To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma ...and ocular hypertension.
Double-masked, randomized noninferiority clinical trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2).
After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 months from both studies are provided in this report.
Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clinically and statistically significant reductions from baseline intraocular pressure (P < .001), and was noninferior to timolol in the per-protocol population with maximum baseline IOP < 25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P < .0001 for netarsudil vs timolol).
In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications.
To evaluate the safety and efficacy of an intravitreal fluocinolone acetonide (FA) implant compared with standard therapy in subjects with noninfectious posterior uveitis (NIPU).
Randomized, ...controlled, phase 2b/3, open-label, multicenter superiority trial.
Subjects with unilateral or bilateral NIPU.
One hundred forty subjects received either a 0.59-mg FA intravitreal implant (n = 66) or standard of care (SOC; n = 74) with either systemic prednisolone or equivalent corticosteroid as monotherapy (> or =0.2 mg/kg daily) or, if judged necessary by the investigator, combination therapy with an immunosuppressive agent plus a lower dose of prednisolone or equivalent corticosteroid (> or =0.1 mg/kg daily).
Time to first recurrence of uveitis.
Eyes that received the FA intravitreal implant experienced delayed onset of observed recurrence of uveitis (P<0.01) and a lower rate of recurrence of uveitis (18.2% vs. 63.5%; P< or =0.01) compared with SOC study eyes. Adverse events frequently observed in implanted eyes included elevated intraocular pressure (IOP) requiring IOP-lowering surgery (occurring in 21.2% of implanted eyes) and cataracts requiring extraction (occurring in 87.8% of phakic implanted eyes). No treatment-related nonocular adverse events were observed in the implant group, whereas such events occurred in 25.7% of subjects in the SOC group.
The FA intravitreal implant provided better control of inflammation in patients with uveitis compared with systemic therapy. Intraocular pressure and lens clarity of implanted eyes need close monitoring in patients receiving the FA intravitreal implant.
Background. The efficacy of TCN-032, a human monoclonal antibody targeting a conserved epitope on M2e, was explored in experimental human influenza. Methods. Healthy volunteers were inoculated with ...influenza A/Wisconsin/67/2005 (H3N2) and received a single dose of the study drug, TCN-032, or placebo 24 hours later. Subjects were monitored for symptoms, viral shedding, and safety, including cytokine measurements. Oseltamivir was administered 7 days after inoculation. Results. Although the primary objective of reducing the proportion of subjects developing any grade ≥2 influenza symptom or pyrexia, was not achieved, TCN-032-treated subjects showed 35% reduction (P = .047) in median total symptom area under the curve (days 1-7) and 2.2 log reduction in median viral load area under the curve (days 2-7) by quantitative polymerase chain reaction (P = .09) compared with placebo-treated subjects. TCN-032 was safe and well tolerated with no additional safety signals after administration of oseltamivir. Serum cytokine levels (interferon γ, tumor necrosis factor α, and interleukin 8 and 10) were similar in both groups. Genotypic and phenotypic analyses showed no difference between virus derived from subjects after TCN-032 treatment and parental strain. Conclusions. These data indicate that TCN-032 may provide immediate immunity and therapeutic benefit in influenza A infection, with no apparent emergence of resistant virus. TCN-032 was safe with no evidence of immune exacerbation based on serum cytokine expression. Clinicaltrials.gov. registry number. NCT01719874
To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT).
Double-masked, randomized, multicenter, parallel-group, noninferiority ...clinical study.
After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata.
On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients.
In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients.
To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic ...Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night.
This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29.
We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p<0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively.
In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity.
NCT02057575.
To compare the intraocular pressure (IOP)-lowering efficacy and safety of netarsudil once daily (QD) and timolol twice daily (BID).
Double-masked, randomized, phase 3, noninferiority study.
