mechanism o ac ion o a lup os is analogous o ha o la anop os 0.005% (Xala an®; P ize , Inc., New Yo k, NY, USA) and a op os 0.004% (T a a an®; Alcon, Inc., Fo Wo h, TX, USA) oph halmic solu ions, whe eas bima op os 0.03% (Lumigan®; Alle gan, Inc., I ine, CA, USA) can be ega ded as bo h a p os aglandin p od ug and a p os amide. The aim o his pape is o p esen he me a-analysis esul s o wo independen clinical Phase IIIb s udies, among which he i s s udy was published as a ull pape and he second published only in he local language.20,21 Bo h s udies in ques ion had an iden ical design and ec ui ed glaucoma pa ien s who had de eloped signs and symp oms o ocula su ace disease du ing ea men wi h p ese ed la ano- p os eye d ops (con aining a high 0.02% concen a ion o BAC). The p ese ed la anop os eye d ops we e swi ched o p ese a i e- ee a lup os eye d ops a e he baseline isi o a pe iod o 12 weeks. Especially, ocula signs and symp oms, IOP, d op discom o , and pa ien p e e ence we e e alua ed and pooled ac oss he s udies o he pu pose o his me a-analysis. Pa ien s and me hods The me a-analysis was based on wo independen , open- label, mul icen e , Phase IIIb clinical s udies: one pe o med in Finland, Sweden, and Ge many du ing 2008 and he o he in Russia du ing 2010.20,21 A o al o 158 pa ien s om 12 cen e s we e en olled in he i s s udy, whe eas 185 pa ien s om se en cen e s we e en olled in he second s udy. Bo h s udies adop ed an essen ially iden ical s udy p o ocol wi h he excep ion ha imp ession cy ology o he conjunc i a was pe o med only in he i s s udy.20 Open- label designs we e used, since he p ese a i e- ee a lup os eye d ops we e comme cially a ailable only in uni dose dispense s and no in con en ional mul idose bo les as wi h p ese ed la anop os . The wo s udies we e comple ed in compliance wi h he Good Clinical P ac ice guideline o he In e na ional Con e ence on Ha moniza ion and he Decla a ion o Helsinki. The s udy p o ocols we e app o ed by he local Independen E hics Commi ees and he Na ional Compe en Au ho i y. W i en in o med consen was p o ided by each pa ien be o e inclusion in he s udy. Pa ien s o ei he sex aged 18 yea s o olde we e sc eened o he wo s udies. Eligible pa ien s we e equi ed o ha e a diagnosis o ocula hype ension (OH) o open-angle glaucoma (OAG) in ei he eye o bo h eyes and a leas 6 mon hs p eceding ins illa ion o p ese ed la anop os eye d ops. OAG comp ised p ima y OAG and pseudoex- olia i e glaucoma (PEX). The p esence o a leas 1) wo symp oms o 2) one sign and one symp om o ocula su ace disease was impe a i e o all pa ien s a he sc eening isi (Table 1). Addi ional inclusion c i e ia we e bes -co ec ed isual acui y sco e o +0.6 loga i hm o he minimum angle Table 1 Eligibili y (abno mali y) c i e ia o he symp oms and signs o ocula su ace disease in he indi idual s udies Ocula symp om G ading Eligibili y c i e ia I i a ion/bu ning/s inging 0–4aa leas g ade 2 Fo eign body sensa ion 0–4aa leas g ade 2 Tea ing 0–4aa leas g ade 2 i ching 0–4aa leas g ade 2 D y eye sensa ion 0–4aa leas g ade 2 Ocula sign Uni /g ading Eligibili y c i e ia Fluo escein ea b eak-up ime ( BUT) secondsb,10 seconds Co neal luo escein s aining 0–Vca leas g ade i Conjunc i al luo escein s aining 0–Xda leas g ade ii Blepha i is 0–3ea leas g ade 1 Conjunc i al hype emia 0–4 a leas g ade 1 Tea p oduc ion mmg#10 mm No es: Fo ocula symp oms, he ea ed eyes we e conside ed oge he , whe eas he signs we e e alua ed by eye (and he analyses we e based on he eye wi h he wo se g ading). a0= none, 1= ace, 2= mild, 3= mode a e, and 4= se e e. bsli lamp mic oscope. cOx o d g ading scale (0–V). dCombined nasal (0–V) and empo al (0–V) sco e by Ox o d g ading scale. e0= none, 1= mild, 2= mode a e, and 3= se e e. Redness scale wi h e e ence pho og aphs (hal g ades allowed); 0= none, 1= mild, 2= mode a e, 3= se e e, and 4= e y se e e. gschi me ’s es . Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 447 F om p ese ed la anop os o p ese a i e- ee a lup os eye d ops o esolu ion (logMAR) o be e in bo h eyes (based on ea ly ea men diabe ic e inopa hy s udy eye cha s) and willingness o ollow ins uc ions and p o ision o a w i en in o med consen . Ocula exclusion c i e ia we e an e io chambe angle ,2 (by gonioscopy and Sha e ’s classi ica ion), co neal abno - mali y o o he condi ion (such as p io e ac i e eye su ge y) p e en ing eliable applana ion onome y, IOP .22 mmHg (a 3 pm wi h p ese ed la anop os ), use o p ese ed a i icial ea s du ing he pas 2 weeks, diagnosis o angle- closu e glaucoma o seconda y glaucoma o he han PEX, con aindica ion o hype sensi i i y o a lup os , glaucoma il a ion su ge y o any o he ocula su ge y (including lase p ocedu es) wi hin 6 mon hs p io o sc eening, and use o con ac lenses. Sys emic exclusion c i e ia we e p egnancy o lac a ion, unwillingness o a oid p egnancy, and cu en alcohol o d ug abuse. In addi ion, any ocula o sys emic condi ion (such as aphakia o diabe es) ha could pu he pa ien a isk, con ound he esul s, o in e e e wi h he pa ien ’s pa icipa ion in he s udy was a cause o exclusion. Pa icipa ion in ano he in es iga ional d ug (o de ice) s udy du ing he pas 30 days was also p ohibi ed. S anda d oph halmic p ocedu es we e used o in es iga e he s udy pa ien s. Ocula symp oms and signs we e que ied/ assessed using he scales and es s men ioned in Table 1. IOP was measu ed (in mmHg) by applana ion onome y. D op dis- com o was e alua ed using a ou -g ade scale: no, mild, mod- e a e, o se e e discom o . Quali y-o -li e (QoL) assessmen s u ilized a alida ed ques ionnai e o compa ing he ole abil- i y o oph halmic medica ions (COMTol).22 The ques ionnai e was managed by an in e iewe a each s udy clinic. Pa ien s’ p e e ence o he ea men op ions (p ese ed la anop os o p ese a i e- ee a lup os ) was e alua ed wi hin his ques- ionnai e using a h ee-g ade scale: la anop os , a lup os , o nei he . Ad e se e en s we e que ied, isual acui y (logMAR sco e) and isual ield we e es ed, and biomic oscopic and oph halmoscopic indings we e e alua ed in o de o u he assess he sa e y o he pa ien s. Bo h s udies accommoda ed a o al o i e isi s o he clinic. The ea men pe iod included a consolida ed sc eening/baseline isi and subsequen isi s 2 weeks, 6 weeks, and 12 weeks a e commencing once-daily ea - men wi h p ese a i e- ee a lup os in he e ening o he baseline isi . A pos -s udy isi was scheduled 1–3 weeks a e he cessa ion o a lup os ea men a 12 weeks. All he a o emen ioned examina ions we e done a he base- line isi . The examina ions we e enewed a he 2-week, 6-week, and 12-week isi s, apa om isual ield es and oph halmoscopy ( edone a 12 weeks only). A he pos - s udy isi , in u n, all examina ions we e done besides he assessmen o ocula symp oms and signs, d op discom o , and ea men p e e ence (QoL). All s udy p ocedu es we e pe o med a app oxima ely he same ime o he day du - ing he cou se o he s udy; o example, IOP was measu ed in a iably a 3 pm ±1 hou . Sample size calcula ions we e done o bo h s udies. An occu ence o 40%–50% was an icipa ed o a single ocula symp om o sign (such as o eign body sensa ion) a baseline. In o he wo ds, 40%–50% o he pa ien s we e expec ed o expe ience a leas