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PurposeTo determine the predictive value of early Phase trials (I–II) for the ocular hypotensive efficacy observed in Phases III and IV.DesignA review of published literature.MethodsThis study evaluated 12 medicines in 65 articles in the literature with at least two phases available.ResultsFor medicines with Phase I results available (n=3), the average reduction in intraocular pressure (IOP) from untreated baseline was 16%, 26% for Phase II, 26% for Phase III, and 24% for Phase IV. For medicines with Phase II results available (n=6), the average reduction in IOP was 23%, 24% for Phase III, and 23% for Phase IV. For medicines with Phase III results available (n=11), the average reduction in IOP was 25% and 24% for Phase IV.ConclusionThis study indicates that early phase trials usually approximated the results of later regulatory studies and post-commercialization trials.Eye (2008) 22, 985–988; doi:10.1038/sj.eye.6702913; published online 22 June 2007 [ABSTRACT FROM AUTHOR]

AIMS:To evaluate the efficacy and safety of latanoprost/timolol maleate fixed combination (LTFC) given once daily vs the concomitant therapy of brimonidine twice daily and latanoprost once daily in primary open-angle glaucoma or ocular hypertensive subjects. METHODS:A prospective, double-masked, active-controlled comparison in which qualified subjects had all glaucoma medicines discontinued for 1 month and then were randomized to either LTFC or brimonidine and latanoprost concomitant therapy for 6 weeks. They were then switched to the other treatment regimen. The intraocular pressure (IOP) was measured at 0800, 1200, and 1600?h at baseline and at the end of Periods 1 and Period 2. RESULTS:In 32 subjects, the diurnal curve of the untreated IOP of 26.0±3.4 decreased to 17.8±2.5 on LTFC and 17.2±2.8?mmHg on brimonidine and latanoprost (P=0.31). At 0800 and 1600 h, the IOPs were statistically similar between the groups (P>0.05). At 1200?h the latanoprost and brimonidine treatment IOP was statistically lower (16.2±3.2) than LTFC (18.0±2.8?mmHg). However, the reduced IOP from untreated baseline was not statistically different at each time point and for the diurnal curve for each therapy (P<0.05). Safety was similar between groups for both solicited and unsolicited side effects (P>0.05). CONCLUSION:This study suggests that LTFC and concomitant therapy of brimonidine and latanoprost provide statistically similar diurnal IOP reduction from an untreated baseline.Eye (2004) 18, 990-995. doi:10.1038/sj.eye.6701375 Published online 19 March 2004 [ABSTRACT FROM AUTHOR]

Purpose To compare ocular tolerability of dorzolamide 2%, brinzolamide 1%, and placebo given three times daily. Methods A prospective, double-masked, three-centre, crossover comparison in which 25 ocular hypertensive or primary-open angle glaucoma subjects were randomized to receive dorzolamide, brinzolamide, or placebo three times daily for 3 days. Intraocular pressure, visual acuity, a visual analogue scale, and ocular and systemic symptom queries were completed at the end of each period. Results After chronic dosing, there was a significant difference in ocular pain on the visual analogue scale among the groups at the 10-s postinstillation time point with dorzolamide having the highest level (22.5±28.9) compared to brinzolamide (5.0±8.7) or placebo (3.2±10.4) (P = 0.0006). No differences between groups were observed preinstillation nor following dosing at 3 or 10-min postinstillation. On the initial instillation, the 10-s postinstillation pain was rated as 43.3±77.1, which was significantly higher than after chronic dosing (P = 0.017). On the ocular symptom query, dorzolamide had the highest incidence of burning/stinging and redness compared to the other groups, but was generally characterized as mild. There were no significant differences in the visual acuity at any time point. Conclusions This study suggests that subjects treated with dorzolamide suffer more ocular pain upon instillation compared to brinzolamide or placebo. However, pain symptoms are fewer following chronic dosing and are generally characterized as mild. [ABSTRACT FROM AUTHOR]

A response by W. C. Stewart and colleagues to a letter to the editor about their article "Untreated 24-h intraocular pressures measured with Goldmann applanation tonometry vs nighttime supine pressures with Perkins applanation tonometry" in the 2010 issue is presented.

Presents a response by W.C. Stewart to a letter to the editor commenting on the article "Diurnal Intraocular Pressure Reduction With Latanoprost 0.005% Compared to Timolol Maleate 0.5% as Monotherapy in Subjects with Exfoliation Glaucoma," published in the February 27, 2004 issue of the journal "Eye."

