Mean Diurnal Intraocular Pressure Research Articles

Assessment of Early Glaucomatous Optic Neuropathy in the Dog by Spectral Domain Optical Coherence Tomography (SD-OCT).

Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg). Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 μm to 9.3 +/- SEM 22.1 μm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.

Travoprost Intracameral Implant for Open-Angle Glaucoma or Ocular Hypertension: 12-Month Results of a Randomized, Double-Masked Trial.

This prospective, multicenter, randomized, double-masked pivotal phase3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36mmHg at each diurnal timepoint (8A.M., 10A.M., and 4P.M.) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8A.M. and 10A.M. at day10, week6, and month3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5mmHg at all six timepoints and < 1mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8A.M. and 10A.M. at month12. Non-inferiority at month12 was achieved if the upper 95%CI was < 1.5mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments. A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3months, and was also non-inferior to timolol at months6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3months, and also at months6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month12 compared to screening (P < 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group. The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12months whereas the FE-implant demonstrated non-inferiority over 9months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT. ClinicalTrials.gov identifier, NCT03519386.

Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension

PurposeEvaluate the safety and intraocular pressure (IOP)-lowering efficacy of two models of the travoprost intraocular implant (fast-eluting [FE-implant] and slow eluting [SE-implant]) from one of two pivotal trials (GC-010). DesignPhase 3, multicenter, randomized, double-masked, sham-controlled, non-inferiority trial. ParticipantsSubjects with open-angle glaucoma or ocular hypertension, using 0 to 3 IOP-lowering medications at screening and having an unmedicated baseline mean diurnal IOP (average of 8AM, 10AM and 4PM timepoints) of ≥ 21 mmHg, and an unmedicated baseline IOP of ≤ 36 mmHg at each timepoint in the study eye. MethodsStudy eyes were randomized to the travoprost intraocular implant (FE-implant [n=200] or SE-implant [n=197] model) plus twice-daily (BID) placebo eye drops, or to sham procedure plus timolol ophthalmic solution, 0.5% BID (n=193). Main Outcome MeasuresThe primary outcome was mean change from baseline IOP in the study eye at 8AM and 10AM, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs), corneal endothelial cell counts, visual acuity, and conjunctival hyperemia assessment. ResultsMean IOP reduction from baseline over the 6 timepoints ranged from 6.6 to 8.4 mmHg for the FE-implant group, from 6.6 to 8.5 mmHg for the SE-implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy endpoint was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 timepoints. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2% and 10.8% of subjects in the FE-implant, SE-implant and timolol groups, respectively. The most common AEs included iritis (FE-implant, 0.5%; SE-implant, 5.1%), ocular hyperaemia (FE-implant, 3.0%; SE-implant, 2.6%), visual acuity reduced (FE-implant, 1.0%; SE-implant, 4.1%; timolol, 0.5%), and IOP increased (FE-implant, 3.5%; SE-implant, 2.6%; timolol, 2.1%). There was one serious study eye AE (endophthalmitis). ConclusionsThe travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period following a single administration. The IOP-lowering efficacy of both implant groups was statistically and clinically non-inferior to the timolol group, with a favorable safety profile.

36-Month Outcomes from the Prospective GEMINI Study: Canaloplasty and Trabeculotomy Combined with Cataract Surgery for Patients with Primary Open-Angle Glaucoma.