mild o eign body sensa ion a he base- line isi . A dec ease o 10% in he incidence o a single symp om o sign was hen ega ded as a easonable basis o sample size calcula ions. Making use o his assump ion and McNema ’s es (wi h a wo-sided ype I e o o 5% and a powe o 80%), a leas 150 eligible pa ien s needed o be en olled in each s udy. The ac ual sample sizes sa is ied his c i e ion (Table 2) and added up o a o al o 343 pa ien s included in his me a-analysis. Indi idual da a we e a ailable o bo h s udies. The esul s we e summa ized a baseline (p ese ed la ano- p os ) and a 6-week and 12-week isi s (p ese a i e- ee a lup os ). A s a is ical model including ixed e ec s o Table 2 Demog aphic cha ac e is ics o he pa ien s a baseline in he indi idual s udies and he en i e me a-analysis coho Va iable S udy 1aS udy 2bMe a-analysis Numbe o pa ien s 158 185 343 sex Male n (%) 54 (34.2%) 75 (40.5%) 129 (37.6%) Female n (%) 104 (65.8%) 110 (59.5%) 214 (62.4%) Age in yea s, median (max–min) 69 (37–88) 63 (23–84) 67 (23–88) P ima y open-angle glaucoma n (%) 109 (69.0%) 183 (98.9%) 292 (85.1%) Pseudoex olia i e glaucoma n (%) 16 (10.1%) 1 (0.5%) 17 (5.0%) Ocula hype ension n (%) 33 (20.9%) 1 (0.5%) 34 (9.9%) No es: In h ee pa ien s, one eye was diagnosed wi h p ima y open-angle glaucoma and he o he eye wi h ocula hype ension; hese pa ien s we e ca ego ized as p ima y open-angle glaucoma. In an addi ional h ee pa ien s, one eye was diagnosed wi h p ima y open-angle glaucoma and he o he eye wi h pseudoex olia i e glaucoma; hese pa ien s we e included as pseudoex olia i e glaucoma. aS udy pe o med in Finland, Sweden, and Ge many. bS udy pe o med in Russia. Abb e ia ions: max, maximum; min, minimum. Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 448 Uusi alo e al s udy (be ween-pa ien e ec ), ea men (wi hin-pa ien e ec ), and hei in e ac ion was i ed o he s udy a iables. A pa ame ic analysis me hod was used o IOP, conjunc i- al edness, ea b eak-up ime ( BUT), and ea p oduc ion (Schi me ’s es ), and a co esponding nonpa ame ic analy- sis me hod was used o he emaining s udy a iables ha we e es ed s a is ically.23 As no eal e idence o he e ogene- i y was de ec ed be ween he wo s udies, he inal analyses did no inco po a e he in e ac ion e ec . Resul s All esul s a e p o ided as means and s anda d de ia ions o con inuous a iables and equencies and pe cen ages (%) o o dinal a iables, unless o he wise indica ed. A summa y o he demog aphic cha ac e is ics o he s udy pa ien s is displayed in Table 2. Bo h s udies succeeded in en olling ep esen a i e samples o OH/OAG pa ien s wi h compa able dis ibu ions o age and sex. The o e all mean age o he pa ien s was 67 yea s ( ange 23–88 yea s). App oxima ely wo- hi ds o he pa ien s we e emales (62.4%). A majo i y o he pa ien s we e diagnosed wi h p ima y OAG (85.1%) and only one- en h wi h OH (9.9%) and one-20 h wi h PEX (5.0%). Only 27 (7.9%) pa ien s discon inued he s udies p ema u ely. The mos common causes o discon inua ion we e p o ocol de ia ion (nine pa ien s), ad e se e en (nine pa ien s), and pa ien eques (six pa ien s). Fou o he discon inued pa ien s did no ha e any pos baseline da a. Consequen ly, he o e all esul s a e summa ized o a coho o 339 pa ien s in he sequel. Ocula symp oms The equency dis ibu ions o ocula symp oms a e sum- ma ized in Table 3 by s udy isi . All i e symp oms we e p e alen a baseline wi h p ese ed la anop os . Mild- o-se e e i i a ion/bu ning/s inging, o eign body sensa ion, ea ing, i ching, and d y eye sensa ion we e epo ed by 59.6%, Table 3 Numbe (%) o pa ien s expe iencing ocula symp oms (i i a ion/bu ning/s inging, o eign body sensa ion, ea ing, i ching, and d y eye sensa ion) o ocula sign (blepha i is) a baseline du ing ea men wi h p ese ed la anop os and a e 6 weeks and 12 weeks o ea men wi h p ese a i e- ee a lup os Symp oms/signs o ocula su ace disease Se e i y g ade Baseline p ese ed la anop os (N=339) 6 weeks* p ese a i e- ee a lup os (N=318) 12 weeks* p ese a i e- ee a lup os (N=316) I i a ion/bu ning/s inging none 97 (28.6%) 187 (58.8%) 210 (66.5%) T ace 40 (11.8%) 62 (19.5%) 53 (16.8%) Mild 113 (33.3%) 36 (11.3%) 29 (9.2%) Mode a e 75 (22.1%) 31 (9.7%) 24 (7.6%) se e e 14 (4.1%) 2 (0.6%) 0 (0.0%) Fo eign body sensa ion none 166 (49.0%) 233 (73.3%) 252 (79.7%) T ace 38 (11.2%) 35 (11.0%) 20 (6.3%) Mild 76 (22.4%) 32 (10.1%) 27 (8.5%) Mode a e 47 (13.9%) 16 (5.0%) 15 (4.7%) se e e 12 (3.5%) 2 (0.6%) 2 (0.6%) Tea ing none 157 (46.3%) 222 (69.8%) 232 (73.4%) T ace 44 (13.0%) 44 (13.8%) 36 (11.4%) Mild 59 (17.4%) 33 (10.4%) 33 (10.4%) Mode a e 56 (16.5%) 17 (5.3%) 12 (3.8%) se e e 23 (6.8%) 2 (0.6%) 3 (0.9%) i ching none 183 (54.0%) 213 (67.0%) 226 (71.5%) T ace 40 (11.8%) 53 (16.7%) 43 (13.6%) Mild 67 (19.8%) 35 (11.0%) 30 (9.5%) Mode a e 38 (11.2%) 15 (4.7%) 14 (4.4%) se e e 11 (3.2%) 2 (0.6%) 3 (0.9%) D y eye sensa ion none 111 (32.7%) 177 (55.7%) 202 (63.9%) T ace 32 (9.4%) 61 (19.2%) 41 (13.0%) Mild 87 (25.7%) 50 (15.7%) 49 (15.5%) Mode a e 85 (25.1%) 25 (7.9%) 22 (7.0%) se e e 24 (7.1%) 5 (1.6%) 2 (0.6%) Blepha i is none 135 (39.8%) 195 (61.3%) 208 (65.8%) Mild 159 (46.9%) 118 (37.1%) 105 (33.2%) Mode a e 44 (13.0%) 5 (1.6%) 3 (0.9%) se e e 1 (0.3%) 0 (0.0%) 0 (0.0%) No es: *The changes om baseline a 6 weeks and 12 weeks we e s a is ically signi ican ; P,0.001. Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 449 F om p ese ed la anop os o p ese a i e- ee a lup os eye d ops 39.8%, 40.7%, 34.2%, and 57.8% o he pa ien s, espec i ely (Figu e 1). A s a is ically signi ican shi (P,0.001) owa d less se e e symp oms was al eady seen 6 weeks a e he swi ch o p ese a i e- ee a lup os . The pe cen ages o pa ien s wi h no o only a ace o a symp om inc eased ema k- ably, and he pe cen ages o pa ien s wi h mild- o-se e e symp oms dec eased acco dingly. A con inued imp o emen was seen in all symp oms om 6 weeks o 12 weeks, bu o a lesse ex en . A he inal 12-week examina ion, mild- o-mode a e i i a ion/bu ning/s inging, o eign body sensa- ion, ea ing, i ching, and d y eye sensa ion we e epo ed by only 16.8%, 13.9%, 15.2%, 14.9%, and 23.1% o he pa ien s (Figu e 1). Thus, he 12-week pe cen ages wi h p ese a i e- ee a lup os we e only a ound one- hi d o hose epo ed o la anop os a baseline. Ocula signs The isi -wise equency dis ibu ions o h ee ocula signs a e p esen ed in Table 3 (blepha i is) and Table 4 (co neal and conjunc i al luo escein s aining). Blepha i is (mild o se e e), co neal luo escein s aining (g ades I–IV), and combined conjunc i al luo escein s aining (g ades II–VIII) we e epo ed by 60.2%, 82.9%, and 87.9% o he pa ien s, espec i ely, a baseline wi h p e- se ed la anop os (Figu e 2). Ocula signs also imp o ed signi ican ly a e he swi ch o p ese a i e- ee a lup os (P,0.001). The u mos se e i y g ades became spo adic by he 12-week examina ion. Fo example, only h ee mode a e cases o blepha i is we e epo ed a 12 weeks. Consequen ly, blepha i is (mild o se e e), co neal luo- escein s aining (g ades I–IV), and combined conjunc i al luo escein s aining (g ades II–VIII) we e epo ed only by 34.2%, 41.8%, and 50.9% o he pa ien s a he 12-week isi wi h p ese a i e- ee a lup os (Figu e 2). These pe cen ages we e only a ound