A 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components

Norbert Pfeiffer, Carlo E Traverso, Katrin Lorenz, Ville Saarela, Johanna Liinamaa, Hannu Uusitalo, Yury Astakhov, Ernest Boiko, Auli Ropo, Preservative-free Tafluprost/Timolol Fixed Combination Study Group, Hannu Uusitalo, Kai Kaarniranta, Ville Saarela, Norbert Pfeiffer, Ulrich Bartz-Schmidt, Stephan Dunker, Thomas Hamacher, Klaas Heidemann, Günter Hofmann, Ines Lanzl, Karin Oehmig, Gernot Petzold, Ulrich Richter, Ulrich Thelen, Axel Zehe, Marie-Luise Scherzer, Nathalie Collignon, U F Tegelberg, Carlo Enrico Traverso, Mirella Blini, Emilio Campos, Marco Centofanti, Federico Grignolo, Gianluca Manni, Enrico Martini, Nicola Pescosolido, Luciano Quaranta, Odilia Vattovani, Giuseppe Ravalico, Luca Rosetti, Vincenzo Russo, Adolfo Sebastiani, Hana Garzozi, Orna Geyer, Shimon Kurtz, Moshe Lusky, Ronit Nesher, Miriam Zalish, Simon Longstaff, Rupert Bourne, Timothy Manners, Velota Sung, Jósef Kaluzny, Danuta Karczewicz, Marta Misiuk-Hojlo, Jerzy Nawrocki, Wanda Romaniuk, Malgorzata Siewierska, Edward Wylegala, Tomasz Zarnowski, Kuldar Kaljurand, Kai Noor, Kadri Tammeaid, Natalie Feldmann, Krista Turman, Evgeniy Egorov, Valeriy Erichev, Ernest Boiko, Yury Astakhov, Vladimir Alexeev, Alla Ryabteva, Norbert Pfeiffer, Carlo E Traverso, Katrin Lorenz, Ville Saarela, Johanna Liinamaa, Hannu Uusitalo, Yury Astakhov, Ernest Boiko, Auli Ropo, Preservative-free Tafluprost/Timolol Fixed Combination Study Group, Hannu Uusitalo, Kai Kaarniranta, Ville Saarela, Norbert Pfeiffer, Ulrich Bartz-Schmidt, Stephan Dunker, Thomas Hamacher, Klaas Heidemann, Günter Hofmann, Ines Lanzl, Karin Oehmig, Gernot Petzold, Ulrich Richter, Ulrich Thelen, Axel Zehe, Marie-Luise Scherzer, Nathalie Collignon, U F Tegelberg, Carlo Enrico Traverso, Mirella Blini, Emilio Campos, Marco Centofanti, Federico Grignolo, Gianluca Manni, Enrico Martini, Nicola Pescosolido, Luciano Quaranta, Odilia Vattovani, Giuseppe Ravalico, Luca Rosetti, Vincenzo Russo, Adolfo Sebastiani, Hana Garzozi, Orna Geyer, Shimon Kurtz, Moshe Lusky, Ronit Nesher, Miriam Zalish, Simon Longstaff, Rupert Bourne, Timothy Manners, Velota Sung, Jósef Kaluzny, Danuta Karczewicz, Marta Misiuk-Hojlo, Jerzy Nawrocki, Wanda Romaniuk, Malgorzata Siewierska, Edward Wylegala, Tomasz Zarnowski, Kuldar Kaljurand, Kai Noor, Kadri Tammeaid, Natalie Feldmann, Krista Turman, Evgeniy Egorov, Valeriy Erichev, Ernest Boiko, Yury Astakhov, Vladimir Alexeev, Alla Ryabteva

Abstract

Introduction: The efficacy, safety and tolerability of the preservative-free (PF) fixed combination (FC) of tafluprost 0.0015% and timolol 0.5% (once daily) were compared to those of the individual components (PF tafluprost 0.0015% once daily and PF timolol 0.5% twice daily) in patients with open-angle glaucoma or ocular hypertension inadequately controlled on prior timolol or prostaglandin monotherapy for 6 months.

Methods: A stratified, double-masked, randomized, multicenter phase III study was conducted. A total of 189 prior timolol users were randomized within the timolol stratum (TS) to receive either FC (n = 95) or timolol 0.5% (TIM; n = 94). Furthermore, a total of 375 prior prostaglandin analog (PGA) users were randomized within the prostaglandin stratum (PS) to receive either FC (n = 188) or tafluprost 0.0015% (TAF; n = 187). To be eligible for participation in the study, the patients were required to have an intraocular pressure (IOP) of ≥22 mmHg when on timolol (TIM) or of ≥20 mmHg when on PGA in either treated eye at the screening and end-of-run-in visits. In addition to these, the study included visits at baseline, 2 and 6 weeks, 3 and 6 months and at a post-study visit. IOP was measured at 8 a.m., 10 a.m., 4 p.m., and 8 p.m.