PurposeTo evaluate 24-h efficacy of travoprost/timolol fixed combination (TTFC) vslatanoprost/timolol fixed combination (LTFC) in exfoliative glaucoma (XFG).DesignA prospective, single-masked, crossover, active-controlled, randomized 24-h comparison.MethodsAfter up to a 6-week medicine-free period, XFG patients were randomized to either TTFC or LTFC for 3 months, dosed each evening, and then changed to the opposite treatment for another 3 months. At the end of the washout, and both treatment periods, a 24-h intraocular pressure (IOP) curve was measured.ResultsIn total, 40 patients completed the study. The TTFC group showed a lower mean absolute 24-h IOP (18.7±2.6 vs19.6±2.6 mm Hg, P<0.001), maximum IOP (20.5±2.6 vs21.5±2.6 mm Hg, P<0.001) and 24-h IOP range (3.4±1.3 vs4.1±1.6 mm Hg, P=0.01). At individual time points, TTFC showed reduced IOPs compared with LTFC, after a Bonferroni correction, at 1000, 1800, and 2200 hours (P0.04). No statistical differences existed at hours: 0600, 1400, and 0200 (P0.05) and for the minimum IOP (P=0.09).ConclusionsThis study suggests that evening-dosed TTFC may provide greater 24-h IOP reduction, primarily at the 1800 hours time point, compared with LTFC in XFG. [ABSTRACT FROM AUTHOR]

AimsTo compare supine nighttime intraocular pressure measurements with Perkins applanation tonometry to 24-h sitting intraocular pressures with Goldmann applanation tonometry.MethodsA prospective, untreated, uncontrolled, observational cohort of qualified consecutive ocular hypertensive or primary open-angle glaucoma patients. Patients underwent sitting intraocular pressure measurements over 24-h by Goldmann and patients had their supine nighttime intraocular pressure measurements by Perkins.ResultsIn 100 completed patients, the mean intraocular pressure at 1000, 2200, 0200 and 0600 hours while sitting was 22.5±3.7 mm Hg, and in the supine position, 23.5±4.3 mm Hg (P<0.001). The mean sitting Goldmann intraocular pressures across the three daytime points was 23.3±3.4 mm Hg and across three nighttime points was 21.5±4.0 mm Hg (P<0.001). In contrast, the mean daytime sitting Goldmann intraocular pressure was not different than the mean nighttime supine intraocular pressure evaluated with Perkins (22.8±4.4 mm Hg, P=0.07). However, only 70% of patients were within 1.0 mm Hg of the highest daytime reading for all nighttime supine and sitting intraocular pressures.ConclusionThis study suggests that with Perkins applanation tonometry the untreated mean supine intraocular pressures are not higher at night than daytime sitting Goldmann applanation tonometry. However, the highest daytime sitting intraocular pressure measurement does not consistently predict the highest nighttime sitting or supine intraocular pressure value. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate 24-hr intraocular pressure (IOP) and blood pressure (BP) with timolol or latanoprost/timolol fixed combination (LTFC). Methods: Patients with primary open-angle glaucoma or ocular hypertension with normal blood pressure were randomized to LTFC, dosed each evening, or timolol dosed twice daily in a cross-over design for 8 weeks and the opposite medicine for 8 weeks. IOP was measured at 02:00, 06:00, 10:00, 14:00, 18:00 and 22:00 hours in the sitting position with Goldmann applanation tonometry and BP monitoring every 30 min while awake and every hour while asleep at the end of each 8-week treatment period. Results: Twenty-nine patients had a 24-hr baseline IOP of 26.3 ± 2.5 mmHg, systolic BP (SBP) of 121.4 ± 12.4 mmHg, diastolic BP (DBP) 72.9 ± 7.1 mmHg, and ocular perfusion pressure (OPP) of 33.9 ± 5.7 mmHg. No statistical differences were found between untreated and treated 24-hr SBP, DBP, mean BP (MBP), heart rate, or nocturnal BP dipping status with either medication. LTFC lowered IOP more at each timepoint compared to timolol (difference between treatments 2.7 mmHg, p = 0.0002). Conclusions: Neither timolol or evening-dosed LTFC reduced SBP, DBP, MBP, OPP, or increased nocturnal dipping. LTFC was more effective than timolol in decreasing IOP. [ABSTRACT FROM AUTHOR]