one-hal o hose epo ed o la anop os a baseline. The emaining h ee ocula signs we e e alua ed on a con inuous scale (as hal g ades we e allowed o conjunc i al hype emia). The deg ee o conjunc i al hype emia was dec eased om 1.51±0.76 a baseline Figu e 1 Incidence o i i a ion/bu ning/s inging and o eign body sensa ion (A), ea ing, i ching (B), and d y eye sensa ion (C) a baseline du ing p ese ed la anop os ea men and a 6 weeks and 12 weeks a e swi ching o p ese a i e- ee a lup os ea men . No es: The numbe o pa ien s su e ing om he ocula symp om is shown abo e each ba , and he o al numbe o pa ien s pe isi is shown in he box.  3HUFHQWDJHRISDWLHQWV       ,WFKLQJ7HDULQJ Q   Q   Q  Q   Q   Q  % 3YVEDVHOLQH 3HUFHQWDJHRISDWLHQWV        )RUHLJQERG VHQVDWLRQ ,UULWDWLRQEXUQLQJVWLQJLQJ Q   Q   Q  Q   Q   Q  $ 3YVEDVHOLQH 3YVEDVHOLQH 3HUFHQWDJHRISDWLHQWV           'U H HVHQVDWLRQ Q   Q   Q  & %DVHOLQH1  ZHHNV1  ZHHNV1  Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 450 Uusi alo e al wi h p ese ed la anop os o 0.86±0.59 and 0.72±0.59 a 6 weeks and 12 weeks, espec i ely, a e he swi ch o p ese a i e- ee a lup os (Table 5; P,0.001 a bo h isi s). The se e i y o conjunc i al hype emia was hus hal ed o e he 12-week ea men pe iod, and he inci- dence o hype emia was also clea ly educed (Figu e 2). BUT was inc eased om 5.9±4.5 seconds a baseline wi h p ese ed la anop os o 7.7±4.2 seconds a 6 weeks wi h p ese a i e- ee a lup os (P,0.001) and 8.7±4.7 seconds a 12 weeks wi h p ese a i e- ee a lup os (P,0.001). Tea p oduc ion (Schi me ’s es ) was also inc eased signi ican ly om 7.8±6.9 mm a baseline wi h p ese ed la anop os o 10.6±8.6 mm and 11.5±8.4 mm a 6 weeks and 12 weeks, espec i ely, wi h p ese a i e- ee a lu- p os (P,0.001 a bo h isi s). IOP educ ion The o e all mean IOP (o ea ed eyes) was 16.6±2.6 mmHg a baseline wi h p ese ed la anop os . Fu he educ ions in IOP o 16.0±2.3 mmHg and 15.7±2.5 mmHg we e seen a 6 weeks and 12 weeks, espec i ely, a e he swi ch o p ese a i e- ee a lup os (P,0.001 a bo h isi s). The IOP- educing e ec was hus well sus ained, and o e all IOP dec eases o 3.6% (a 6 weeks) and 5.4% (a 12 weeks) we e achie ed wi h p ese a i e- ee a lup os ela i e o he baseline (p ese ed la anop os ). Table 4 Numbe (%) o pa ien s expe iencing co neal o conjunc i al luo escein s aining du ing ea men wi h p ese ed la anop os and a e 6 weeks and 12 weeks o ea men wi h p ese a i e- ee a lup os Fluo escein s aining Se e i y g ade Baseline p ese ed la anop os (N=339) 6 weeks* p ese a i e- ee a lup os (N=318) 12 weeks* p ese a i e- ee a lup os (N=316) Co nea 0 58 (17.1%) 144 (45.3%) 184 (58.2%) i132 (38.9%) 132 (41.5%) 109 (34.5%) ii 125 (36.9%) 41 (12.9%) 22 (7.0%) iii 22 (6.5%) 1 (0.3%) 1 (0.3%) IV 2 (0.6%) 0 (0.0%) 0 (0.0%) Conjunc i aa (combined) 020 (5.9%) 69 (21.7%) 102 (32.3%) i21 (6.2%) 59 (18.6%) 53 (16.8%) ii 115 (33.9%) 129 (40.6%) 108 (34.2%) iii 42 (12.4%) 22 (6.9%) 22 (7.0%) IV 100 (29.5%) 35 (11.0%) 25 (7.9%) V 13 (3.8%) 1 (0.3%) 3 (0.9%) VI 25 (7.4%) 3 (0.9%) 3 (0.9%) VII 0 (0.0%) 0 (0.0%) 0 (0.0%) VIII 3 (0.9%) 0 (0.0%) 0 (0.0%) No es: *The changes om baseline a 6 weeks and 12 weeks we e s a is ically signi ican ; P,0.001. ag ades iX and X we e no epo ed. Figu e 2 Incidence o blepha i is, co neal s aining (A) and combined conjunc i al s aining and conjunc i al hype emia (B) a baseline du ing p ese ed la anop os ea men and a 6 weeks and 12 weeks a e swi ching o p ese a i e- ee a lup os ea men . No es: The numbe o pa ien s su e ing om he ocula sign is shown abo e each ba , and he o al numbe o pa ien s pe isi is shown in he box. 