Thomas R. Walters

Brimonidine Tartrate: A One-month Dose Response Study

BACKGROUND Brimonidine tartrate is a relatively selective alpha2-agonist that effectively reduces mean intraocular pressure (IOP) and the incidence of IOP spikes after laser trabeculoplasty. The authors were interested in evaluating the dose response of brimonidine when applied topically for a longer duration in patients with elevated IOPs. METHODS The authors conducted a 1-month, multicentered, double-masked, randomized, placebo-controlled, parallel clinical study in 194 patients with ocular hypertension or glaucoma (mean IOP, 25.6 +/- 3.2 mmHg). The authors administered three concentrations of brimonidine (0.08%, 0.2%, and 0.5%) or placebo bilaterally every 12 hours for 1 month. The authors evaluated the following parameters: IOP, heart rate, blood pressure, visual acuity, pupil size, basal tear secretion as well as patient comfort at baseline, day 1, week 1, week 3, and week 4. RESULTS All concentrations of brimonidine significantly reduced IOP, compared to baseline and placebo, at all follow-up visits. Maximum mean IOP decreases from baseline of 20.8%, 27.2%, and 30.1% were observed for the 0.08%, 0.20%, and 0.5% treatment groups, respectively. On days 1 and 21, the 0.2% and 0.5% treatment groups exhibited significantly greater IOP decreases than did the 0.08% group. After the initial steep decline in IOP, the effect decreased slightly and stabilized at day 14 at the level that was maintained throughout the study. The most frequent side effects reported were fatigue and dry mouth. No significant changes in heart rate were reported. Statistically significant decreases in mean blood pressure without clinical symptoms were observed within the 0.2% and 0.5% treatment groups. CONCLUSION Brimonidine 0.2% is well tolerated, efficacious, and shows potential as an agent in the long-term treatment of elevated IOP.

The Use of Dorzolamide and Pilocarpine as Adjunctive Therapy to Timolol in Patients with Elevated Intraocular Pressure

PURPOSE To report the results of two studies on the use of dorzolamide as adjunctive therapy to timolol in patients with elevated intraocular pressure (IOP). In the larger study, the additive effect of dorzolamide administered twice daily also was compared with 2% pilocarpine. METHODS Both studies were parallel, randomized, double-masked, placebo-controlled comparisons. In the pilot study, 32 patients received 0.5% timolol twice daily plus either 2% dorzolamide twice daily or placebo twice daily for 8 days. In the Pilocarpine Comparison Study, 261 patients received 0.5% timolol twice daily plus 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, 2% pilocarpine four times daily, or placebo (twice daily or 4 times daily) for 2 weeks. Patients then entered a 6-month extension period and received 0.5% timolol twice daily plus either 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, or 2% pilocarpine four times daily. RESULTS In the pilot study, after 8 days, additional mean percent reductions in IOP for 2% dorzolamide and placebo were 17% and 3% at morning trough and 19% and 2% at peak, respectively. In the Pilocarpine Comparison Study, after 6 months, additional mean percent reductions in IOP (morning trough) were 9%, 13%, and 10% for 0.7% dorzolamide, 2% dorzolamide, and 2% pilocarpine, respectively. Patients receiving 2% pilocarpine had the highest rate of discontinuation due to a clinical adverse experience, and the use of dorzolamide was not associated with systemic side effects commonly observed with the use of oral carbonic anhydrase inhibitors. CONCLUSION Dorzolamide twice daily was effective and well tolerated by the patients in these studies as adjunctive therapy to timolol. The larger study demonstrated that both concentrations of dorzolamide produce similar IOP-lowering effects to 2% pilocarpine.

Duration of IOP reduction with travoprost BAK-free solution.