PurposeTo determine the incidence of glaucomatous progression at mean intraocular pressure (IOP) levels in patients with ocular hypertension (OHT).MethodsA retrospective, multicentre, cohort analysis of 230 OHT patients with 5 years of follow-up evaluated for risk factors associated with progressive optic disc and visual field loss to determine the incidence of glaucomatous progression.ResultsForty percent of patients with IOPs 24 mmHg, 18% of patients with IOPs of 21–23 mmHg, 11% of patients with IOPs with 18–20 mmHg, and 3% of patients with IOPs of 17 mmHg progressed to glaucoma. The mean IOP was 19.8±2.4 mmHg in the stable group and 21.7±2.6 mmHg in the progressed group (P=0.0004). The highest average peak IOP was 23.4±4.0 mmHg in the stable group and 25.2±3.1 mmHg in the progressed group (P=0.006). Based on the pachymetry values for central corneal thickness, patients with thinner corneas more often progressed to glaucoma (P<0.0001). A multivariant regression analysis to determine risk factors for progression was positive primarily for higher peak IOPs, older age, male gender, argon laser trabeculoplasty, visual acuity 20/50, and no topical medical therapy or β-blocker therapy prior to the study.ConclusionsIOP reduction within the normal range over 5 years of follow-up reduces the chance of progression to primary open-angle glaucoma in OHT patients.Eye (2009) 23, 73–78; doi:10.1038/sj.eye.6702995; published online 5 October 2007 [ABSTRACT FROM AUTHOR]

PurposeTo evaluate the 24-h intraocular pressure (IOP) control of brimonidine/timolol fixed combination (BTFC) versusthe unfixed combination of its individual components, each dosed twice daily, in patients with primary open-angle glaucoma or ocular hypertension.MethodsAn observer-masked, randomized, crossover, active-controlled, two-centre comparison. Following a 6-week medicine-free period, patients were randomized to BTFC or to the unfixed combination of brimonidine and timolol for 3 months. Patients then were crossed over to the opposite treatment for another 3 months. At the end of the medicine-free period, and each treatment period, patients underwent 24-h IOP measurements at 0600, 1000, 1400, 1800, 2200, and 0200 hours.ResultsTwenty-eight patients completed this study. Both BTFC and the unfixed components showed a significant IOP reduction from untreated baseline (P<0.0001), and were statistically equal when compared directly, for each individual time point and for the 24-h IOP curve (P>0.05). The mean 24-h IOP was 24.6±1.9 for baseline, 19.2±1.9 for BTFC, and 19.2±1.6 mmHg for the unfixed components (P=1.0). Four patients were discontinued due to side effects. The most common ocular adverse event was ocular hyperaemia (n=3 with BTFC and n=5 with the unfixed components, P=0.7) and systemic adverse events were rare.ConclusionThis study suggests that both BTFC and the unfixed components of brimonidine and timolol provide a significant 24-h IOP reduction from untreated baseline, and statistically equal control when compared directly, at each time point and for the 24-h pressure curve.Eye (2008) 22, 1391–1397; doi:10.1038/sj.eye.6702906; published online 15 June 2007 [ABSTRACT FROM AUTHOR]

Objective: To evaluate open-angle glaucoma patients, who were insufficiently controlled on latanoprost mono- therapy, to determine the 24 h intraocular pressure (lOP) efficacy and safety when changing them to dorzolamide/timolol (DTFC) or latanoprost/timolol fixed combination (LTFC) or adding DTFC. Methods: A prospective, observer-masked, placebo-controlled, crossover, comparison. Consecutive adults with primary open-angle or exfoliative glaucoma who exhibit a mean baseline lOP >21 mm Hg on latanoprost monotherapy were randomised for 3 months to: OTFC, LTFC or DTFC and latanoprost. Patients were then crossed over to the next treatment for periods 2 and 3. At the end of the latanoprost run-in and after each 3-month treatment period, patients underwent 24 h lOP monitoring. Results: 31 patients completed this study. All three adjunctive therapies significantly reduced the lOP at each time point and for the mean 24 h curve, except at 18:00 and 02:00 with DTFC and 02:00 with LTFC. When the three treatments were compared directly, the DTFC and latanoprost therapy demonstrated lower lOPs versus the other treatment groups, including: the mean 24 h pressure, maximum as well as minimum levels and individual time points following a modified Bonferroni correction (p<0.0032). Conclusions: This study showed DTFC, LTFC and the addition of DTFC to latanoprost significantly decrease the lOP compared with latanoprost alone, but the latter therapy regime yields the greatest OP reduction. [ABSTRACT FROM AUTHOR]