3HUFHQWDJHRISDWLHQWV            &RUQHDOVWDLQLQJ Q   Q   Q  %OHSKDULWLV Q   Q  Q  $ 3HUFHQWDJHRISDWLHQWV            &RQMXQFWLYDOK SHUHPLD Q   Q   Q  &RQMXQFWLYDOVWDLQLQJ Q   Q  Q  % 3YVEDVHOLQH3YV EDVHOLQH %DVHOLQH1  ZHHNV1 ZHHNV1  Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 451 F om p ese ed la anop os o p ese a i e- ee a lup os eye d ops D op discom o and ea men p e e ence A majo i y o he pa ien s su e ed om d op discom o a baseline wi h p ese ed la anop os . Speci ically, 42% o he pa ien s expe ienced mild discom o , 31% mode a e discom- o , and 1% se e e discom o , whe eas only ~25% o he pa ien s expe ienced no discom o a all. Con e sely, 22% o he pa ien s expe ienced mild discom o , 2% mode a e discom o , and 76% no discom o a e 12 weeks ea - men wi h p ese a i e- ee a lup os . The imp o emen was s a is ically signi ican (P,0.001). Fu he mo e, mos o he pa ien s clea ly p e e ed p ese a i e- ee a lup os o e p ese ed la anop os : up o 72% o he pa ien s we e in a o o a lup os and only 6% o la anop os when medica ion p e e ence was e alua ed as pa o QoL assess- men s (Figu e 3). Ad e se e en s and ocula sa e y A small numbe o ea men - ela ed ocula ad e se e en s (o he han he symp oms and signs summa ized in he Ocula symp oms and Ocula signs sec ions) we e epo ed du ing he 12-week pe iod wi h p ese a i e- ee a lup os . Only nine pa ien s (2.6%) discon inued he s udies due o ad e se e en (s). The majo i y o he e en s we e ea men ela ed and ocula . In pa icula , one o he discon inued pa ien s expe ienced i i is and ke a i is in he s udy conduc ed in Russia. The mos p e alen nonocula ad e se e en was headache. Only i e se ious ad e se e en s we e epo ed, o which all we e nonocula and no ela ed o he ea men . A 12 weeks, ad e se e en s (including ocula symp oms and signs) had no impac on QoL in 72% o he pa ien s ea ed wi h p ese a i e- ee a lup os . The co esponding igu e wi h p ese ed la anop os a baseline was only 36%. Signi ican changes in isual acui y o isual ields ha could be a ibu ed o he ea men wi h p ese a- i e- ee a lup os we e no seen. Mo eo e , no pa ho- logical changes we e seen in ei he biomic oscopy o oph halmoscopy. Discussion The a ionale o his s udy was o in es iga e whe he glau- coma pa ien s who exhibi diminished ocula ole abili y o BAC-p ese ed p os aglandin ea men wi h la anop os would bene i om swi ching o a p ese a i e- ee p os- aglandin ea men wi h a lup os . A me a-analysis o wo la ge Phase IIIb clinical ials – adop ing essen ially he same s udy p o ocols – was ca ied ou o in es iga e his subjec . E idence o BAC-induced oxici y on ocula su ace has accumula ed in ecen yea s. BAC has shown o be oxic o bo h mic oo ganisms and mammalian cells; hence, i may be associa ed wi h he su ace side e ec s o a a ie y o eye d ops.4–8,10,11 The de imen al e ec o BAC is u he accen- ua ed when many di e en eye d ops p ese ed wi h BAC a e used oge he , a si ua ion ha is qui e equen ly encoun- e ed in glaucoma ea men . The e o e, he eme gence o a new gene a ion o BAC- ee an iglaucoma medica ions (o an iglaucoma medica ions wi h negligible concen a ions o BAC) is ex emely impo an .24,25 I has been u he s a ed ha BAC – h ough i s de e gen ac i i y – would enhance he e ec i eness o some d ugs by acili a ing hei pene a ion in o he eye and deli e y o he co nea. Undeniably, he me a-analysis esul s con u ed his obsole e claim. Equal IOP-lowe ing e icacy was demon- s a ed be ween he wo p os aglandin analogs, p ese a i e- ee a lup os and BAC-p ese ed la anop os . In ac , a sligh u he dec ease in IOP was seen wi h p ese a i e- ee a lup os compa ed