Randomized Clinical Trial of the Efficacy and Safety of Preservative-free Tafluprost and Timolol in Patients With Open

-Angle Glaucoma or Ocular Hypertension
ALMIRA CHABI, ROHIT VARMA, JAMES C. TSAI, ROBERT LUPINACCI, JOSEPH PIGEON, CHRISTINE BARANAK, LILIANE NOBLE, CHRISTOPHER LINES, AND TONY W. HO To compare the efficacy and safety of tafluprost, a preservative-free (PF) prostaglandin analogue, with PF timolol in patients with open-angle glaucoma or ocular hypertension. ● DESIGN: Randomized, double-masked, multicenter clinical trial. ● METHODS: After discontinuation and washout of existing ocular hypotensive treatment, patients who had intraocular pressure (IOP) >23 and <36 mm Hg in at least 1 eye at the 08:00 hour time point were randomized 1:1 to 12 weeks of treatment with either PF tafluprost 0.0015% or PF timolol 0.5%. IOP was measured 3 times during the day (08:00, 10:00, 16:00 hours) at baseline and at weeks 2, 6, and 12. It was hypothesized that PF tafluprost would be noninferior to PF timolol over 12 weeks with regard to change from baseline IOP. The trial was powered for a noninferiority margin of 1.5 mm Hg at each of the 9 time points assessed. ● RESULTS: A total of 643 patients were randomized and 618 completed (PF tafluprost ‫ ؍‬306, PF timolol ‫ ؍‬312). IOPs at the 3 time points assessed during the baseline visit ranged from 23.8 to 26.1 mm Hg in the PF tafluprost group and 23.5 to 26.0 mm Hg in the PF timolol group. IOPs at the 3 time points assessed during the 12-week visit ranged from 17.4 to 18.6 mm Hg for PF tafluprost and 17.9 to 18.5 mm Hg for PF timolol. At all 9 time points, the upper limits of the 2-sided 95% confidence intervals for the difference between treatments in IOP lowering were less than the prespecified noninferiority margin. Similar percentages of PF tafluprost and PF timolol patients reported ocular pain/ stinging/irritation (4.4% vs 4.6%) and pruritus (2.5% vs 1.5%). The percentages of PF tafluprost and PF timolol patients reporting conjunctival hyperemia were 4.4% vs 1.2% (nominal P ‫ ؍‬.016).
Supplemental Material available at AJO.com. Accepted for publication Nov 8, 2011. From Clinical Neuroscience & Ophthalmology, Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey (A.C., R.L., C.B., L.N., C.L., T.W.H.); University of Southern California, Doheny Eye Institute, Los Angeles, California (R.V.); Yale Eye Center, Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, Connecticut (J.C.T.); and Villanova University, Villanova, Pennsylvania (J.P.). Inquiries to Almira Chabi, Merck Sharp & Dohme Corp, PO Box 1000, North Wales, PA 19454-1099; e-mail: almira.chabi@merck.com
0002-9394/$36.00 doi:10.1016/j.ajo.2011.11.008

● PURPOSE:

● CONCLUSIONS:

The IOP-lowering effect of PF tafluprost was noninferior to that of PF timolol. PF tafluprost is an efficacious and generally well-tolerated ocular hypotensive agent. (Am J Ophthalmol 2012;xx:xxx. © 2012 by Elsevier Inc. All rights reserved.)
ROSTAGLANDIN ANALOGUES ARE A RELATIVELY

new class of ocular hypotensive medications that have proven effective in lowering intraocular pressure (IOP), the major modifiable risk factor implicated in glaucomatous optic nerve damage and chronic visual loss.1,2 Prostaglandin analogues act through increased uveoscleral outflow,1,2 allowing for IOP reductions that can be additive to the effect of medications that lower IOP through other mechanisms.1,3– 6 The first prostaglandin analogue available in the United States was latanoprost, which has been shown to be effective in reducing IOP but has been associated with a number of local side effects, including ocular hyperemia, increased pigmentation of the iris, and changes to the eyelashes.7,8 Similar side effects have also been reported for other more recently approved prostaglandin analogues, including isopropyl unoprostone,9 bimatoprost,10 and travoprost.11 Many topical eye drop formulations have been formulated with variable concentrations of benzalkonium chloride as a preservative. Benzalkonium chloride may be toxic to a variety of tissues of the ocular surface12,13 and may play a role in the tolerability of these formulations over time, especially in those patients with comorbid ocular surface disease such as chronic dry eye.14,15 In addition, a subset of patients have delayed-type hypersensitivity (allergy) to benzalkonium chloride.16 These findings have motivated recent efforts to develop preservative-free (PF) formulations of existing treatments, such as timolol17 and the dorzolamide/timolol fixed combination.18 To date, no PF formulations of prostaglandin analogues are available in the United States. Tafluprost is a new prostaglandin analogue19 –21 that is being developed in a PF formulation for lowering IOP in patients with glaucoma or ocular hypertension.22 Tafluprost has been marketed since 2008 in Japan and several European countries, but is not yet approved in the United States. Studies on the preservative-containing (PC) forRIGHTS RESERVED.