Aim: To evaluate 24 h intraocular pressure (lOP) and blood pressure (BP) with bimatoprost or latanoprost in patients with normal-tension glaucoma. Design: Prospective, randomised, crossover, active-controlled, observer-masked study. Methods: After a 6-week medicine-free period, we randomised patients to either latanoprost or bimatoprost for 8 weeks and then to the opposite medicine for 8 weeks. At baseline, and at the end of each treatment period, we evaluated lOP and BP at 08:00 and then every 2 h over the 24 h day. Diastolic ocular perfusion pressure (DOPP) was calculated from the above parameters. Results: Forty completed patients had a 24 h untreated baseline lOP of 15.5 (2.3) mm Hg, and a DOPP of 59.2 (6.1) mm Hg. Both treatments lowered lOP at each time point (p<0.006), and over the 24 h curve (p<0.001, both medicines 13.1 mm Hg, 16% decrease). No difference existed between treatments in absolute lOP, at each time point, and over the 24 h curve (p⩾0.26). Additionally, no differences were found between treated 24 h systolic (p⩾0.29) and diastolic BP )p⩾0.12). The mean 24 h DOPP for latanoprost was increased from baseline (3%, p = 0.031) but not for bimatoprost (2%, p = 0.21). However, no difference in DOPP existed between treatments at any time point or over the 24 h curve (p⩾0.17). No difference was observed between treatments for any adverse event (p>0.05). Conclusions: In patients with normal-tension glaucoma, both bimatoprost and latanoprost reduce the 24 h intraocular pressure from untreated baseline to a similar extent. Latanoprost is associated with slightly improved ocular diastolic perfusion pressure over 24 h but similar absolute perfusion levels to that of bimatoprost. [ABSTRACT FROM AUTHOR]

PurposeTo provide initial validation of the Treatment Satisfaction Survey-Intraocular Pressure (TSS-IOP) quality-of-life survey that analyses specific issues related to side effects, patient satisfaction, and compliance.MethodsA prospective, observational cohort of 250 consecutive patients with primary open-angle glaucoma or ocular hypertension was administered the TSS-IOP survey.ResultsFactors that correlated with patient satisfaction included perceived effectiveness of the medicine (F=7.47, P<0.001), ocular irritation (F=6.06, P<0.001), conjunctival hyperaemia (F=4.40, P<0.001), ease of use (F=8.52, P<0.001), and convenience of use (F=6.90, P<0.001). Patient compliance, acceptance of their illness, and knowledge of glaucoma were also related to perceived effectiveness of the medicine (P<0.001), ease of use (P<0.05) and convenience (P<0.001). Physician ratings of patient pressure control, side effects, and instillation problems also were significantly correlated to patient satisfaction (R=0.13–0.26, P=0.05–0.001). The physician ratings of patient compliance, however, were not significantly related to any dimension of patient satisfaction (P>0.05). Among monotherapy prostaglandin treatments, latanoprost demonstrated statistically greater satisfaction than bimatoprost or travoprost regarding conjunctival hyperaemia (P<0.05) and eye irritation (P<0.01).ConclusionsThis study provides initial evidence that patient satisfaction may be related to compliance, perceived effectiveness of treatment, adverse side effects, ease and convenience of use, acceptance of illness, and knowledge of glaucoma.Eye (2006) 20, 583–590. doi:10.1038/sj.eye.6701932; published online 3 June 2005 [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy and safety of brimonidine 0.2% vs unoprostone 0.15%, both added to timolol maleate 0.5% each given twice daily.Methods: In this prospective, multi-centred, double-masked, crossover comparison, patients were randomized to one treatment group for a 6-week treatment period, and then crossed over to the opposite treatment. Measurements were performed at 0800, 1000, 1600, 1800, and 2000 h at baseline and at the end of each treatment period.Results: In all, 33 patients entered this trial and 29 completed. The baseline trough intraocular pressure (IOP) was 23.3+/-2.4 and the diurnal curve IOP was 22.0+/-1.3 mmHg. For the brimonidine and timolol maleate treatment group, the trough IOP was 21.6+/-3.3 and the diurnal curve IOP was 19.8+/-2.1 mmHg, while the timolol and unoprostone treatment showed a trough IOP of 20.9+/-3.8 and a diurnal curve IOP of 19.3+/-2.4 mmHg. There was no significant difference between treatment groups at any time point for the diurnal curve, or in the reduction from baseline (P>0.05). Both treatments failed to statistically reduce the IOP from baseline at 1800 h. There was no difference between treatment groups regarding ocular and systemic unsolicited adverse events, but patients admitted to more dryness (P=0.02) and burning upon instillation (P<0.0001) with unoprostone by survey.Conclusion: Brimonidine 0.2% or unoprostone 0.15% added to timolol maleate 0.5% provide similar efficacy and safety throughout the daytime diurnal curve. [ABSTRACT FROM AUTHOR]