wi h p ese ed la anop os (~1 mmHg a week 12). Table 5 Deg ee o conjunc i al hype emia du ing ea men wi h p ese ed la anop os and a e 6 weeks and 12 weeks o ea men wi h p ese a i e- ee a lup os Visi T ea men N Absolu eaChangea,* Baseline P ese ed la anop os 339 1.51±0.76 – 6 weeks P ese a i e- ee a lup os 318 0.86±0.59 -0.64±0.79 12 weeks P ese a i e- ee a lup os 316 0.72±0.59 -0.78±0.82 No es: aMean ± SD o conjunc i al hype emia scale (wi h hal g ades allowed) and he co esponding changes om baseline. *The changes om baseline a 6 weeks and 12 weeks we e s a is ically signi ican ; P,0.001. Abb e ia ion: SD, s anda d de ia ion. Figu e 3 Pa ien p e e ence on ea men op ions a 12 weeks. No es: All pa ien s we e ea ed wi h p ese ed la anop os up o baseline. A baseline, hei ea men was swi ched o p ese a i e- ee a lup os o 12 weeks. 3HUFHQWDJHRISDWLHQWV          3DWLHQWSUHIHUHQFH    /DWDQRSURVW 7DIOXSURVW 1RSUHIHUHQFH Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 452 Uusi alo e al Conside able alle ia ion o all ocula symp oms and signs was seen du ing he s udies a e he swi ch om BAC-p ese ed la anop os eye d ops o p ese a i e- ee a lup os eye d ops. Na u ally, only a subse o he symp oms and signs was epo ed by a single pa ien a baseline while on la anop os (ie, a leas wo symp oms o one symp om and one sign we e he inclusion c i e ia o a pa ien ). Fo example, 29%–54% o he pa ien s summa ized in Table 3 did no expe ience a speci ic ocula symp om a baseline wi h la anop os . By concen a ing solely on he pa ien s who had a leas a ace o a symp om (46%–71%), ema kable a es o imp o emen (o a leas one class) we e achie ed wi h p ese a i e- ee a lup os a 12 weeks: 82% o i i a ion/ bu ning/s inging, 84% o o eign body sensa ion, 83% o ea ing, 78% o i ching, and 83% o d y eye sensa ion. Abo e all, ~40% o all pa ien s we e en i ely symp om ee a he end o he 12-week ea men pe iod. The se e i y o conjunc i al hype emia was hal ed du ing he 12-week ea men pe iod wi h p ese a i e- ee a lup os (Table 5). The hype emic e ec o la anop os may be la gely caused by he high concen a ion o BAC (0.02%) in he oph halmic solu ion, since no clea di e ences be ween he BAC-p ese ed o mula ions o la anop os and a lup os we e seen o conjunc i al hype emia in a p e i- ous la ge, andomized, double-masked, Phase IIIb clinical ial.19 In essence, he hype emic e ec may lead o educed ea men compliance. I may also be a sign o conjunc i al in lamma ion. The e o e, a d ug ha causes less o no hype- emia is p e e able. HLA-DR-posi i e conjunc i al epi helial cells and MUC5AC-exp essing goble cells we e s udied in imp ession cy ology specimens as pa o he s udy conduc ed in Finland, Sweden, and Ge many. Signi ican changes owa d no mal- iza ion we e seen du ing he ea men wi h p ese a i e- ee a lup os in compa ison wi h BAC-p ese ed la anop os .20 The esul s sugges ha p ese a i e- ee a lup os induces less ha m ul e ec s on he conjunc i a, which is he p incipal a ge o he oxic e ec s o opical oph halmic p epa a ions. Pa ien - ela ed ou comes indica ed he supe io i y o p ese a i e- ee a lup os . Fo example, pa ien s’ epo s on d op discom o educed subs an ially du ing he 12-week ea men wi h p ese a i e- ee a lup os . Mo eo e – on he basis o he QoL ques ionnai e (COMTol) – a clea majo i y o he pa ien s (72%) p e e ed p ese a i e- ee a lup os o e BAC-p ese ed la anop os . The side e ec s had also less impac on he QoL du ing he ea men wi h p ese a i e- ee a lup os . P os aglandin analogs ha e p og essi ely eplaced be a-blocke s as he i s -line he apy o OH/OAG, because hey a e he mos e ec i e