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ELSEVIER INC. ALL

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27.6 logMAR (Snellen equivalent of 20/80) or better in each eye and a mean (or median) IOP Յ36 mm Hg in both eyes. 16:00 hours) at the baseline visit. 16:00 hours). double-masked.29 retinal disease.5%) in glaucomatous or ocular hypertensive patients. Study investigators. anterior/posterior uveitis (either eye within 6 months of screening). 6. 2010 through September 17.or ␤-adrenergic agonists. history of certain ocular surgeries. patients were to be contacted by telephone to assess for serious adverse events at least 14 days after the last dose of study medication (ie. Other study visits occurred at weeks 2. ocular opacity or insufficient dilation preventing retinal evaluation.28 The results of a meta-analysis suggested that prostaglandin analogues were most effective for lowering IOP but timolol was almost as effective. At these visits. statistical analysis plan. following discontinuation of study medication or after the last study visit at week 12).23–25 A small. short-duration (4-week). study found that the PF and PC formulations of tafluprost had equivalent efficacy and tolerability. patients had to meet the entry criteria of a mean (or median) IOP of Ն23 and Յ36 mm Hg at 08:00 hours and a Ͻ5 mm Hg difference in mean (or median) IOP measurement between eyes at 3 time points (08:00. and authoring of the manuscript. ocular medications (other than antiglaucoma medications or topical lubricants) within 1 week of screening. in the investigator’s opinion. eligible patients entered a 5-day to 4-week washout period prior to the baseline visit. At the baseline visit. condition preventing tonometry. 8. was chosen as the comparator against tafluprost because it is an FDA-accepted standard for glaucoma studies with a well-understood efficacy and safety profile. Patients were assigned to treatment using a computer-generated randomized allocation schedule prepared by a statistician at Merck. Key exclusion criteria included abnormal corneal sensation. At the screening visit. and history of pulmonary disease including asthma.0015%) or PF timolol maleate (0. or if investigators were concerned that that would occur over the 4-week washout. patients.5%) ophthalmic solutions were used. except at week 8 when the patient returned to the clinical study site for study medication resupply and assessment of dosing compliance only. A Scientific Advisory Committee composed of non-Merck and Merck scientists contributed to the development of the protocol. All medications were dispensed from identical unit dose containers. a beta-blocker. Patients on a stable ocular hypotensive medication treatment regimen that began at least 30 days prior to the screening visit. Men and women 18 years and older who had a diagnosis of primary open-angle glaucoma.0015%) and PF timolol (0. The 12-week double-masked treatment period began on the day following the baseline visit. active comparator-controlled clinical trial comparing the efficacy and safety of PF tafluprost (0. analysis and interpretation of the data. During the post-study period. Investigators were allowed to use dorzolamide as rescue treatment (up to 1 week before randomization) if. previous use of tafluprost. pigmentary glaucoma. The trial (Merck Protocol 001) was conducted from February 16. multicenter. capsular glaucoma/pseudoexfoliation. and those who were treatment-naïve.mulation of tafluprost have demonstrated that it is effective and well tolerated for reducing IOP. PF tafluprost (0. randomized. significant visual field defect or progressive visual field loss within the last year. and 12. 12-week.5%). narrow anterior chamber angle. a patient’s IOP was getting too high. 10:00. and Merck monitoring staff remained masked to treatment allocation throughout the study. Patients had to be willing to avoid wearing contact lenses during the study. IOP was measured at 08:00. and 4 sites in Switzerland. were eligible. timolol was instilled twice daily. PF tafluprost (0. progressive 2 AMERICAN JOURNAL ● PATIENTS: OPHTHALMOLOGY MONTH 2012 . parallel-group. dependent upon which prior glaucoma treatment they had used prior to screening (4 weeks for prostaglandin analogues and ␤-adrenergic antagonists. Following discontinuation of any existing ocular hypotensive treatment (see Procedure). 6 sites in Spain. 1 week for carbonic anhydrase inhibitors and cholinergic agonists. Patients who met the study requirements were randomized to 1 of the 2 active treatment groups. 10:00. 10:00.0015%) and PF timolol maleate (0. site staff. and 16:00 hours and other ocular assessments were performed. 2 weeks for ␣. Consistent with the current FDA-approved label for glaucoma. in a 1:1 ratio and were stratified according to baseline IOP (Ͻ25 mm Hg or Ն25 mm Hg at 08:00 hours at the baseline visit) and ocular diagnosis (open-angle glaucoma or ocular hypertension).26 The purpose of the present study was to compare the safety and efficacy of the PF formulation of tafluprost with PF timolol in a large 12-week phase 3 clinical trial conducted primarily in the United States. inflammatory ocular surface disease. patients had to have a mean (or median) IOP of Ն23 and Յ36 mm Hg in at least 1 eye at the 08:00 hour time point at the baseline visit and Ͻ5 mm Hg difference in mean (or median) IOP between eyes at each of 3 time points (08:00. significant cardiovascular disease. Timolol. or ocular hypertension were eligible. After screening. 5 days for miotics). patients had to have a best-corrected visual acuity of ϩ0. significant ocular signs/symptoms. Patients randomized to PF timolol OF ● PROCEDURE: METHODS ● DESIGN: This was a phase 3. ocular inflammation/infection. Personnel at each study site used an interactive voice response system to determine which masked treatment containers should be given to which patient. allergic conjunctivitis. 2010 at 40 sites in the United States.