Aims: To evaluate efficacy and safety in patients with ocular hypertension or open angle glaucoma changed to latanoprost/timolol fixed combination (LTFC). Methods: A prospective, multicentre, historical control in which qualified patients had their previous therapy substituted by LTFC and were followed for at least 2 months. Results: In 1676 patients LTFC was continued in 93% throughout the observation period. In all patients LTFC reduced the intraocular pressure (IOP) from 20.6 (SD 3.8) to 17.7 (3.0) mm Hg (p<0.001) compared to previous monotherapies including latanoprost, timolol, α agonists or carbonic anhydrase inhibitors (CAI). LTFC provided more efficacy after changing from adjunctive therapies including: a β blocker added to either CAI, α agonist, or pilocarpine, or CAI added to an α agonist, or latanoprost added to either CAI, α agonist, or β blocker (unfixed combination), and travoprost added to timolol (p<0.007). LTFC was as effective as latanoprost used with dorzolamide/timolol fixed combination (-0.9 mm Hg, p =0.1792). The most common reason to discontinue therapy was lack of efficacy (n = 70, 4%) and adverse event (n = 17, 1%). Conclusion: In a clinical selling, patients who have their monotherapy or adjunctive therapy substituted with LTFC may experience reduced IOP, good tolerability, and continuation of therapy for the first 2-3 months of treatment. [ABSTRACT FROM AUTHOR]

Aims To compare the diurnal intraocular pressure (IOP) efficacy and safety of timolol vs latanoprost in subjects with exfoliation glaucoma (XFG). Methods A 3-month prospective, single- masked, active-controlled, parallel comparison performed in six centres in Greece that randomized subjects in a 1:1 ratio to either latanoprost in the evening (2000 hours) and placebo in the morning (0800 hours), or timolol twice daily (0800 and 2000 hours). Results In all, 103 subjects completed the study. After 3 months of chronic dosing, the latanoprost group exhibited a trend to a greater diurnal IOP reduction from an untreated baseline (24.9±3.2–17.4±2.9) compared with timolol (24.7±2.8–18.3±1.9 mmHg) (P=0.07). Latanoprost showed a significantly greater IOP reduction at 0800 hours (-8.5 vs -6.0 mm Hg for timolol, P<0.0001) whereas no difference was observed between the two medications at 1000, 1400, and 2000 hours after a Bonferroni Correction. In addition, latanoprost demonstrated a narrower range of diurnal IOP (2.4) than timolol (3.2 mmHg)(P=0.0017). Safety was similar between groups, except there was more conjunctival hyperaemia with latanoprost (n=8) than timolol (n = 1)(P=0.01). Conclusions This study suggests that latanoprost provides a statistically lower 08:00-hour IOP and better range of IOP than timolol in the treatment of XFG glaucoma. Eye (2004) 18, 893–899. [ABSTRACT FROM AUTHOR]

Background/aims: To evaluate the efficacy of brimonidine purite versus dorzolamide given twice daily in primary open angle glaucoma or ocular hypertensive subjects. Methods: In this double masked, multicentre, prospective, crossover comparison 33 subjects were randomised to brimonidine purite or dorzolamide for the first 4 week treatment period alter a 4 week washout. Subjects began the opposite treatment for the second 4 week period after another 4 week washout. Intraocular pressure (lOP) was measured at 08:00 (trough) and 10:00, 18:00, and 20:00 hours after dosing at each baseline and at the end of each treatment period. Results: The baseline diurnal lop was 22.9 (SD 2.8) for brimonidine purite and 22.2 (SD 2.4) mm Hg for dorzolomide. The trough lOP following 4 weeks of therapy was 21.0 (SD 3.7) for brimonidine purite and 21.0 (SD 3.1) mm Hg for dorzolamide (p = 0.90). The mean diurnal lOP was 19.3 (SD 3.1) for brimonidine purite and 19.8 (SD 2.4) mm Hg for dorzolamide (p=0.46). Dorzolomide caused more ocular stinging upon instillation (n = 8) than brimonidine purite (n = 1) (p = 0.02). No statistical differences existed between groups for systemic adverse events. Conclusions: This study suggests that brimonidine purite and dorzolamide each given twice daily have similar efficacy in primary open angle glaucoma or ocular hypertensive subjects. However, a trend was observed at 10:00 of greater brimonidine purite efficacy compared with dorzolamide. [ABSTRACT FROM AUTHOR]