To provide long-term intraocular pressure (IOP) and ocular hypotensive medication usage outcomes through 36 months for patients treated with canaloplasty and trabeculotomy (OMNI Surgical System) combined with cataract surgery as participants in the GEMINI study. Eleven ophthalmology practices in 10 US states. Non-interventional 36-month extension of the 12-month, prospective, multicenter, GEMINI study. GEMINI patients had visually significant cataract, mild-to-moderate glaucoma (ICD-10 guidelines), medicated IOP <33 mmHg, and unmedicated mean diurnal IOP (DIOP) (after washout) 21-36 mmHg. Patients from GEMINI were eligible for inclusion. Outcome measures were reduction in mean unmedicated DIOP, reduction in mean IOP-lowering medications, percent of eyes with ≥20% reduction in unmedicated DIOP, and percent of eyes with unmedicated DIOP ≥6 and ≤18 mmHg. A total of 66 patients provided consent and were enrolled. Mean (SD) unmedicated DIOP was 23.1 (2.7) mmHg at baseline, 16.7 (4.1), 16.3 (3.3) at 24 and 36 months; mean reductions of 6.2 (4.1) and 6.9 (3.4) mmHg. Twelve-month IOP at the end of GEMINI was 15.6 mmHg. The proportion of eyes with ≥20% reduction in IOP was 77% and 78% (months 24 and 36) compared to 87% at month 12 from GEMINI. About 68% of patients had an IOP between 6 and 18 mmHg at 24 months and 71% at 36 months. Mean IOP-lowering medications was 1.7 at baseline, which was reduced to 0.4 (24 months, -1.3) and 0.3 (36 months, -1.4). About 74% of patients (46 of 62) were medication free at 36 months. GEMINI demonstrated 12-month effectiveness of canaloplasty and trabeculotomy with OMNI combined with cataract surgery for IOP and medication reduction in mild-to-moderate glaucoma. However, longer-term data is key to the decision making in the selection of a surgical treatment. This GEMINI extension demonstrates that the 12-month outcomes from GEMINI were sustained through 36 months.

Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: Two-Year Results from a Randomized, Multicenter Study

PurposeTo compare the effectiveness and safety of the MicroShunt (Santen Inc., Emeryville, CA, USA) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). DesignProspective, randomized, multicenter trial conducted in the United States and Europe. ParticipantsAdult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥15 mmHg and ≤40 mmHg. MethodsPatients were randomized 3:1 to standalone MicroShunt implantation (n=395) or trabeculectomy (n=132), both augmented with mitomycin C (MMC) 0.2 mg/mL for 2 minutes. Main Outcome MeasuresThe primary effectiveness endpoint was surgical success, defined as ≥20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary endpoints included changes in mean IOP and medication use from baseline and the need for postoperative interventions. ResultsAt 2 years, the rate of surgical success was lower in the MicroShunt than in the trabeculectomy group (50.6% versus 64.4%, p=0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (p<0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (p<0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the two groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% versus 30.9%, p<0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. ConclusionAt 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success.

COMfort Eye Trial (COMET) results - a non-inferiority, randomized, investigator-masked, two-parallel group, phase III clinical trial, to evaluate the efficacy and safety of a preservative free formulation of latanoprost versus a reference drug (Xalatan®) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT)

ABSTRACT Aim To prove non-inferiority of preservative-free (PF) latanoprost versus benzalkonium chloride (BAK) containing latanoprost in lowering intraocular pressure (IOP) in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients. Design and methods This phase III, randomized, investigator-masked trial primarily aimed to demonstrate non-inferiority of YSLT PF latanoprost 50 μg/ml (Yonsung GmbH) to latanoprost (Xalatan®) 50 μg/ml (Pfizer) in reducing IOP from Baseline to Week 12. Secondary aims included conjunctival hyperemia evaluation and difference in ocular comfort levels. Total 130 patients with POAG or OHT were enrolled and randomized (1:1 ratio) to receive YSLT or latanoprost, instilling eye drops daily for 12 weeks. Results At Week 12, mean diurnal IOP reduction was −7.67 ± 2.104 mmHg for YSLT PF latanoprost and −7.77 ± 2.500 for latanoprost. The 97.5% confidence interval of between-treatment group difference in IOP reduction from Baseline to Week 12 was [−0.846, +∞), not crossing the non-inferiority margin of −1.5 mmHg. A low incidence of mild topical treatment emergent adverse events (TEAEs) was observed in both groups, while no serious TEAEs were reported. Conclusions YSLT eye drops demonstrated non-inferiority to latanoprost in reducing IOP. Both products were well tolerated without serious TEAEs reported.

MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension

Purpose To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT).MethodsMERCURY-3 was a 6-month prospective, double–masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3.ResultsOverall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%).ConclusionsOnce-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

PRESERFLO ™ MicroShunt versus trabeculectomy: 1-year results on efficacy and safety.

To compare the efficacy and safety of the PRESERFLO™ MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG) after one year. Institutional prospective interventional cohort study comparing eyes with POAG, which had received the PRESERFLO™ MicroShunt versus trabeculectomy. The MicroShunt group was matched with the trabeculectomy group for age, known duration of disease, and number and classes of intraocular pressure (IOP) lowering medications to have similar conjunctival conditions. The study is part of the Dresden Glaucoma and Treatment Study, using a uniform study design, with the same inclusion and exclusion criteria, follow-ups and standardized definitions of success and failure for both procedures. mean diurnal IOP (mdIOP, mean of 6 measurements), peak IOP, and IOP fluctuations. success rates, number of IOP lowering medications, visual acuity, visual fields, complications, surgical interventions, and adverse events. Sixty eyes of 60 patients, 30 in each group, were analyzed after 1-year follow-ups. Median [Q25, Q75] mdIOP (mmHg) dropped from 16.2 [13.8-21.5] to 10.5 [8.9-13.5] in the MicroShunt and from 17.6 [15.6-24.0] to 11.1 [9.5-12.3] in the trabeculectomy group, both without glaucoma medications. Reduction of mdIOP (P = .596), peak IOP (P = .702), and IOP fluctuations (P = .528) was not statistically significantly different between groups. The rate of interventions was statistically significantly higher in the trabeculectomy group, especially in the early postoperative period (P = .018). None of the patients experienced severe adverse events. Both procedures are equally effective and safe in lowering mdIOP, peak IOP and IOP fluctuations in patients with POAG, one year after surgery. NCT02959242.

Triple Fixed-Combination Bimatoprost/Brimonidine/Timolol in Glaucoma and Ocular Hypertension in India: A Multicenter, Open-Label, Phase 3 Study.

IntroductionTo evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a triple fixed-combination of bimatoprost, brimonidine, and timolol (TFC) in patients with glaucoma or ocular hypertension (OHT) treated with fixed-combination or unfixed brimonidine and timolol therapy (dual-combination therapy).MethodsIn this multicenter, open-label, phase 3 study, patients who received 4–8 weeks of dual-combination therapy twice daily and had an IOP >18 and <34 mmHg in at least one eye were switched (at baseline) to treatment with TFC twice daily for 12 weeks. At Weeks 4, 8, and 12 on TFC, IOP was assessed at Hours 0, 2, and 8. Primary efficacy variable: mean diurnal IOP change from baseline in the study eye at Week 12 (modified intent-to-treat [mITT] population). Sensitivity (per-protocol [PP] population) and subgroup (≤65 vs >65 years) analyses were performed. Safety, including adverse events (AEs), was assessed at each visit.ResultsOf 126 patients enrolled, 121 and 103 formed the mITT/safety and PP populations, including 109 (90.1%) and 94 (91.3%) who completed the study, respectively. In the mITT/safety population, mean age was 58.6 years. Patients had open-angle glaucoma (51.2%), angle-closure glaucoma with patent iridotomy (36.4%), and/or OHT (13.2%). At Week 12, the mean diurnal change in IOP from dual combination-treated baseline was statistically significant (P<0.001) with TFC in the mITT (–3.98 mmHg) and PP (–4.22 mmHg) populations. Results were similar at all visits, regardless of the age subgroup. The most frequent treatment-related AEs were conjunctival hyperemia (14.0%) and dry eye (4.1%); 5.8% of the patients discontinued treatment due to ocular AEs.ConclusionTFC offers a beneficial therapeutic alternative for patients with glaucoma or OHT whose IOP is not sufficiently controlled with dual-combination therapy. Safety and efficacy findings support those of published studies of TFC in primary open-angle glaucoma and OHT, despite differences in study designs.