1) 49 (15. XX.3) 191 (59.6) 107 (33.TABLE 1.3 (11.6) 192 (59. in the judgment of the investigator.7) 25 (7.0) 28 (8.1) 54 (16.4) 63.1) 32 (9.7) 129 (40.4) 48 (15.3) 127 (39. years Race White Black/African American Asian Other Geographic location United States Other Baseline IOP Ͻ25 mm Hg Ն25 mm Hg Ocular diagnosis Open-angle glaucomab Ocular hypertension Randomization stratum (baseline IOP/ocular diagnosis) Ͻ25 mm Hg/open-angle glaucomab Ͻ25 mm Hg/ocular hypertension Ն25 mm Hg/open-angle glaucomab Ն25 mm Hg/ocular hypertension Prior prostaglandin use No use Use Prior ophthalmologic medicationsc Bimatoprost Brinzolamide Carboxymethylcellulose sodium Dorzolamide hydrochloride Latanoprost Polyethylene glycol (ϩ) propylene glycol Timolol Timolol maleate Travoprost a 137 (42.5) 127 (39.3) 196 (60.3 (11. Both eyes were to be treated with study medication regardless of whether 1 or both met the IOP criteria unless.0) 5 (1.9) 79 (24.6) 244 (75.9) 31 (9.4) 42 (13. where mean (SD) is given.8) 75 (23.0) 115 (35. periocular topical or intravitreal corticosteroids unless associated with cataract surgery.8) 145 (44.9) 78 (24.5) 63 (19.9) 260 (80.7) 194 (60.1) 11 (3.9) 80 (24.9) 266 (83.7) 16 (5.2) 63.9) 126 (39.8) 47 (14. or anti-infective medications that could interfere with the study. Patients randomized to PF tafluprost received masked PF vehicle in the morning pouches and active PF tafluprost in the evening pouches. b received unit dose pouches of PF timolol marked for morning and evening administration.9) 28 (8. NO. Patients were instructed to administer the morning drops at 08:00 hours (Ϯ1 hour) and the evening drops at 20:00 hours (Ϯ1 hour).8) 183 (57.8) 75 (23. topical ocular anti-allergy.9) 19 (5.4) 131 (40.3) 25 (7.7) 236 (73.7) 118 (36. preservative-containing topical ocular lubricants. pseudoexfoliative glaucoma.2) 116 (35.0) 47 (14. anti-inflammatory.4) 6 (1. or pigmentary glaucoma.5) 71 (22.9) 178 (55. Includes patients with primary open-angle glaucoma.7) 67 (20. the nonqualifying eye should not be treated.9) 3 (0.7) 40 (12.7) 78 (24.5) 3 (0. Baseline Characteristics of Patients With Open-Angle Glaucoma or Ocular Hypertension Randomized to Preservative-free Tafluprost or Timolola Preservative-free Tafluprost Preservative-free Timolol (N ϭ 320) (N ϭ 323) Characteristic Sex Male Female Age Mean (SD).5) 36 (11. systemic administration of prednisone or equivalent steroids in sufficient doses and/or for sufficient time such that the investigator had concerns about additional ocular exposure to steroids AND PRESERVATIVE-FREE TAFLUPROST TIMOLOL 3 .7) Values are number (%) of patients except for age.4) 194 (60.1) 129 (39. VOL. c Incidence Ն5% in 1 or more treatment groups.6) 193 (60. X TRIAL OF Use of the following medications was prohibited during the study: ocular hypotensive medications other than study medications.