Patients ...with open-angle glaucoma or ocular hypertension (unmedicated baseline IOP >20 to <30 mm Hg at 8:00 AM) were randomized to netarsudil ophthalmic solution 0.02% QD (PM) or timolol ophthalmic solution 0.5% BID. The primary endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP <25 mm Hg (per-protocol population). Safety was recorded over the 6-month treatment period.
A total of 186 patients from each treatment arm were included in the primary efficacy analysis. Netarsudil QD met the criteria for noninferiority to timolol BID. Mean treated IOP ranged from 16.3 to 17.9 mm Hg for netarsudil and 16.7 to 17.6 for timolol, with mean reductions from baseline of 3.9 to 4.7 mm Hg and 3.8 to 5.2 mm Hg, respectively. In prespecified secondary analyses, netarsudil demonstrated noninferiority to timolol in patients with baseline IOP <27 mm Hg and <30 mm Hg. The IOP-lowering effects of netarsudil were sustained over 6 months of treatment. No treatment-related serious adverse event (AE) was reported for either study drug. However, statistically significant reductions in mean heart rate were recorded at all study visits for the timolol group. The most frequent ocular AE among netarsudil-treated patients was conjunctival hyperemia (47.9%), which was predominately mild.
Netarsudil QD (PM), a first-in-class IOP-lowering medication, was noninferior to timolol BID and was associated with tolerable ocular AEs.
In pooled phase III analyses, once-daily netarsudil 0.02% resulted in intraocular pressure (IOP) reduction that was noninferior to twice-daily timolol 0.5%, with minimal treatment-related serious or ...systemic adverse events (AEs). Ocular AEs were generally tolerable.
The purpose of this study was to assess the efficacy and safety of the Rho kinase inhibitor netarsudil in patients with open-angle glaucoma or ocular hypertension.
Pooled analysis of data from the ROCKET-1 to 4 phase III studies of once-daily (PM) netarsudil or twice-daily timolol in patients with open-angle glaucoma or ocular hypertension. The primary efficacy measure was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP <25 mm Hg.
In the pooled primary efficacy population (netarsudil, n=494; timolol, n=510), once-daily netarsudil was noninferior to twice-daily timolol at all 9 timepoints through month 3. Mean treated IOP ranged from 16.4 to 18.1 mm Hg among netarsudil-treated patients and 16.8 to 17.6 mm Hg among timolol-treated patients. In the pooled safety population (n=839 in each treatment group), treatment-related serious AEs occurred at similar frequencies in each treatment group (netarsudil, 0.1%; timolol, 0%). The most common ocular AE, conjunctival hyperemia (netarsudil, 54.4%; timolol, 10.4%), was graded as mild in 77.6% (354/456) of affected netarsudil-treated patients.
Once-daily netarsudil resulted in IOP lowering that was noninferior to twice-daily timolol, with tolerable ocular AEs that were generally mild and self-resolving. As a first-in-class agent in the United States, with a novel mechanism of action, netarsudil may provide a useful therapeutic option for patients who would benefit from IOP lowering.
To compare the clinical and antimicrobial efficacy of besifloxacin ophthalmic suspension 0.6% with that of moxifloxacin ophthalmic solution 0.5% for the treatment of bacterial conjunctivitis.
...Multicenter, randomized, double-masked, parallel-group, active-controlled, noninferiority study.
Patients 1 year of age or older with clinical manifestations of bacterial conjunctivitis.
Eligible patients were randomized to either besifloxacin suspension or moxifloxacin solution, instilled in the infected eye(s) 3 times daily for 5 days, and participated in study visits on days 1, 5 (+/-1 day), and 8 (+1 day). Assessments included clinical evaluation of signs and symptoms, visual acuity, biomicroscopy, and culture of the infected eye(s) at each visit, as well as direct ophthalmoscopy on days 1 and 8.
The primary efficacy end points were clinical resolution and microbial eradication of baseline bacterial infection on day 5 in patients with culture-confirmed bacterial conjunctivitis. Secondary end points included clinical resolution and microbial eradication on day 8, individual clinical outcomes, microbial and clinical outcomes by bacterial species, and safety.