PurposeTo compare the duration of action of travoprost ophthalmic solution 0.004% (Travatan® Z)™ formulated without benzalkonium chloride (BAK) to travoprost ophthalmic solution 0.004% formulated with BAK (Travatan®). MethodsThis was a prospective, randomized, double-masked study. Patients with open-angle glaucoma or ocular hypertension were randomized to receive 2 weeks of once-daily therapy with travoprost BAK-free or travoprost with BAK. Patients received the last dose of medication on day 13 and then intraocular pressure (IOP) was assessed every 12 hours for 60 hours. Statistical analysis included change in IOP from baseline for each group and comparison of mean IOP between groups. ResultsOf the 109 patients enrolled, 106 patients completed the study. Untreated mean baseline IOP at 8 AM was 26.9 mm Hg in the travoprost BAK-free group and 27.1 mm Hg in the travoprost with BAK group. At 12, 24, 36, 48, and 60 hours after the last dose, mean IOP in the travoprost BAK-free group was 18.7, 17.2, 19.5, 18.7, and 20.8 mm Hg, respectively; whereas mean IOP in the travoprost with BAK group was 18.5, 16.8, 19.7, 18.0, and 20.8 mm Hg, respectively. Mean IOP at all time points after the last dose of medication was >6 mm Hg lower than the 8 AM baseline in both groups. Between-group differences were within ±0.6 mm Hg at all postdose time points. There were no statistically significant differences between the 2 treatment groups at baseline or at any postdose time point. Drug-related side effects were uncommon, mild in intensity, and comparable between groups. ConclusionsTravoprost without BAK has similar IOP-lowering efficacy and safety compared with travoprost preserved with BAK. Both formulations of travoprost have a prolonged duration of action, with statistically and clinically significant reductions from baseline persisting up to 60 hours after the last dose.

A One-Week Comfort Study of BID-Dosed Brinzolamide 1%/Timolol 0.5% Ophthalmic Suspension Fixed Combination Compared to BID-Dosed Dorzolamide 2%/Timolol 0.5% Ophthalmic Solution in Patients with Open-Angle Glaucoma or Ocular Hypertension

PURPOSE The aim of this study was to evaluate the ocular discomfort of brinzolamide 1%/timolol 0.5% ophthalmic suspension fixed combination dosed twice-daily compared to dorzolamide 2%/timolol 0.5% ophthalmic solution fixed combination dosed twice-daily. METHODS This was a prospective, double-masked, parallel-group, randomized, clinical trial. Patients had open-angle glaucoma or ocular hypertension and were randomized to twice-daily therapy with either brinzolamide 1%/timolol 0.5% or dorzolamide 2%/timolol 0.5%. Patients completed ocular discomfort assessments (based on burning, stinging, a feeling of heat or warmth, sharp pain, or smarting pain) on their current intraocular pressure-lowering therapy at baseline and on study medication after 1 week of dosing. RESULTS In the intent-to-treat analyses, mean ocular discomfort scores at 1 week were significantly lower in eyes receiving brinzolamide 1%/timolol 0.5% than dorzolamide 2%/timolol 0.5% (0.77 vs. 1.53; P = 0.0003). Mean increases from baseline in ocular discomfort scores were statistically significant in both groups but were smaller in eyes receiving brinzolamide 1%/timolol 0.5% (0.49; P = 0.0028) than dorzolamide 2%/timolol 0.5% (1.32; P < 0.0001). Over threefold more patients on brinzolamide 1%/timolol 0.5% (23/47, 49%) than dorzolamide 2%/timolol 0.5% (7/47, 15%) reported no ocular discomfort after 1 week of therapy (P = 0.0004). CONCLUSIONS Brinzolamide 1%/timolol 0.5% ophthalmic suspension is associated with a statistically significantly less ocular discomfort profile than dorzolamide 2%/timolol 0.5% ophthalmic solution.

Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (Lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial

Background/Aim To evaluate efficacy and safety of bimatoprost 0.03% preservative-free (PF) ophthalmic solution versus bimatoprost 0.03% (Lumigan) ophthalmic solution for glaucoma or ocular hypertension. Methods In this double-masked, parallel-group study, patients were randomised to bimatoprost PF or bimatoprost for 12 weeks. The primary analysis for non-inferiority was change from baseline in worse eye intraocular pressure (IOP) in the per-protocol population at week 12. For equivalence, it was average eye IOP in the intent-to-treat population at each time point at weeks 2, 6 and 12. Results 597 patients were randomised (bimatoprost PF, n=302 and bimatoprost, n=295). The 95% CI upper limit for worse eye IOP change from baseline was <1.5 mm Hg at each week 12 time point, meeting prespecified non-inferiority criteria. The 95% CI upper limit for the treatment difference for average IOP was 0.69 mm Hg and the lower limit was −0.50 mm Hg at all follow-up time points (hours 0, 2 and 8 at weeks 2, 6 and 12), meeting equivalence criteria. Both treatments showed decreases in mean average eye IOP at all follow-up time points (p<0.001), were safe and well tolerated. Conclusions Bimatoprost PF is non-inferior and equivalent to bimatoprost in its ability to reduce IOP-lowering with a safety profile similar to bimatoprost.

