24-Hour Efficacy and Ocular Surface Health with Preservative-Free Tafluprost Alone and in Conjunction with Preservative-Free Dorzolamide/Timolol Fixed Combination in Open-Angle Glaucoma Patients Insufficiently Controlled with Preserved Latanoprost Monotherapy

Introduction The aim of the present study was to evaluate the 24-h efficacy, tolerability, and ocular surface health with preservative-free (PF) tafluprost and a PF triple drug regimen comprising tafluprost and dorzolamide/timolol fixed combination (DTFC) in open-angle glaucoma patients who were insufficiently controlled with preserved branded or generic latanoprost monotherapy and who exhibited signs or symptoms of ocular surface disease (OSD). Methods Prospective, observer-masked, crossover, comparison. Eligible consecutive open-angle glaucoma patients were randomized to either PF tafluprost or the triple PF regimen for 3 months. They were then crossed over to the opposite therapy for another 3 months. At the end of the latanoprost run-in period and after each PF treatment period, patients underwent habitual 24-h intraocular pressure (IOP) monitoring with Goldmann tonometry in the sitting position (at 10:00, 14:00, 18:00, and 22:00) and Perkins tonometry in the supine position (at 02:00 and 06:00). Tolerability and selected ocular surface parameters were evaluated at baseline and the end of each treatment period. Results Forty-three open-angle glaucoma patients completed the trial. Mean 24-h IOP on preserved latanoprost was 22.2 ± 3.9 mmHg. Compared with latanoprost monotherapy, PF tafluprost obtained a greater reduction in mean, peak, and fluctuation of 24-h IOP including the 02:00 and 06:00 time points (P < 0.05). With the exception of 24-h fluctuation, the triple PF regimen provided significantly lower IOP parameters than latanoprost or PF tafluprost (P < 0.001). Finally, PF tafluprost therapy displayed significantly improved tear film break-up times (6.7 vs 6.0 s), corneal staining (1.3 vs 2.2), and Schirmer I test results (9.1 vs 8.2 mm) compared with the preserved latanoprost baseline (all P < 0.01). The triple PF regimen demonstrated similar tear film break-up times (6.1 vs 6.0 s) and Schirmer I test results (8.2 vs 8.2 mm) to latanoprost, but revealed a significant improvement in the corneal stain test (1.7 vs 2.2; P < 0.001). Conclusions In this trial PF tafluprost therapy provided statistically greater 24-h efficacy and improved tolerability compared with preserved latanoprost. The combination of PF tafluprost and PF dorzolamide/timolol fixed combination was statistically and clinically more efficacious than both monotherapies and demonstrated similar ocular surface characteristics to preserved latanoprost monotherapy. Trial registration ClinicalTrials.gov (NCT02802137). Funding Santen.


INTRODUCTION
A meaningful intraocular pressure (IOP) reduction remains the mainstay of current glaucoma management [1][2][3]. Although therapy ideally commences with a monotherapy agent, inevitably monotherapies will not suffice for most patients in the long term [3]. Therefore, stepwise medical therapy is often necessary [1,3]. It has been established, however, that combined antiglaucoma therapy can adversely influence adherence, tolerability, and ocular tissue health [4][5][6]. These parameters markedly reduce the success of long-term medical therapy [6,7]. Treatment advances have been introduced to facilitate the success of combined therapy in real life. For instance, fixed combinations (FCs) were introduced to enhance convenience by minimizing the number of daily drops, improve adherence, enhance tolerability, and conceivably improve long-term ocular outcomes [1,[8][9][10].
In glaucoma a direct consequence of lifelong combined medical therapy is the cumulative toxic effect of preservatives upon and within ocular tissues [10]. The most common preservative contained in glaucoma medications is benzalkonium chloride (BAK), a quaternary ammonium salt that acts as a detergent by disrupting lipid membranes and denaturing proteins [11]. There is convincing scientific evidence to suggest that BAK elicits substantial toxic damage upon the ocular surface [11][12][13][14]. A range of BAK-related ocular surface findings include tear film instability [14,15], corneal and conjunctival epithelial apoptosis [15], increased tear osmolarity [16], and meibomian gland dysfunction [10]. These signs of ocular surface disease (OSD) cause a variety of ocular symptoms that adversely impact quality of life and ultimately reduce long-term adherence and success of glaucoma therapy [17,18]. Moreover, chronic exposure to preservatives (especially BAK) may elicit ocular tissue inflammatory and fibrotic reactions that can undermine the potential long-term success of future glaucoma surgery [19][20][21]. Lastly, there is growing suspicion that BAK can also damage deeper ocular tissues (e.g., the trabecular meshwork) [10,22]. Importantly, preservative-related ocular tissue toxicity is cumulative; therefore, patients receiving combined therapies with multiple preserved drops over a long period may be particularly prone to OSD [10]. It is now well documented that the majority of chronically treated glaucoma patients exhibit signs or symptoms of OSD [12][13][14]. Simplifying stepwise therapy by employing FCs and switching when possible to preservative-free (PF) medications may ameliorate these toxic effects and enhance the success of long-term stepwise therapy.
Branded or generic latanoprost 0.005% containing BAK is currently the most popular first-choice monotherapy in Europe for patients with ocular hypertension or glaucoma [23]. However since the branded latanoprost formulation contains a high concentration of BAK (0.02%) [24], there will be, over time, a  [26,27]. Additionally, patient-reported complaints and symptoms as well as investigator-noted adverse events were recorded at the end of each treatment period.

Ocular Surface Assessment
After recording any self-reported ocular surface symptoms, we performed the following tests:

Statistics
The primary efficacy endpoint of this trial was the mean 24-h IOP (the average pressure for the six time points). The individual time points, peak, trough, and fluctuation of 24-h IOP were considered secondary endpoints. A mixed model was used for the crossover 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 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

Patients
Forty-three open-angle glaucoma patients (22 women and 21 men) completed the study out of 45 enrolled (Fig. 1    An asterisk denotes a statistically significant difference (P\0.001) vs latanoprost baseline. All three ocular surface parameters were also significantly better (P\0.001) with PF tafluprost vs triple PF therapy SD standard deviation

Adverse Events
All three study regimens were well tolerated (

ACKNOWLEDGEMENTS
The current study was funded in part by Santen.