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.

PRCIS: 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.

Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan® (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

ADVISE: First Results of a European Interoperative Information System Network Developed for the ADenoVirus Initiative Study in Epidemiology.

Adenoviral conjunctivitis is extremely contagious, causes a form of conjunctivitis. Therefore, it is important to identify patients who suffer from adenoviral conjunctivitis, as early as possible, in order to contain the disease. We present the 6 independent but interoperable platforms developed for the purpose of a large European epidemiologic study (ADVISE), which has been implemented independently in France, Germany, Spain, Italy and the UK. ADVISE is a non-interventional, observational epidemiology study with the objectives of assessing clinical characteristics and incidence of adenovirus conjunctivitis. One of the challenges faced in developing this network of European epidemiology platforms has been the multilingual context. Actually, we have established independent platforms fully dedicated to each of the participating countries. Similar protocols have been submitted across these countries, allowing individual and pooled analyses of the data. A standardized questionnaire is used to collect patient ocular medical history. The electronic questionnaire contains 151 items with automatic coherence control. The first platform ADVISE was set up in France. Development, evaluation and validation of this platform were carried out between January and July 2013. The Medical Informatics and Knowledge Engineering Laboratory (LIMICS), proposes through this project, a tool that allows the installation and application of epidemiologic monitoring in any part of the world.

Blood pressure effects of naproxcinod in hypertensive patients.

The blood pressure (BP) effects of naproxcinod and naproxen were assessed in an 8-week, double-blind, crossover study in 131 hypertensive patients aged 50 to 74 years. Patients received naproxcinod 750 mg twice daily or naproxen 500 mg twice daily, then the alternate treatment, each for 14 days, with placebo run-in/washout before each active treatment period and 24-hour ambulatory BP monitoring conducted before and after each active treatment period. Mean change from baseline in average 24-hour systolic BP (SBP) after 2 weeks of treatment numerically favored naproxcinod 750 mg twice daily (least-squares [LS] mean for naproxcinod minus naproxen: -1.6 mm Hg; P=.12). Post hoc analyses showed statistically significant SBP differences favoring naproxcinod for the 8 elapsed hours (LS mean: -4.4 mm Hg; P<.0001) and the 24 hours following morning dosing (LS mean: -2.4 mm Hg; P=.006). Naproxcinod may be a beneficial alternative for patients with osteoarthritis requiring nonsteroidal anti-inflammatory drugs.

Effects of naproxcinod on blood pressure in patients with osteoarthritis.

Nonsteroidal anti-inflammatory drugs are associated with increases in blood pressure (BP), particularly in patients treated with antihypertensive therapy. Naproxcinod is a nitric oxide-donating cyclooxygenase inhibitor in development for osteoarthritis (OA). Thus, we characterized the effects of naproxcinod on BP in an integrated safety analysis of 3 pivotal trials of patients with OA of the hip or knee involving 2,734 patients. The changes from baseline in the systolic BP after 13 weeks of therapy with naproxcinod (375 and 750 mg), naproxen 500 mg (equipotent to naproxcinod 750 mg), or placebo twice daily were evaluated in all patients and in the subgroup taking renin-angiotensin system inhibitors. Heterogeneity testing showed no treatment-by-study interaction. The effects of naproxcinod 750 mg on the systolic BP was not different from placebo (mean change from baseline vs placebo -0.4 mm Hg, 95% confidence interval -1.6 to 0.8). Naproxen increased the systolic BP relative to placebo (mean change from baseline vs placebo +1.4 mm Hg, 95% confidence interval 0.1 to 2.7). In the renin-angiotensin system inhibitor-treated patients, the effect of naproxcinod 750 mg compared to naproxen 500 mg in the changes from baseline in the systolic BP was -4.3 mm Hg (95% confidence interval -8.5 to -0.0). In conclusion, naproxcinod had effects on BP similar to that of placebo in patients with OA. These results imply that naproxcinod would be less likely to alter systolic BP control in patients with OA than a conventional nonsteroidal anti-inflammatory drug, particularly in those treated with renin-angiotensin system inhibitor agents.

Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study.