Ocular pulse amplitude and hemodynamic in controlled asymmetric glaucoma: a cross-sectional study

Purpose: The aim of this study was to explore the relationship between glaucoma severity, ocular pulse amplitude (OPA), and hemodynamic variables.&#x0D; Methods: Thirty-one Asymmetric primary open-angle glaucoma (POAG) cases (one eye with better MD, fellow eye with worst MD) who applied to the glaucoma outpatient clinic of Gulhane Military Medical Faculty Hospital between January 1, 2006, and June 30, 2007, were included in this cross-sectional study. Patients using beta-blockers or alpha-adrenergic agonists were excluded. The patients went on using glaucoma medications. Asymmetricity was assessed if a visual field means deviation (MD) difference ≥6 decibels existed between the eyes. Mean MD and pattern standard deviation, diurnal OPA, and intraocular pressure( IOP) (7 am, 9 am, 11 am, 1 pm, 3 pm, 5 pm, 7 pm, 9 pm,11 pm, 1 am, 4 am), central corneal thickness, peak systolic velocity (PSV), end-diastolic velocity (EDV), PSV/EDV, pulsatility index (PI), resistivity index (RI) for internal carotid artery and ophthalmic artery were measured with color Doppler ultrasonography.&#x0D; Results: The differences in mean diurnal IOP and mean diurnal OPA between the eyes were statistically insignificant. Each diurnal IOP and OPA values and coefficient of variability of diurnal IOP and OPA were statistically insignificant between the groups. There was no significant difference in PSV, EDV, PSV/EDV, PI, and RI between the better-MD and worse-MD eyes. The correlations between mean IOP/mean OPA, and each diurnal IOP/OPA values were insignificant.&#x0D; Conclusion: These results suggest that ocular hemodynamics are affected after a critical point in the evolution of glaucoma. The severity of glaucoma is not directly related to pulsatile ocular blood flow.

A Randomized, Double-Masked, Active-Controlled, Crossover Phase III Equivalence Study of Generic Dorzolamide 2% versus Innovator Trusopt® Eye Drop Solution in Subjects with Open-Angle Glaucoma or Ocular Hypertension.

Background The aim of this study was to demonstrate the equivalence of generic dorzolamide 2% eye drops solution versus the innovator formulation (Trusopt® eye drops solution) in patients with open-angle glaucoma or ocular hypertension. Methods This prospective, monocentric, double-masked, active-controlled crossover phase III study included 32 patients. After washout, patients were randomized to reference product (Trusopt®) or test product (dorzolamide 2% eye drops, Rompharm Company SRL) for a 4-week period. Subsequent washout and crossover were performed. Drops were applied t.i.d. The primary efficacy endpoint was the difference in mean diurnal IOP. Goldmann applanation tonometry was performed at 8 am, 12 pm, and 4 pm at each visit, and safety was assessed by documentation of adverse events (AEs). Therapy adherence was documented by self-reporting and eye drop bottle weighing. An ANOVA with treatment, sequence, study period, and patient within the sequence as effects was performed and an additional post hoc ANCOVA including the baseline IOP was also performed. Results 34 patients were randomized and analyzed in the safety population. The per-protocol population included 32 patients. According to the self-report, all patients were >80% compliant. Under the ANCOVA model, the 90% confidence interval for the average change of the IOP −0.27 mmHg (−1.17 mmHg–0.64 mmHg) is included by the acceptance range −1.5 mmHg to +1.5 mmHg after excluding 2 patients, which had falsely reported high therapy adherence. No clinically relevant difference was observed in frequency or severity of the AEs between both treatments. Conclusions This study showed the equivalence of the tested generic dorzolamide 2% eye drops solution to the reference product Trusopt® eye drops solution. Trial Registration. This trial is registered with (ClinicalTrials.gov (identifier: NCT00878917) on April 9, 2009).