IOP-lowe ing agen s, lack ele an sys emic side e ec s, and equi e only once-daily dosing.25,26 P ese a i e- ee p os aglandin analogs – such as a lup os – minimize he isk o ocula side e ec s and inc ease he likeli- hood o good ea men adhe ence. Hence, p ese a i e- ee solu ions should be conside ed when a ailable. They could be pa icula ly bene icial o pa ien s who 1) ha e p eexis - ing ocula su ace disease, 2) a e expec ed o de elop ocula su ace disease (d y eye) du ing long- e m medica ion, 3) a e using mul iple concomi an opical ocula ea men s, and/o 4) a e abou o unde go glaucoma su ge y.27,28 In gene al, he cu en glaucoma ea men guidelines call o he apies ha can main ain isual unc ion, minimize side e ec s, inc ease adhe ence, and imp o e QoL o he pa ien s. A co ec choice o i s -line he apy is undamen al o achie ing hese pa ien ou comes and educing he economic cos s in he long un. P ese a i e- ee p os aglandin analogs cu en ly p o ide he bes mono he apy op ion o i s -line ea men o OH/OAG. The cos s o disease managemen could e en be hal ed, i OH/OAG is p e en ed/delayed e ec i ely.29 The s udies included in he me a-analysis we e limi ed by hei open-label designs. An open-label design could no be a oided, since comme cial BAC-p ese ed la anop os was a ailable only in con en ional eye d op bo les and p ese a i e- ee a lup os in uni dose dispense s. The s udies we e no designed o mi iga e he e ec o eg es- sion o he mean (RTM) ei he . In o he wo ds, pa ien s ini ially iden i ied by high alues could ha e lowe alues on emeasu emen e en in he absence o an in e en ion. A andomized, con olled s udy would ha e been he ob ious choice o con ol he possible bias caused by RTM. Ins ead o RTM, he u he dec ease in IOP wi h p ese a i e- ee a lup os could be a ibu ed o imp o ed ea men compli- ance achie ed by be e ole ance. Fu he mo e, he limi ed 12-week du a ion o he s udies did no allow o in es iga- ion o he long- e m e ec s. Conclusion The p esen me a-analysis con i med ha p ese a i e- ee a lup os eye d ops o e ed clinical bene i s o OH/ OAG pa ien s ha ou weighed hose o he BAC-p ese ed la anop os eye d ops. The IOP-lowe ing e icacy was sus ained (o e en sligh ly imp o ed) a e eplacing p ese ed la anop os wi h p ese a i e- ee a lup os . In addi ion, p ese a i e- ee a lup os signi ican ly dec eased he symp oms and signs o ocula su ace disease and Clinical Oph halmology 2016:10 submi you manusc ip | www.do ep ess.com Do ep ess Do ep ess 453 F om p ese ed la anop os o p ese a i e- ee a lup os eye d ops ou a ed p ese ed la anop os in d op com o and ea - men p e e ence. Acknowledgmen s The au ho s would like o hank Oy 4Pha ma L d, Finland – especially Jouni Vuo inen o w i ing assis ance and Teppo Hu unen o pe o ming he me a-analysis. S udy pe o med in Finland, Sweden, and Ge many. In es iga o s in Finland: Kai Kaa ni an a, Ma kku Leino, Päi i Puska, Hannu Uusi alo. In es iga o s in Sweden: Enping Chen, Elina Palmg en. In es iga o s in Ge many: Thomas Hamache , Gün e Ho - man, Ge no Pe zold, Tobias Riedel, Ul ich Rich e , and Ma in Win e . S udy pe o med in Russia: Yu iy Se gee ich As akho , E nes Vi alye ich Boiko, Alexande Vic o o ich Doga, E geniy Alexee ich Ego o , Olga Alexand o na Kisele a, Alla Alexee na Ryab se a, and Vladimi Pa lo ich Se gee . The au ho s ecei ed edi o ial and w i ing suppo in he p epa a ion o his manusc ip , unded by San en Oy, Tampe e, Finland. The au ho s we e ully esponsible o he ex , da a, and edi o ial decisions o he pape . The manu- sc ip has no been p esen ed a any mee ings. 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