2. if only 1 eye satisfied the entry criteria. ● SAFETY ASSESSMENTS: FIGURE. and likelihood of being related to study medication. and quinidine). 6. fluoxetine. 1.in terms of safety and/or efficacy. The examiner graded the degree of conjunctival hyperemia in each eye using a 0-4 scale with increments of 0. the severity. Missing IOP data were imputed by carrying the last observation forward from previous treatment visits (for a specific time point). The eye with the highest baseline IOP was designated as the “study eye” for the primary efficacy analysis. This included patients who received at least 1 dose of study treatment. right eye measurements were followed by left eye measurements. Mean (؎ 95% confidence interval) intraocular pressure at each visit and time point in patients with open-angle glaucoma or ocular hypertension receiving preservative-free (PF) tafluprost or timolol. Percent compliance was then calculated as: % compliance ϭ (number of days on therapy/number of days should be on therapy) ϫ 100. paroxetine. IOP was measured prior to any dilation. ● EFFICACY ASSESSMENTS: IOP was measured using a Goldmann applanation tonometer at the screening clinic visit and at 08:00. In addition to adverse event reports. In practice.1% for PF tafluprost and 3. Ocular abnormalities identified as clinically relevant were reported as adverse events. then a third measurement was performed and the median of the 3 measurements was determined. conjunctival hyperemia was assessed using the Conjunctival Hyperemia Scale (Ora Inc. while masked. a compliant day on therapy was defined as one in which both the morning and evening eye drops were administered as directed. which were counted by the investigator. and 16:00 hours at weeks 2. The full analysis set consisted of all randomized patients who received at least 1 dose of study treatment and had at least 1 posttreatment efficacy measurement available for the analysis (and baseline measurement for change from baseline analyses). AMERICAN JOURNAL OF The primary endpoint used to evaluate efficacy was the mean IOP change from baseline at all 9 time points during the study (08:00. Patients were included in the treatment group to which they were randomized for the analysis of efficacy data. ocular surface examination using fluorescein staining. If both eyes had the same IOP at baseline. At each IOP time point. 10:00. ● STATISTICAL ANALYSIS: The primary hypothesis was that PF tafluprost would be noninferior to PF timolol with respect to IOP change from baseline over 12 weeks of therapy. Similarity between tafluprost and timolol was assessed by a noninferiority analysis. external and adnexa ocular examination. which was reviewed for compliance at each visit in the treatment period. and 12). had at least 1 efficacy measurement available for the analysis endpoint. and 16:00 hours at baseline. If these 2 consecutive measurements differed by Յ2 mm Hg. USA). and vital signs. 3. 6. potent CYP2D6 inhibitors (bupropion. ● COMPLIANCE WITH TREATMENT: Patients completed a dosing diary. based on a noninferiority margin of 1. A set of color photographs was provided displaying examples of grade 0. For each adverse event. In practice. For all ophthalmic procedures. gonioscopy. then that eye was designated as the “study eye. Goldmann applanation tonometry. To confirm compliance with the dosing regimen. and did not commit any protocol violations that may have substantially affected the results of the primary efficacy endpoints. the examiner took 2 consecutive measurements for each eye. The final determination on protocol violations was made prior to the final unmasking of the database. the median was used for less than 1% of the data. A supportive analysis using the full-analysis-set population was performed for the primary efficacy endpoint.” The per-protocol population was used for the analysis of efficacy.9% for PF timolol. and at week 2. and 4 conjunctival hyperemia. the percentages of data imputed at week 12 were 7. Andover. For each patient. then the average IOP for each eye was calculated. However. slit-lamp examination (including fundus examination and hyperemia assessment). then the right eye was designated as the “study eye”. patients were asked to return to each study visit with their used and unused study drug containers. 5 mm Hg. Ocular assessments were performed at each study visit except week 8. and 12 clinic visits. automated perimetry (Humphrey or Octopus). seriousness. Ocular assessments included the ETDRS visual acuity test.5 allowed. Massachusetts. if the 2 consecutive measurements differed by Ͼ2 mm Hg. Patients were queried at each study visit for any adverse events occurring while dosing with study drug. An analysis of covariance (ANCOVA) model was used including terms for treatment and ocular diagnosis (openangle glaucoma or ocular hypertension) and baseline IOP OPHTHALMOLOGY MONTH 2012 4 . the investigator determined. 10:00.