Once-daily nepafenac ophthalmic suspension 0.3% to prevent and treat ocular inflammation and pain after cataract surgery: Phase 3 study

Purpose To evaluate once‐daily nepafenac 0.3% to prevent and treat ocular pain and inflammation after cataract surgery. Setting Sixty‐five centers in the United States and Europe. Design Randomized double‐masked vehicle‐ and active‐controlled phase 3 study. Methods Patients received nepafenac 0.3% once daily, nepafenac 0.1% 3 times daily, or their respective vehicles from day −1 to day 14 after cataract extraction. An additional drop of study drug was administered 30 to 120 minutes preoperatively. The primary endpoint was the percentage of patients with a cure for inflammation (score of 0 for both aqueous cells and flare) at day 14. Results Of randomized patients, 817 received nepafenac 0.3%, 819 received nepafenac 0.1%, and 200 and 206 received the respective vehicles. Significantly more nepafenac 0.3% patients had no inflammation (68.4% versus 34.0%) and were pain free (91.0% versus 49.7%) at day 14 than vehicle patients (both P<.0001). Nepafenac 0.3% was noninferior to nepafenac 0.1% for inflammation (95% confidence interval [CI], −5.73% to 3.17%) and pain‐free rates (95% CI, −3.08% to 2.70%). At all postoperative visits, fewer treatment failures (P≤.0012) and more clinical successes (P≤.0264) were observed with nepafenac 0.3% versus vehicle. Nepafenac 0.3% was well tolerated and had a safety profile comparable to that of nepafenac 0.1%. Conclusions Once‐daily nepafenac 0.3% was noninferior to nepafenac 0.1% 3 times daily for prevention and treatment of ocular inflammation and pain following cataract surgery. The safety of nepafenac 0.3% was comparable to that of nepafenac 0.1%, with the added convenience of once‐daily dosing. Financial Disclosure Drs. Modi, Lehmann, Walters, Fong, Christie, Roel, Nethery, and Reiser have been paid consultants to Alcon Research, Ltd. Ms. Sager is an employee of Alcon Research, Ltd. Drs. Tsorbatzoglou, Philipson, and Traverso have no financial or proprietary interest in any material or method mentioned.

Nepafenac Dosing Frequency for Ocular Pain and Inflammation Associated with Cataract Surgery

PURPOSE Nepafenac ophthalmic suspension 0.1% was dosed topically once (QD), twice (BID), or three-times (TID) daily to assess the resolution of ocular pain and anterior-segment inflammation following cataract surgery. METHODS This was a prospective, multicenter, double-masked, randomized, placebo-controlled study of 212 adults. Patients received nepafenac 0.1% or placebo, 1 drop QD, BID, or TID beginning 1 day before cataract surgery, continuing on the day of surgery, and for 14 days thereafter. One (1) additional drop was administered 30-120 min prior to surgery. The primary efficacy endpoint was percent of treatment failures (>or=16 aqueous cells, aqueous flare = severe, or ocular pain score = moderately severe or severe) through postoperative day 14. RESULTS On days 7 and 14, the QD, BID, and TID all nepafenac posologies significantly reduced the percent of treatment failures, compared to placebo ( p <or= 0.0029). Compared with placebo, the TID posology achieved statistical significance beginning on day 3 ( p <or= 0.0080). Nepafenac treatment significantly increased the proportion of patients with resolved ocular inflammation, compared to placebo, beginning on day 1 for TID dosing ( p <or= 0.0208) and beginning on day 3 for QD dosing ( p <or= 0.0483). A significantly greater percentage of nepafenac-treated patients were pain free, compared to placebo, beginning on postoperative day 1 with BID and TID dosing ( p <or= 0.0150) and beginning on day 3 for QD dosing (p <or= 0.0220). No serious ocular adverse events were reported, and fewer patients experienced adverse events in the nepafenac groups than in the placebo group. CONCLUSIONS Nepafenac ophthalmic suspension 0.1% was well tolerated and effectively resolved ocular inflammation and increased the incidence of ocular pain-free patients following cataract surgery when dosed QD, BID, or TID. By postoperative day 14, all nepafenac posologies significantly reduced the incidence of treatment failures and the incidence of patients presenting with ocular inflammation, and significantly increased the incidence of ocular pain-free patients relative to placebo.