A total of 1161 patients (533 with culture-confirmed bacterial conjunctivitis) were randomized. Based on the 95% confidence interval (CI) of the difference, besifloxacin was noninferior to moxifloxacin for clinical resolution on day 5 (58.3% vs. 59.4%, respectively; 95% CI, -9.48 to 7.29) and day 8 (84.5% vs. 84.0%, respectively, 95% CI, -5.6% to 6.75%) and for microbial eradication on day 5 (93.3% vs. 91.1%, respectively, 95% CI, -2.44 to 6.74) and day 8 (87.3% vs. 84.7%; 95% CI, -3.32 to 8.53). There was no statistically significant difference between the 2 treatment groups for either efficacy end points on days 5 or 8 (P>0.05). Besifloxacin and moxifloxacin were well tolerated. The cumulative frequency of ocular adverse events was similar between treatments (12% and 14% with besifloxacin and moxifloxacin, respectively). However, eye irritation occurred more often in moxifloxacin-treated eyes (0.3% for besifloxacin vs. 1.4% for moxifloxacin; P = 0.0201).
Besifloxacin ophthalmic suspension was non inferior to moxifloxacin ophthalmic suspension and provided similar safety and efficacy (clinical and microbiological) outcomes when used for the treatment of bacterial conjunctivitis.
Proprietary or commercial disclosure may be found after the references.
Purpose
A randomized, double-masked, multicenter, phase 2 trial to evaluate the long-term safety and efficacy of travoprost intraocular implant, an extended-release drug delivery system designed to ...provide uninterrupted sustained intraocular pressure (IOP)-lowering therapy, thereby reducing patient treatment burden and improving adherence with IOP-lowering medication.
Methods
Patients with open-angle glaucoma or ocular hypertension were administered a fast-eluting implant (FE implant,
n
= 51) and received twice-daily (BID) placebo eye drops, a slow-eluting (SE implant,
n
= 54) and received BID placebo eye drops, or underwent a sham surgical procedure and received BID timolol 0.5% (
n
= 49). IOP was measured at baseline, day 1–2, day 10, week 4, week 6, month 3, and every 3 months thereafter through 36 months. Efficacy was evaluated by mean change from 8:00 AM unmedicated baseline IOP through month 36, and the percentage of patients receiving the same or fewer topical IOP-lowering medications as at screening (pre-study). Safety was evaluated by adverse events and ophthalmic parameters.
Results
Clinically and statistically relevant IOP-lowering treatment effects were observed through month 36 after a single administration of the travoprost implant compared with BID timolol with mean IOP reductions ranging from 7.6 to 8.8 mmHg for the FE implant group, from 7.3 to 8.0 mmHg for the SE implant group, and from 7.3 to 7.9 for the timolol group at the 8:00 AM timepoint (
P
< 0.0001 for all treatment groups at all visits). At months 12, 24, and 36, a greater percentage of FE and SE implant patients versus timolol patients were well controlled on the same or fewer topical IOP-lowering medications compared with screening with 63 and 69% for the FE and SE implants groups, respectively, versus 45% for the timolol group at month 36. The safety profile of the implant was favorable; there were no dislodgements, no explantations, no adverse events of conjunctival hyperemia or periorbital fat atrophy, no discontinuations due to study eye adverse events, nor any serious adverse events in the study eye. Comparable changes from baseline in corneal endothelial cell counts were observed in the three treatment groups over the 36 months.
Conclusion
The travoprost intraocular implant demonstrated robust IOP-lowering and substantially reduced topical IOP-lowering medication burden for up to 36 months following a single administration, while maintaining a favorable safety profile. The travoprost intraocular implant promises to be a meaningful addition to the interventional glaucoma armamentarium by addressing the key shortcomings of topical IOP-lowering medications, including low adherence and topical side effects while controlling IOP for up to 36 months.
Trial Registry
ClinicalTrials.gov identifier NCT02754596 registered 28 April 2016.
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