USA). Analysis of Intraocular Pressure Change From Baseline by Visit and Time Point in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Preservative-free Tafluprost or Timolol Preservative-free Tafluprost Least Squares Mean (mm Hg) Preservative-free Timolol Least Squares Mean (mm Hg) Differencea Least Squares Mean (mm Hg) Visit Time Point N (95% CI) N (95% CI) (95% CI)b Week 2 Week 6 Week 12 08:00 10:00 16:00 08:00 10:00 16:00 08:00 10:00 16:00 280 293 289 294 298 295 296 298 295 Ϫ7.3 (Ϫ1. The following groupings of adverse events were prespecified as being of special interest: conjunctival hyperemia.1 Ϫ5. Ϫ7. Data were analyzed using SAS version 9.9.0) 6.2) (Ϫ7. 0.4.2) (46. 62. Number and Percentage (95% Confidence Interval) of Open-Angle Glaucoma or Ocular Hypertension Patients Receiving Preservative-Free Tafluprost or Timolol With Ն25% Reduction in Diurnal Intraocular Pressurea From Baseline Preservative-free Tafluprost Visit m/n b Preservative-free Timolol (95% CI) m/n b Treatment Differencec (95% CI) % (95% CI) % % Week 2 Week 6 Week 12 166/293 175/298 178/298 56. patients who discontinued because of an adverse event.4)c (Ϫ0.7) (Ϫ6.7) (Ϫ6.8 Ϫ6. Ϫ5.2 4.7. North Carolina.1 Ϫ0.1)c (Ϫ1. Two supportive statistical methods—an analysis of variance (ANOVA) model including a term for treatment and a constrained longitudinal data analysis (cLDA) model including terms for treatment.0) (Ϫ3.3 Ϫ7.8.8) (Ϫ7.8 Ϫ6. a drug-related adverse event.5.9. 0.4. and 12) to estimate the treatment difference and 95% confidence interval (CI) in terms of the mean change from baseline to the time point.9.6 Ϫ5.3)c (Ϫ1. and ocular diagnosis (open-angle glaucoma or ocular hypertension).6)c (Ϫ0. 10:00. Safety and tolerability were primarily assessed by counts and clinical review of adverse events within 14 days after the last dose of treatment (or after discontinuation). 6.3. Ϫ6. 0. calculated based on Miettinen and Nurminen method. and 16:00 hours at weeks 2.0) (Ϫ7.1. Diurnal IOP was calculated as the mean of the IOPs in the “study eye” at the 3 time points for each clinic visit (08:00.8) (Ϫ5. Ϫ0.0 Ϫ6. which included all patients who received at least 1 dose of study drug. Ϫ6.3.4 (44.8 0. 58. A secondary efficacy endpoint was the proportion of patients with a favorable IOP response.5 mm Hg.7.1) (Ϫ1.1) (Ϫ7. baseline intraocular pressure.5)c (Ϫ0. 56. Ϫ5.5 Ϫ6.1)c CI ϭ confidence interval. 10:00. defined as Ն25% reduction in diurnal IOP from baseline at weeks 2.9.9.7 (Ϫ7. and adverse events reported by at least 4 patients in any treatment group were calculated. 65.3. Ϫ6.4) (52. 6.0.3) 154/305 164/312 173/312 50.7 Ϫ0.3 Ϫ7.7 (50. Ϫ0.0)c (Ϫ1.7.5. Ϫ5. Ϫ6. Ϫ6.1 Ϫ6.1) CI ϭ confidence interval.5 52.5.3 Ϫ7.7 58.9.6.3. b Based on analysis of covariance with terms for treatment.5) (Ϫ6.TABLE 2. Ϫ7. Ϫ5.3) (Ϫ6. week.1.4 Ϫ7.2) (49. and cLDA models and a noninferiority margin of 1. 14. and 12. 16:00 hours). and 12.2 6.9) (Ϫ7. or a serious adverse event.8 0.8.8.7. Ϫ6.4 Ϫ0. c Noninferiority of tafluprost based upon prespecified noninferiority margin of 1.5 Ϫ7. a Difference ϭ Preservative-free tafluprost – preservative-free timolol.1) (Ϫ7. N ϭ number of patients included in the analysis at the corresponding visit and time point.4) Ϫ0. The proportions and 95% CIs were provided for each treatment group and for the VOL. ocular pain/stinging/irriAND PRESERVATIVE-FREE TAFLUPROST TIMOLOL 5 .4 Ϫ0.5) (Ϫ6. The primary population used for safety analyses was the allpatients-as-treated population. Cary. XX.3) (Ϫ5. 12.1) (Ϫ6.9) (Ϫ7.7.2 (Ϫ7. Ϫ6. 14.7. X TRIAL OF treatment difference using the Miettinen and Nurminen method. a Average of the measurements made at 3 time points per visit.0.4) (53.3)c (Ϫ0.9.0) (Ϫ7. Ϫ5. Ϫ7.0 Ϫ0.7 59. Ϫ0. c Difference ϭ preservative-free tafluprost – preservative-free timolol.0 Ϫ6.5 mm Hg. b m/n ϭ number of patients with Ն25% reduction in diurnal intraocular pressure from baseline/number of patients in the analysis.4 Ϫ6. A separate ANCOVA model was used for each time point (08:00.9) 295 305 302 308 312 310 308 312 310 Ϫ6.0. NO.4 Ϫ0. An additional endpoint was the mean (95% CI) change from baseline in diurnal IOP at weeks 2. ANOVA. which was analyzed using the ANCOVA. Ϫ6.1 software (SAS Institute. Ϫ6. 6. as a covariate.6 55. TABLE 3.0)c (Ϫ1.8.4. Ϫ5.6 Ϫ5. Ϫ0.2 Ϫ7. ocular diagnosis. 0. 0.6 (Ϫ0. 64.8.6. and the interaction of week by treatment—were also used as sensitivity analyses. The proportion of patients who reported 1 or more adverse events. 61.1.