Sustained-release dexamethasone for the treatment of ocular inflammation and pain after cataract surgery.

Purpose To evaluate the safety and efficacy of dexamethasone as a sustained‐release drug depot when placed in the canaliculus for the treatment of ocular inflammation and pain in cataract surgery patients. Setting Four private practice sites in the United States. Design Multicenter randomized double‐masked clinical trial. Methods Patients were randomized (1:1) to receive either the sustained‐release dexamethasone or a placebo vehicle punctum plug inserted into the inferior distal canaliculus of the operated eye intraoperatively during cataract surgery. The primary endpoints were the proportions of patients with absence of cells or pain in the anterior chamber at 8 days. Secondary endpoints included cells, flare, pain, and the presence of the device at various timepoints through 30 days. Results Approximately one fifth (20.7%) of patients in the sustained‐release dexamethasone group had an absence of anterior chamber cells at 8 days compared with 10.0% in the placebo group (P = .1495). A higher proportion of patients in the sustained‐release dexamethasone group (79.3%) than in the placebo group (30.0%) had an absence of ocular pain at 8 days (P < .0001) and at all other timepoints (P < .0002). There were significantly higher proportions of patients in the sustained‐release dexamethasone group than in the placebo group with an absence of anterior chamber cells, anterior chamber flare, and pain at several timepoints through 30 days (P ≤ .0251). Conclusion Sustained‐release dexamethasone provided elution of drug for up to 1 month after cataract surgery, providing clinically significant reductions in inflammation and pain. Financial Disclosure Dr. Masket is a consultant to and shareholder in Ocular Therapeutix, Inc. No other author has a financial or proprietary interest in any material or method mentioned.

Efficacy and Safety of Sustained Release Dexamethasone for the Treatment of Ocular Pain and Inflammation after Cataract Surgery: Results from Two Phase 3 Studies

Background: These studies evaluated the safety and efficacy of a single-dose sustained release dexamethasone depot (DEXTENZA™, Intracanalicular Depot) for the treatment of pain and inflammation following cataract surgery. Methods: Patients were randomized (2:1) on Day 1 to receive a sustained release dexamethasone depot, (0.4 mg; Study 1, n=164; Study 2, n=161) or placebo vehicle depot (Study 1, n=83; Study 2, n=80) in the inferior canaliculus. Results: A significantly greater proportion of patients in the dexamethasone groups (Study 1, 80.4% [131/164] vs. 43.4% [36/83], P<0.0001; Study 2, 77.5% [124/161] vs. 58.8% [47/80], P=0.0025) had an absence of ocular pain at Day 8. At Day 14 more patients in the dexamethasone groups had an absence of anterior chamber cells (Study 1, 33.1% [54/164] vs. 14.5% [12/83], P=0.0018; Study 2, 39.4% [63/161] vs. 31.3% [25/80], P=0.2182). Statistically significant differences favoring dexamethasone were observed in both studies for proportions of patients with: an absence of ocular pain at days 2, 4, 8, and 14; an absence of anterior chamber flare at days 8 and 14; mean anterior cell scores at days 8 and 14. Significantly fewer patients in the dexamethasone groups required rescue medications on days 8 and 14. No serious adverse events related to treatment occurred in either group. Transient IOP increases of ≥ 10 mmHg in the study eye were observed in similar proportions of patients in the sustained release dexamethasone groups, (6.8% in Study 1 and 4.4% in Study 2) and the placebo groups (3.6% and 5.0%, respectively). However, only 1 incidence of IOP elevation was thought to be product related (0.3%). Conclusions: These two studies demonstrate that a single dose, sustained release dexamethasone intracanalicular depot is safe and effective for the treatment of ocular pain and inflammation following cataract surgery.