Results: In the TS, a significant reduction from baseline IOP was seen with FC and TIM throughout the study. Average diurnal IOP change from baseline at month 3 was -8.55 mmHg (32%) for FC and -7.35 mmHg (28%) for TIM. The model-based treatment difference (FC-TIM) was -0.885 mmHg [95% confidence interval (CI) -1.745 to -0.024; p = 0.044] demonstrating the superiority of FC over TIM. In the PS, a significant reduction in IOP was seen with both FC and TAF throughout the study. The average diurnal IOP change from baseline at month 3 was -8.61 mmHg (33%) for FC and -7.23 mmHg (28%) for TAF. The model-based treatment difference (FC-TAF) was -1.516 mmHg (95% CI -2.044 to -0.988; p < 0.001) demonstrating the superiority of FC over TAF. In the TS, related ocular adverse events (AEs) were more frequent for patients treated with FC compared to TIM (16.8% versus 6.4%), whereas related non-ocular AEs were more frequent with TIM compared to FC (2.1% versus 0.0%). In the PS, AEs were similarly distributed between FC and TAF. The frequency of conjunctival hyperemia of FC was low (6.4%).

Conclusion: The preservative-free fixed combination of tafluprost and timolol provided a substantial and significant IOP reduction in both strata. The IOP reduction was superior to both tafluprost 0.0015% and timolol 0.5% when given as monotherapies. Overall, the study treatments were safe and well tolerated.

Funding: Santen Oy, Tampere, Finland.

Trial registration: ClinicalTrials.gov NCT01292460.

Figures

Fig. 1
Fig. 1
An overview of scheduled study visits for both prostaglandin stratum and timolol stratum. PGA prostaglandin analog, PS prostaglandin stratum, TS timolol stratum
Fig. 2
Fig. 2
Stratification, number of patients, and medical treatment. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%. PGA prostaglandin analog, PS prostaglandin stratum, TAF monotherapy preservative-free tafluprost 0.0015%, TIM monotherapy preservative-free timolol 0.5%, TS timolol stratum
Fig. 3
Fig. 3
Changes of mean (SD) intraocular pressure (IOP) from baseline at weeks 2 and 6, and months 3 and 6 at 8 a.m., 10 a.m., 4 p.m. and 8 p.m. in the TS. Worse eye analysis in the ITT dataset. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, IOP intraocular pressure, ITT intention to treat, SD standard deviation, TIM monotherapy preservative-free timolol 0.5%, TS timolol stratum
Fig. 4
Fig. 4
Changes of mean (SD) intraocular pressure (IOP) from baseline at month 3 for both strata by treatment group at 8 a.m., 10 a.m., 4 p.m., and 8 p.m.. Worse eye analysis in the ITT dataset. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, IOP intraocular pressure, ITT intention to treat, PGA prostaglandin analog, PS prostaglandin stratum, SD standard deviation, TAF monotherapy preservative-free tafluprost 0.0015%, TIM monotherapy preservative-free timolol 0.5%, TS timolol stratum
Fig. 5
Fig. 5
a Scatterplot of mean change in diurnal IOPs (mmHg) from baseline to month 3 in the TS and b corresponding box-whisker plot of mean diurnal IOPs (mmHg) at month 3 versus baseline for FC and TIM. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, IOP intraocular pressure, TIM monotherapy preservative-free timolol 0.5%, TS timolol stratum
Fig. 6
Fig. 6
Changes of mean (SD) intraocular pressure from baseline at weeks 2 and 6 and months 3 and 6 at 8 a.m., 10 a.m., 4 p.m. and 8 p.m. in the prostaglandin stratum (PS). Worse eye analysis in the ITT dataset. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, IOP intraocular pressure, ITT Intention to treat, TAF monotherapy preservative-free tafluprost 0.0015%, SD standard deviation
Fig. 7
Fig. 7
a Scatterplot of mean change in diurnal IOPs (mmHg) from baseline to month 3 in the PS and b corresponding box-whisker plot of mean diurnal IOPs (mmHg) at month 3 versus baseline for FC and TAF. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, IOP intraocular pressure, TAF monotherapy preservative-free tafluprost 0.0015%, PS prostaglandin stratum
Fig. 8
Fig. 8
Change of conjunctival hyperemia expressed as the mean value of the largest change from baseline in severity score values (scored between 0 and 4 in 0.5 increments) for (a) timolol stratum and (b) prostaglandin stratum. FC preservative-free fixed combination tafluprost 0.0015%/timolol 0.5%, TAF monotherapy preservative-free tafluprost 0.0015%, TIM monotherapy preservative-free timolol 0.5%

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