burning sensation. and ocular hyperemia.9 (Ϫ7.2 4.0 due to rounding.8) (Ϫ6.1 Ϫ6. f Actual value of upper bound of 95% CI was Ϫ0. hyperemia.2 0.6 11. b N ϭ number of patients included in the analysis at the corresponding visit. Mean (95% Confidence Interval) Change From Baseline in Diurnal Intraocular Pressurea in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Preservative-free Tafluprost or Timolol Preservative-free Tafluprost Mean (mm Hg) Preservative-free Timolol Mean (mm Hg) Mean (mm Hg) Differencec Visit Nb (95% CI) Nb (95% CI) (95% CI)d Week 2 Week 6 Week 12 293 298 298 Ϫ6.9 2.7.6 1.0)e.9 1.3 73 36 7 3 4 15 5 0 3 3 7 2 0 5 4 4 6 5 22.9 Ϫ6. c Difference ϭ preservative-free tafluprost – preservative-free timolol.0 0. a Average of the measurements made at 3 time points per visit. d Ocular pruritus ϭ eye pruritus. b tation.5 Determined by the investigator to be related to the drug.5 mm Hg.30 6 AMERICAN JOURNAL OF ● SAMPLE SIZE: The primary hypothesis was that PF tafluprost would be noninferior to PF timolol with respect to IOP change from baseline over 12 weeks of therapy.8.8 12.4 2. e Noninferiority of tafluprost based upon prespecified noninferiority margin of 1.6 0.6 0.6) (Ϫ7. Ϫ5.2 1.5 1.5 Ϫ-6. and pruritus.4e 4. TABLE 5. instillation site pruritus. eye irritation.5 0.004. Ϫ6. and ocular diagnosis (open-angle glaucoma or ocular hypertension).2 0.6 1.4 Ϫ0. and ocular pruritus.2 1.1. Ϫ0.5) (Ϫ7.7 Ϫ0. c Ocular pain/stinging/irritation ϭ abnormal sensation in eye. shown as Ϫ0.3 0.9 0.6) 305 312 312 Ϫ6.2. instillation site erythema.9 1.9 0. and ocular discomfort.6 1. Summary of Clinical Adverse Events in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Preservative-free Tafluprost or Timolol Preservative-free Tafluprost (N ϭ 320) n % Preservative-free Timolol (N ϭ 323) n % One or more adverse events Drug-relateda adverse event Serious adverse event Discontinued due to an adverse event Groupings of events of special interest Conjunctival hyperemiab Ocular pain/stinging/irritationc Ocular pruritusd Specific events occurring in Ն4 patients in a treatment group Conjunctival hyperemia Eye pruritus Headache Instillation site pain Ocular hyperemia Photophobia Punctate keratitis Dry eye Eye irritation Vision blurred Dizziness a 73 39 2 4 14 14 8 9 6 5 5 5 4 4 3 3 2 1 22.3 1.016 vs preservative-free timolol.8 1.2) (Ϫ6. P values for the betweentreatment differences for these adverse events of special interest were calculated using the Miettinen and Nurminen method. eye pain.9.1)e CI ϭ confidence interval.3 (Ϫ1. Ϫ6. Conjunctival hyperemia ϭ conjunctival hyperemia. The trial was powered for a noninferiority margin of 1.7 Ϫ6.6 (Ϫ6. d Based on analysis of covariance with terms for treatment. Ϫ6. e Nominal P value of .9 0.TABLE 4.2.0 1. Ϫ0. Ϫ6.5 2.5 mm OPHTHALMOLOGY MONTH 2012 .8.2 0.1 2. baseline intraocular pressure.3)e (Ϫ0.f (Ϫ0.0. instillation site pain.3. 0.3) Ϫ0.6 1.3 4.9 1.6 1. Ϫ6.