Two-Year Follow-up of MicroPulse Transscleral Laser Therapy in Patients with Primary Open-Angle Glaucoma.

To determine the long-term efficacy and safety of MicroPulse transscleral laser therapy (TLT) over a 24-month period in patients with primary open angle glaucoma. This prospective interventional case series evaluated data from 44 medically treated eyes of primary open angle glaucoma (POAG) patients who received MicroPulse TLT to achieve further reduction in IOP. The reduction in 24-hr mean diurnal intraocular pressure (IOP), diurnal IOP fluctuations, and peak IOP were monitored after 3, 12, and 24 months. Postoperative complications, failure rates, and factors influencing IOP reduction were also evaluated. IOP decreased from 16.1 ± 3.4 mmHg preoperatively to 13.0 ± 2.9 mmHg (n = 31; p < 0.001), 12.3 ± 3.0 mmHg (n = 27; p < 0.001), and 13.1 ± 2.6 mmHg (n = 23; p < 0.001) at the 3-month, 12-month and 24-month follow-ups. At 24months, 23 eyes (52%) had a sufficient IOP reduction to reach the individual target pressure. No severe complications were observed. No parameters could be identified that correlated with successful IOP reduction after treatment. The highest failure rate was observed during the first 3 months and remained stable thereafter. For about 50% of POAG eyes receiving the maximum tolerated treatment, MicroPulse TLT proved an effective method of further lowering IOP so as to reach the individual target pressure.

A Randomized, Controlled Comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and Latanoprost 0.005% in Patients With Open-angle Glaucoma or Ocular Hypertension: The Dolomites Study.

Précis:NCX 470 0.042% and 0.065% were statistically superior in intraocular pressure (IOP) lowering to latanoprost 0.005%, and NCX 470 0.021% was noninferior. All NCX 470 concentrations were safe and well tolerated.Purpose:The purpose of this study was to compare varying concentrations of NCX 470 (a nitric oxide–donating bimatoprost) to latanoprost in a dose-response safety and efficacy trial.Patients and Methods:Adult patients with bilateral open-angle glaucoma or ocular hypertension were randomized to NCX 470 0.021% (n=111), 0.042% (n=108), 0.065% (n=107), or latanoprost 0.005% (n=107) once daily in the evening. IOP was measured at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. The primary efficacy endpoint was the reduction from baseline in mean diurnal IOP at week 4. Secondary efficacy endpoints included reductions from baseline in mean diurnal IOP at weeks 1 and 2, and reductions from baseline in time-matched IOP at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. Adverse events were evaluated.Results:All concentrations of NCX 470 resulted in significant reductions of mean diurnal IOP. The 0.042% and 0.065% concentrations were statistically superior to latanoprost 0.005%, and 0.021% was noninferior to latanoprost for change from baseline in mean diurnal IOP at week 4. The 0.065% concentration was also superior to latanoprost by up to 1.4 mm Hg for reduction from baseline at 8:00 am, 10:00 am, and 4:00 pm at week 4. NCX 470 was safe and well tolerated; conjunctival hyperemia was the most frequently reported adverse event.Conclusions:NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy.

Phase 2b, Randomized, 3-Month, Dose-Finding Study of Sepetaprost in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: The ANGEL Study.

Purpose:This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension.Methods:After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence.Results:Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose–response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia.Conclusion:In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.

Tie2 Activation via VE-PTP Inhibition With Razuprotafib as an Adjunct to Latanoprost in Patients With Open Angle Glaucoma or Ocular Hypertension.