OBJECTIVE: Comparison of naproxcinod (375 and 750 mg), placebo (up to 13 weeks), and naproxen 500 mg (all bid) for treatment of osteoarthritis (OA) signs and symptoms. METHODS: A 53-week, randomized, double-blind, parallel-group study. One thousand twenty patients with primary knee OA were randomized to naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo (all bid). Coprimary efficacy endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC™) pain and function subscales and patient overall rating of disease status. An analysis of covariance model tested superiority for both naproxcinod doses over placebo at week 13, and noninferiority of naproxcinod 750 mg bid versus naproxen at weeks 13 and 26. RESULTS: Least-square mean changes from baseline were greater for both naproxcinod doses compared with placebo at week 13 for WOMAC pain (-31.3 [standard error 1.67], -28.1 [1.64], and -20.4 [1.62] mm with naproxcinod 750 mg bid [P < 0.0001], 375 mg bid [P = 0.0008], and placebo, respectively), WOMAC function (-27.8 [1.60], -23.8 [1.58], and -14.9 [1.56] mm, respectively, P < 0.0001), and patient overall rating of disease status (1.00 [0.061], 0.81 [0.060], and 0.49 [0.059], respectively, P < 0.0001). Naproxcinod 750 mg bid was noninferior to naproxen at weeks 13 and 26. Naproxcinod was well tolerated, with no notable differences in orthostatic blood pressure response between treatments. CONCLUSION: Naproxcinod 750 mg bid and 375 mg bid demonstrated superior efficacy over placebo for treatment of OA and were well tolerated over 1 year. Naproxcinod 750 mg bid was noninferior to naproxen 500 mg bid.

Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: a randomized, double-blind, parallel-group, multicenter study.

OBJECTIVE: To test the superiority of naproxcinod compared with placebo in relieving the signs and symptoms of hip osteoarthritis and to assess the safety of naproxcinod and its effects on blood pressure. METHODS: In a 13-week, randomized, double-blind, parallel-group, multicenter study, 810 patients were randomized to receive either naproxcinod 750 mg twice daily, placebo, or naproxen 500 mg twice daily (2:2:1). Primary efficacy analyses compared naproxcinod and placebo using an analysis of covariance for 3 co-primary end points (the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain and function subscales and patient's overall rating of disease status). Safety assessments included adverse events and in-office blood pressure measurements. RESULTS: The least squares mean changes from baseline were significantly greater with naproxcinod than with placebo (P < 0.0001) and were similar to those with naproxen at week 13 for the WOMAC pain score (-25.81, -17.97, and -24.31 mm, respectively), the WOMAC function score (-22.24, -13.45, and -21.67 mm, respectively), and patient's rating of disease status (0.86, 0.51, and 0.82, respectively). Changes from baseline in systolic blood pressure were similar in the naproxcinod and placebo groups at weeks 2, 6, and 13 (differences between groups of 0.25, -0.45, and -0.11 mm Hg, respectively). Changes in the naproxen group were greater than those in the placebo group (differences of 3.11, 3.03, and 2.00 mm Hg, respectively). Systolic blood pressure increases ≥10 mm Hg from baseline to week 13 occurred in 13.3%, 15.0%, and 20.3% of patients receiving naproxcinod, placebo, and naproxen, respectively. Naproxcinod and naproxen had similar adverse event and general safety profiles. CONCLUSION: The efficacy of naproxcinod for treating the signs and symptoms of hip osteoarthritis was statistically superior to that of placebo and similar to that of naproxen. Naproxcinod was well tolerated, with effects on systolic blood pressure similar to those of placebo.

Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis.

Traditional nonsteroidal anti-inflammatory drugs are associated with the destabilization of blood pressure (BP) control, particularly in hypertensive patients treated with blockers of the renin-angiotensin system. To assess the potential impact of nitric oxide donation, the effects of naproxcinod with naproxen and placebo on changes in BP were compared in a randomized clinical trial of 916 patients with osteoarthritis after 13 weeks of therapy. In addition, the effects of naproxcinod versus naproxen and placebo on systolic BP in patients with hypertension treated with renin-angiotensin system blockers were evaluated. Naproxcinod 750 mg twice daily reduced systolic BP compared to naproxen 500 mg twice daily (p <0.02). The 2 doses of naproxcinod showed reductions from baseline in diastolic BP relative to naproxen (p <0.04) and similar changes compared to placebo. In 207 patients with hypertension treated with renin-angiotensin-blocking agents alone or with diuretics, the difference in mean change from baseline in systolic BP between naproxen 500 mg and naproxcinod 750 mg was 6.5 mm Hg in favor of naproxcinod (p <0.02). The proportion of patients in the overall population with systolic BP increases > or =10 mm Hg was greater with naproxen 500 mg (22%) compared to naproxcinod 750 mg (14%, p = 0.04), naproxcinod 375 mg (14%, p = 0.055), and placebo (15.6%, p = 0.155). In conclusion, naproxcinod did not induce elevations of BP seen with naproxen, and it had similar effects on BP to that of placebo in patients with osteoarthritis.