to study treatment was 80.Hg. The specific ocular treatments used prior to the study are summarized in Table 1. NO.6 days in the PF tafluprost group and 82. and was designed to enroll 620 patients (310 per treatment group) to yield 576 evaluable patients (288 per treatment group). 6.3% vs 0. Approximately 60% of patients had previously used prostaglandin analogues. ● TREATMENT COMPLIANCE: The mean percentages of days that patients were fully compliant (ie.5 mm Hg was greater than 99% at each of the 9 time points during the study (08:00.025 (1-sided).5 mm Hg.1% for PF timolol. More than half of the patients had Ն25% reduction in diurnal IOP from baseline in both treatment groups (secondary endpoint). The results were also similar using an analysis based on the full-analysis-set population.2) in the proportions of patients taking any of the prostaglandins or timolol/timolol maleate prior to enrollment. The reasons for discontinuation were similar among the treatment groups. respectively. X TRIAL OF PRESERVATIVE-FREE TAFLUPROST TIMOLOL 7 . noninferiority margin ϭ 1. and 12). The same percentage of patients in each treatment group (19/320 [5. ● TOLERABILITY AND SAFETY: Adverse events are summarized in Table 5.8) mm Hg in the PF tafluprost group and 24. the 4 excluded patients all had a history of asthma in violation of the exclusion criteria—if these patients had been assigned to PF timolol they could have stopped taking study treatment because of an increase in asthma symptoms and/or taken steroids to treat asthma.6 mm Hg at the 9 time points during the study. (available at AJO.6% of patients in the PF tafluprost and PF timolol groups. Main reasons for discontinuation were patient withdrawal (N ϭ 12) or adverse events (N ϭ 7. The results for the primary endpoint of mean change from baseline in IOP are shown in Table 2.9%) discontinued early. Patient characteristics were generally similar among the treatment groups. PF tafluprost and PF timolol were both well tolerated. 3 were at the 16:00 time point on weeks 2. race. 21 in the PF tafluprost group and 10 in the PF timolol group. Mean (SD) diurnal IOP at baseline was 24. No specific adverse event reAND ● EFFICACY: RESULTS ● PATIENT ACCOUNTING AND DEMOGRAPHICS: The trial profile is shown in Supplemental Figure 1. which were based on the results from a previous noninferiority study vs timolol: ␣ ϭ 0. Mean changes from baseline in diurnal IOP are shown in Table 4.9%] for PF timolol) had a history of conjunctival hyperemia. Characteristics of the randomized patients by treatment group are summarized in Table 1. At 4 of the 9 time points.9 (2.com).com). and in sensitivity analyses using an ANOVA model and a cLDA model (data not shown). Of 643 randomized patients.5 mm Hg. Reductions in IOP were observed in both treatment groups as early as week 2. The power and sample size were based on the following assumptions at each of the 9 time points during the study. and 12.2% vs 11. With this sample size. sex. 618 patients (96.7 (2. directionally favoring PF tafluprost. PF tafluprost was noninferior to PF timolol with respect to the IOP change from baseline over the entire 12 weeks of therapy. and ocular diagnosis (Supplemental Figure 2. respectively). Adverse events were reported with a similar incidence in both treatment groups (22. standard deviation ϭ 3.5 mm Hg.9%] for PF tafluprost and 19/323 [5. The criterion for declaring PF tafluprost noninferior to PF timolol with respect to diurnal IOP reduction was met.1%) completed the study and 25 patients (3. The criterion for declaring PF tafluprost noninferior to PF timolol was met since all the upper limits of the 2-sided 95% CIs for the between-group differences in mean change from baseline in IOP were less than the prespecified noninferiority margin of 1. 10:00. the upper bounds of the CIs were less than 0.9%) in the PF tafluprost and PF timolol groups.4 to 0. with the upper limit of the 95% CI for the difference between groups (tafluprost minus timolol) ranging from Ϫ0. true treatment difference ϭ 0 mm Hg. Mean IOPs at each time point during the 12-week study are shown in the Figure. rather than the per-protocol population. There were also similar incidences of drug-related adverse events (12.1 days in the PF timolol group.5) mm Hg in the PF timolol group. and 16:00 hours at weeks 2. baseline IOP. The between-group differences in mean IOP change from baseline at each time point at week 12 were generally consistent among the subgroups defined by age. and there were numerically more responders in the PF tafluprost group than in the PF timolol group at all 3 visits (Table 3).9% for PF tafluprost and 98.8% and 22. discussed below). took the protocol-specified daily dose) were 97. the probability that the upper bound of the 2-sided 95% confidence interval for the between-treatment difference in mean IOP change from baseline (PF tafluprost minus PF timolol maleate) is Յ1. 6. available at AJO. Directionally. A total of 31 patients were excluded from the perprotocol population used for the primary efficacy analysis. although the upper bound of the 95% CI for the difference was less than 0 only at weeks 2 and 6. Of the 4 instances where the upper limit was less than 0. Over the 12-week treatment period. There were no significant differences (P Ͼ . XX. there was a greater mean diurnal IOP reduction from baseline in the PF tafluprost group compared to that of the PF timolol group at all 3 visits. The mean duration of exposure VOL.1%) and discontinuations attributable to an adverse event (1. The main reasons why more patients in the PF tafluprost group were excluded were “patient’s medical history may have had an effect on efficacy data” (4 for PF tafluprost vs 0 for PF timolol. which might have had an effect on IOP) and “patient received incorrect study medication” (3 for PF tafluprost vs 0 for PF timolol).