PurposeTo evaluate the ocular hypotensive efficacy and safety of razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).MethodsSubjects with OAG or OHT and an unmedicated IOP from ≥22 mm Hg to <36 mm Hg were randomized to one of three treatment arms: razuprotafib every day (QD) + latanoprost; razuprotafib twice daily (BID) + latanoprost; or latanoprost monotherapy. The primary endpoint was change in mean diurnal IOP from baseline at day 28.ResultsA total of 194 subjects were randomized, and 193 (99.5%) completed the study. Razuprotafib BID + latanoprost resulted in a significantly larger reduction in diurnal IOP than latanoprost alone (7.95 ± 0.26 mmHg vs. 7.04 ± 0.26 mm Hg, P < 0.05). A smaller improvement was observed after 14 days of treatment (7.62 ± 0.26 mm Hg vs. 7.03 ± 0.26 mm Hg, P = 0.11). Razuprotafib QD dosing did not demonstrate additional IOP lowering compared to latanoprost alone. Conjunctival hyperemia on Day 28 increased by 1.1 units on the four-point Efron scale two hours post dose from a baseline value of 0.6 units, and decreased thereafter.ConclusionsTopical ocular razuprotafib as an adjunct to latanoprost therapy was well tolerated and significantly reduced IOP in patients with OAG/OHT.Translational RelevanceThese data support the IOP lowering efficacy of targeting Tie2 activation in Schlemm's canal in the relevant patient population.

Efficacy of Selective Laser Trabeculoplasty on Circadian Intraocular Pressure Following Trabeculectomy in Advanced Primary Open-angle Glaucoma.

In about 50% of post-trabeculectomy (TE) eyes, selective laser trabeculoplasty (SLT) is effective in further lowering intraocular pressure (IOP). To investigate the efficacy and safety of SLT in post-TE eyes, uncontrolled on maximum tolerated medication, and/or with progression of visual field loss. This retrospective study consecutively included post-TE eyes of patients diagnosed with primary open-angle glaucoma who had been treated with 360 degrees SLT and had a follow-up after 12 months. Primary endpoints were the reduction of mean diurnal intraocular pressure (mdIOP, mean of 6 measurements), peak IOP, and diurnal IOP fluctuations. Secondary outcomes were factors influencing IOP reduction, SLT success, and failure rates. Forty-three eyes of 43 patients were included. During the first year, 10 eyes (23%) needed additional procedures to reduce mdIOP and were accounted as failures and excluded from final analysis. Of the remaining 33 eyes (77%) mdIOP [Q25, Q75] dropped from 15.2 [12.2 to 16.5] to 13.2 [11.6 to 15.3] mm Hg (P=0.027), 23 eyes (54%) showed a sufficient mdIOP reduction, 1 year after SLT. SLT is effective and safe in lowering mdIOP to target IOP in about 50% of eyes after prior incisional glaucoma surgery.

Comparison of intraocular pressure peak and fluctuations among Filipino patients with non-glaucomatous eyes and glaucoma suspects using water drinking test and diurnal intraocular pressure.

To compare the intraocular pressure (IOP) peaks and fluctuations using water drinking tests (WDTs) and mean diurnal IOP among Filipino patients with normal eyes and glaucoma suspects. This prospective study included normal and glaucoma suspect patients. Each patient underwent both WDT and mean diurnal examination on separate visits. For mean diurnal examination, IOP was recorded every 2h for 8h while in WDT, IOP was recorded prior to WDT, and post-WDT at 5, 15, 30, 45, and 60min. IOP peak was recorded as the highest IOP for both methods, and IOP fluctuation was recorded as highest IOP minus lowest IOP. With the comparison of diagnostic tests, both normal eyes and glaucoma suspect groups, the peak IOP was caught at 15min. Comparative analysis of both groups also showed that the peak IOP measurements were statistically higher for the WDT compared to mean diurnal IOP (P=0.039, P=0.048 under normal group and P=0.032 and P=0.031 under glaucoma suspect group). Similarly, the WDT had a statistically higher mean IOP fluctuation score than the mean diurnal IOP method in both groups (P=0.003, P=0.011 under normal group; P=0.002 and P=0.005 under glaucoma suspect group). This study shows that WDT is a comparable diagnostic exam in predicting IOP fluctuations than mean diurnal measurement. WDT is a promising diagnostic procedure for risk assessment in glaucoma.

