A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium.

Purpose: To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia. Design: Phase II clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with primary or recurrent pterygia. Main Outcome Measures: The primary efficacy end point was lesion vascularity based on masked grading of photographs by an independent reading center. Other end points included dimensions of pterygia and safety. Methods: In stage 1, 24 eyes of 24 patients received 1 drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events (AEs) and blood drug levels. In stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed 3 times a day for 4 weeks with a 20-week follow-up. Results: In stage 1, the plasma maximum concentration values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/ml). The most commonly reported AEs were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, the mean change from baseline in pterygium vascularity scores was -0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle (P < 0.001; 95% confidence interval: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. The mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared with vehicle at weeks 2, 4, and 8 (P ≤ 0.014). The most commonly reported AEs were ocular, mild in severity, resolved after therapy, and did not result in discontinuation. Conclusions: CBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Topical lipoic acid choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: a safety and preliminary efficacy trial.

OBJECTIVES: This study evaluated the safety of topical lipoic acid choline ester (UNR844, 1.5%) ophthalmic solution and its efficacy in improving distance-corrected near visual acuity (DCNVA) in subjects with presbyopia. SUBJECTS AND METHODS: This was a prospective, randomized, double-masked, and multicentre clinical trial. Subjects with a diagnosis of presbyopia (n = 75) were randomized 2:1 to UNR844 or placebo. On days 1-7, all subjects were dosed unilaterally (twice a day, b.i.d.) in their non-dominant eye to ensure safety and tolerability prior to days 8-91 when dosing was changed to bilateral (b.i.d.). Clinical assessments, including DCNVA and adverse events (AEs), were recorded at each study visit. Patients who completed the study were recruited into a non-interventional follow-up study that monitored them until 7 months after their final UNR844 exposure. The primary endpoints were safety and the mean change in DCNVA from baseline in the study eye. RESULTS: UNR844 administration (n = 50) produced no safety concerns and was well-tolerated, with no clinically-relevant changes in best-corrected distance visual acuity, pupil size, intraocular pressure, or discontinuations due to adverse events. DCNVA improved in the study eye in the UNR844 group compared to placebo during the 91 days of treatment [UNR844 vs. placebo, mean change in LogMAR (SD); -0.159 (0.120) vs. -0.079 (0.116)]. Bilateral DCNVA improved, with 53.1% UNR844 vs. 21.7% placebo subjects gaining ≥10 letters. Improvements in DCNVA were sustained at 5 and 7 months after UNR844 dosing ceased. CONCLUSIONS: These results support further development of UNR844 ophthalmic solution for the treatment of presbyopia.

A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 2 and 4 Weeks of Twice-Daily Ocular Trabodenoson in Adults with Ocular Hypertension or Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the safety and ocular hypotensive efficacy of 4 trabodenoson doses administered twice daily over 14 or 28 days in subjects with ocular hypertension or primary open-angle glaucoma (POAG). METHODS: In this multicenter, randomized, double-masked, placebo-controlled, dose-escalation Phase 2 study, patients received unilateral topical twice-daily trabodenoson (50, 100, or 200 mcg) or placebo for 14 days, or 500 mcg trabodenoson or placebo for 28 days. Ocular and systemic safety and tolerability were assessed by examinations, clinical and laboratory studies. Intraocular pressure (IOP) was assessed using Goldmann tonometry. RESULTS: Trabodenoson was well tolerated; no clinically meaningful ocular or systemic side effects were identified. Trabodenoson produced a dose-dependent IOP reduction. IOP reductions in the 500 mcg group were significantly greater than placebo at all time points at Day 28. Mean IOP reductions from diurnal baseline ranged from -3.5 to -5.0 mmHg with a mean change of -4.1 mmHg in the 500 mcg group compared -1.0 to -2.5 mmHg with a mean change of -1.6 mmHg for the placebo group, and the Day 28 drop was significantly greater than at Day 14 (P = 0.0163) indicating improvement in IOP lowering with longer treatment time. IOP remained significantly reduced 24 h after the final 500 mcg dose (P = 0.048). CONCLUSION: Twice-daily ocular doses of trabodenoson, from 50 to 500 mcg, were well tolerated and showed a dose-related decrease in IOP that was statistically significant and clinically relevant at 500 mcg in patients with ocular hypertension or POAG.

Dorzolamide/timolol combination versus concomitant administration of brimonidine and timolol: six-month comparison of efficacy and tolerability.

PURPOSE: To compare the efficacy and tolerability of the 2% dorzolamide/0.5% timolol combination ophthalmic solution twice daily to the concomitant administration of 0.2% brimonidine ophthalmic solution twice daily and 0.5% timolol ophthalmic solution twice daily. DESIGN: Randomized, multicenter, observer-masked, parallel-group study. PARTICIPANTS: Two hundred ninety-three patients with ocular hypertension or primary open-angle glaucoma participated. INTERVENTION: After an open-label 3-week 0.5% timolol run-in period, patients with an hour 2 intraocular pressure (IOP) of > or = 22 mmHg were randomly assigned to receive either the dorzolamide/timolol combination twice daily or the concomitant use of brimonidine twice daily and timolol twice daily (brimonidine + timolol) for 6 months. MAIN OUTCOME MEASURES: The IOP-lowering effects at hour 0 and hour 2 were collected at 1, 3, and 6 months. We hypothesized that both treatment regimens would have comparable hour 2 IOP-lowering effects at month 3. The treatments were considered comparable if the two-sided 95% confidence interval of the treatment difference was within +/- 1.5 mmHg. Tolerability data were also collected at 1, 3, and 6 months. RESULTS: The primary efficacy analysis was based on the modified intent-to-treat population. At month 3, hour 2, the dorzolamide/timolol group had an adjusted mean (standard error) change in IOP of -5.04 (0.30) mmHg versus -5.41 (0.30) mmHg in the brimonidine + timolol group, with a treatment difference of 0.36 (0.40) mmHg (95% confidence interval [CI] of -0.42-1.14 mmHg). At month 3, hour 0, the dorzolamide/timolol group had a change in IOP of -3.66 (0.29) mmHg versus -4.15 (0.28) mmHg in the brimonidine + timolol group, with a treatment difference of 0.49 (0.39) mmHg (95% CI of -0.27-1.25 mmHg). Likewise, at all other observed time points, the 95% confidence interval of the treatment difference was within +/- 1.5 mmHg. Ninety-three patients (64%) in the dorzolamide/timolol group and 88 patients (60%) in the brimonidine + timolol group had adverse experiences that were deemed drug related by the investigator, for which 7 patients (5%) in the dorzolamide/timolol group and 8 patients (5%) in the brimonidine + timolol group were discontinued from the study. CONCLUSIONS: The efficacy of the dorzolamide/timolol combination and the concomitant administration of brimonidine and timolol were comparable. The incidence of drug-related adverse experiences and the incidence of discontinuations caused by drug-related adverse experiences were similar between groups.