hernia. In the PF timolol group.2%). In addition to adverse event reports of conjunctival hyperemia.7. tendon rupture. At baseline. the majority of changes were mild.3). Few patients in either group discontinued because of an adverse event and there were relatively few adverse events categorized as serious. In addition. The results of the primary endpoint were supported by analyses of change from baseline in diurnal IOP. the PF formulation of tafluprost achieves good diurnal control of IOP and is well tolerated in patients with open-angle glaucoma or ocular hypertension. conjunctival hyperemia/redness was evaluated during the slit-lamp biomicroscopy examination using a standardized grading scale. and 18.0% (54/317) of patients at week 2.4% (166/323) of patients in the PF timolol group had some grade of hyperemia. a hyperemia worsening of Ͼ0. but this did not influence the findings.7.5 grade was apparent in 6. the determination of violators was made prior to unmasking. The IOP-lowering effect of PF tafluprost was noninferior to that of PF timolol at all visits and time points over 12 weeks. ophthalmoscopy. An increase in the prostaglandinassociated adverse event of iris pigmentation was not observed for PF tafluprost.sulted in discontinuation of more than 1 patient in either treatment group (PF tafluprost: erythema of eyelid.4% (56/304) of patients at week 12.6%) treated with PF tafluprost (atrial fibrillation and myocardial infarction) and 7 patients (2. pulmonary embolism). but this typically only becomes apparent after longer-term use.34 Previous studies using the PC formulation of tafluprost in patients include a 6-week comparison to latanoprost.9% (15/304) at week 12 in the PF tafluprost group.016).23 The present findings support and extend those from a previous small 4-week study comparing PF and PC formulations of tafluprost.5 grade was apparent in 17. and a supportive analysis in which protocol violators were included found similar results. PF timolol: atrial fibrillation. Most adverse events were ocular in nature.9% (48/302) of patients at week 6. a hyperemia worsening of Ͼ0.8 However.24 a 24-month comparison to latanoprost. The demographic characteristics of patients included in the present trial were consistent with the epidemiology of the disorders in the United States. Results for the prespecified groupings of adverse events of special interest are shown in Table 5.4% vs 1. More patients were excluded from the PF tafluprost group than the PF timolol group. The absolute number of protocol violators was relatively small. For example. 7.2% (22/305) of patients at week 6. hypersensitivity). ocular hyperemia. chest pain. Adverse events were reported in about 20% of patients and the incidences were similar in both treatment groups. suggesting 8 AMERICAN JOURNAL OF a numerical advantage for PF tafluprost vs PF timolol. the hyperemia rate was low overall. colitis. eyelash abnormalities (including growth and thickening) increased from 3. the upper boundary of the 95% CI was less than 0 at 4 of 9 time points. It may be of particular value in patients who are allergic to preservatives or who have adverse events related to PC ocular hypotensives. fracture. Serious adverse events occurred in 2 patients (0. cough. fatigue. Ocular pain/stinging/irritation and ocular pruritus groupings were reported with a similar incidence in both treatment groups (P Ͼ . joint dislocation. 46. No increases were observed in the PF timolol group. No other clinically significant changes were seen in visual acuity testing. Specific individual adverse events occurred at low incidence for both treatment groups.7% (24/311) of patients at week 12. which also suggested that PF tafluprost was noninferior to PF timolol. As anticipated. Both PF tafluprost and PF timolol were generally well tolerated. The primary analytic approach was based on a perprotocol approach in which patients who violated prespecified criteria were excluded. or blood pressure and heart rate. or systemic vital signs in the present study. biomicroscopy. visual field testing. previous 12week studies with PC latanoprost have reported hyperemia rates of 12% to 47%. In the slit-lamp biomicroscopy examination.8 Iris pigmentation was reported in a 24-month trial of the PC formulation of tafluprost. including changes in iris pigmentation. DISCUSSION THE RESULTS FROM THIS PHASE 3 CLINICAL TRIAL IN OVER 600 patients with open-angle glaucoma or ocular hypertension demonstrated that both PF tafluprost and PF timolol had a substantial IOP-lowering effect that was apparent after 2 weeks of treatment and was sustained throughout the 12week assessment period. patients had a mean age of 63 years.25 No other clinically significant changes were seen in visual acuity testing. and 7. visual field testing.31–33 There was also a small increase in the prostaglandin-associated sign of eyelash growth/thickening for PF tafluprost. retinal detachment.26 which found equivalent clinical profiles for both formulations. From a clinical use perspective.22 OPHTHALMOLOGY MONTH 2012 .2%) treated with PF timolol (atrial fibrillation. 15. ophthalmoscopy. 58% were women.6% (21/318) of patients at week 2. The results from the present 12-week trial of the PF formulation of tafluprost are in line with previous findings from clinical trials using the PC formulation of tafluprost. as expected given that the pharmacokinetics of the PF and PC formulations are similar. No other clinically significant findings were apparent in the biomicroscopy examination. There were no deaths. This is a known prostaglandin-associated adverse event. ocular hyperemia occurred at a higher rate in the PF tafluprost group compared with PF timolol (4.4% (11/320) at baseline to 4.6% (149/320) of patients in the PF tafluprost group and 51. and 23% were black. The conjunctival hyperemia grouping showed a higher rate for PF tafluprost vs PF timolol (P ϭ .25 and a 12-week study of adjunctive use with timolol. with the highest incidence under 3%. None of the serious adverse events were thought to be drug-related by the investigator and there was no discernible pattern. In the PF tafluprost group.

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