Treatment Success Across Different Levels of Preoperative Disease Burden: Stratified Two-Year Outcomes from the Pivotal Trial of iStent inject ® Trabecular Micro-Bypass in Primary Open-Angle Glaucoma and Cataract.

PurposeTo examine effectiveness outcomes stratified by preoperative disease burden in the pivotal trial of iStent inject® with cataract surgery (INJ) vs cataract surgery alone (CS).Materials and MethodsProspective, 3:1 randomized, single-masked, concurrently-controlled, multicenter trial enrolling 505 subjects with cataract and mild-to-moderate primary open-angle glaucoma who underwent iStent inject implantation with phacoemulsification or phacoemulsification alone, and were followed for 2 years including annual medication washouts. Post hoc stratification was completed for baseline mean diurnal intraocular pressure (BL DIOP; Low-DIOP <25mmHg, Mid-DIOP ≥25 to <30 mmHg, High-DIOP ≥30mmHg) and preoperative medication burden (Low-Med 1 medication, Mid-Med 2 medications, High-Med ≥3 medications).ResultsThe 24-month primary and secondary effectiveness endpoints were met, with significant treatment-over-control differences in percent of eyes achieving ≥20% unmedicated DIOP reduction and in unmedicated DIOP reduction, respectively. In subgroup analyses, the proportions of INJ eyes achieving the primary endpoint remained steady across all BL DIOP (75.4%, 77.1%, 74.4% in Low/Mid/High-DIOP strata, respectively) and preoperative medication levels (76.8%, 70.8%, 79.7% in Low/Mid/High-Med strata, respectively); meanwhile, the proportions of CS eyes diminished with higher BL DIOP (64.5%, 63.6%, 33.3%, respectively) and more medications (69.0%, 63.3%, 29.4%, respectively). Regarding secondary effectiveness, postoperative DIOP reduction increased with higher BL DIOP in INJ eyes (6.2mmHg, 7.8mmHg, 9.8mmHg, respectively) but plateaued in CS eyes (5.2mmHg, 5.8mmHg, 5.4mmHg, respectively). INJ eyes also had consistent DIOP reduction regardless of preoperative medication burden (6.8mmHg, 6.7mmHg, 7.8mmHg, respectively), while DIOP reduction diminished with more medications in CS eyes (6.1mmHg, 5.0mmHg, 3.3mmHg, respectively). Safety was favorable, comparable to phacoemulsification alone.ConclusionSignificant IOP reductions occurred across all levels of BL DIOP and preoperative medication burden in iStent inject eyes. DIOP reductions increased with higher BL DIOP and remained stable across all levels of preoperative medication burden, suggesting the device’s potential utility in more medically challenging cases.

Safety and efficacy of topically administered netarsudil-latanoprost fixed dose combination (FDC; Rocklatan™) in normal and glaucomatous dogs with ADAMTS10-open-angle glaucoma (ADAMTS10-OAG).

The aim of the study was to evaluate safety and efficacy of topically administered 0.02% netarsudil-0.005% latanoprost fixed-dose combination (FDC) (Rocklatan™; Aerie Pharmaceutical) in normal and glaucomatous dogs with ADAMTS10-open-angle glaucoma (ADAMTS10-OAG). Five normal and five glaucomatous beagle dogs with ADAMTS10-OAG were the study animals. In each dog, left (OS) or right eye (OD) was randomly selected for netarsudil-latanoprost FDC treatment. Contralateral eyes served as latanoprost-treated controls. The study was divided into four consecutive study periods: following a 4-day baseline period, two sequential 8-day study periods followed with once daily (q24h) and twice daily (q12h) treatments and ending with a washout period. Efficacy was measured by diurnal intraocular pressure (IOP) and pupil diameter. Safety was assessed by routine ophthalmic examination, gonioscopy, and pachymetry. Differences in least square means of quantitative outcome measures were compared between FDC and latanoprost treatments by using the linear Gaussian model. Baseline IOPs were 13.6±0.7mmHg (mean ± SEM) in normal and 28.3±1.4mmHg in OAG-affected dogs. There was a significant decrease in mean diurnal IOP following FDC administration in both normal (q24h: -2.1mmHg; q12h: -4.1mmHg) and glaucomatous dogs (q24h: -14.2mmHg; q12h: -17.7mmHg; p<.0001). There was no significant difference in the treatment effect when comparing FDC to latanoprost. Both FDC and latanoprost administration resulted in similarly significant pupil constriction (p<.0001). The FDC administration was well-tolerated but resulted in conjunctival hyperemia. Once or twice daily administration of netarsudil-latanoprost FDC (Rocklatan™) and latanoprost was equally effective in lowering IOP in normal and OAG-affected dogs. There was no netarsudil-related added treatment effect.

Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: One-Year Results from a 2-Year Randomized, Multicenter Study

To compare the effectiveness and safety of the MicroShunt versus trabeculectomy in patients with primary open-angle glaucoma (POAG). One-year results from a 2-year, prospective, randomized, multicenter, noninferiority study (NCT01881425) conducted in the United States and Europe. Eligible patients were aged 40-85 years with intraocular pressure (IOP) ≥15 and ≤40 mmHg and mild-to-severe POAG inadequately controlled on maximum tolerated medical therapy. Patients were randomized 3:1 to undergo stand-alone MicroShunt implantation or trabeculectomy, both performed with adjunctive mitomycin C (0.2 mg/ml for 2 minutes). The primary effectiveness end point was surgical success, defined as ≥20% reduction in mean diurnal IOP from baseline (no medication washout) at year 1 without increasing the number of glaucoma medications. Secondary effectiveness end points at year 1 were the mean IOP change from baseline and requirement for postoperative intervention. Additional end points included glaucoma medication use and adverse events. Overall, 395 (MicroShunt) and 132 (trabeculectomy) patients were randomized (mean Humphrey visual field mean deviation,-12.34 decibels [dB]). At year 1, probability of success was lower in the MicroShunt group compared with the trabeculectomy group (53.9% vs. 72.7%, respectively; P < 0.01). In the MicroShunt group, mean IOP ± standard deviation decreased from 21.1 ± 4.9 mmHg at baseline to 14.3 ± 4.3 mmHg (-29.1%; P < 0.01) at year 1, with a mean of 0.6 ± 1.1 glaucoma medications (baseline 3.1 ± 1.0; P < 0.01). In the trabeculectomy group, mean IOP decreased from 21.1 ± 5.0 mmHg to 11.1 ± 4.3 mmHg (-45.4%; P < 0.01), with a mean of 0.3 ± 0.9 glaucoma medications (baseline 3.0 ± 0.9; P < 0.01). Postoperative interventions, including laser suture lysis, were reported in 40.8% (MicroShunt) versus 67.4% (trabeculectomy) of patients (P<0.01). Reported incidence of transient hypotony was higher in the trabeculectomy group versus the MicroShunt group (49.6% vs. 28.9%; P < 0.01). Vision-threatening complications were uncommon and reported in 1.0% of MicroShunt versus 0.8% of trabeculectomy patients. Probability of success was lower with MicroShunt compared with trabeculectomy. Although reductions in IOP and glaucoma medications over 1 year were observed in both groups, the trabeculectomy group had a lower mean IOP on fewer medications.