A Randomized, Controlled Trial of Cyclosporine A Cationic Emulsion in Pediatric Vernal Keratoconjunctivitis: The VEKTIS Study.

PURPOSE: Vernal keratoconjunctivitis (VKC) is a chronic, allergic, and potentially severe ocular disease affecting children and adolescents that can lead to impaired quality of life (QoL) and loss of vision. This study evaluated the efficacy and safety of an investigational therapy for severe VKC, cyclosporine A (CsA) cationic emulsion (CE), an oil-in-water emulsion with increased bioavailability versus conventional CsA formulations. DESIGN: The VErnal KeratoconjunctiviTIs Study (VEKTIS) is a phase 3, multicenter, double-masked, vehicle-controlled trial. PARTICIPANTS: Pediatric patients (4 to younger than 18 years) with active severe VKC (grade of 3 or 4 on the Bonini severity scale) and severe keratitis (corneal fluorescein staining [CFS] score of 4 or 5 on the modified Oxford scale). METHODS: One hundred sixty-nine patients were randomized to CsA CE 0.1% (1 mg/ml) eye drops 4 times daily (high dose), CsA CE twice daily (low dose) plus vehicle twice daily, or vehicle 4 times daily for 4 months. MAIN OUTCOME MEASURES: The primary end point was a mean composite score that reflected CFS, rescue medication use (dexamethasone 0.1% 4 times daily), and corneal ulceration over the 4 months. RESULTS: Differences in least-squares means versus vehicle for the primary end point were statistically significant for both the high-dose (0.76; P = 0.007) and the low-dose (0.67; P = 0.010) groups, with treatment effect mainly driven by CFS score. Significant differences were found between both active treatment groups and vehicle for use of rescue medication. Vernal keratoconjunctivitis symptoms and patient QoL (assessed by visual analog scale and the Quality of Life in Children with Vernal Keratoconjunctivitis questionnaire) improved in all 3 groups, with significant improvements for high-dose CsA CE versus vehicle. CONCLUSIONS: The efficacy of high-dose CsA CE in improving keratitis, symptoms, and QoL for those with severe VKC was demonstrated in these study patients. In addition, in this study cohort, CsA CE was well tolerated.

Review of clinical outcomes of a cationic emulsion tear substitute in patients with dry eye disease.

First-line options for the treatment of dry eye disease (DED) rely on artificial tears (ATs), among which cationic emulsion (CE)-based ATs have been developed in order to mimic the healthy tear film for an improved restoration of the ocular surface homeostasis. In this review, we describe the outcomes reported in several studies, assessing the mode of action, ocular tolerance and clinical performance of a CE-based AT. Pilot studies have revealed that CE-based ATs can increase the volume and stability of the tear film while limiting its evaporation rate. Larger studies have demonstrated that CE-based ATs play a significant role in the improvement of both objective and subjective DED parameters, including superior efficacy on DED symptoms compared to several other available AT formulation types. Concomitantly, CE-based ATs have been shown to help patients to prevent or recover from corneal defects associated with refractive surgery. These positive outcomes on ocular surface epithelia are likely due to the combination of unique rheological behaviour and intrinsic anti-inflammatory properties. Based on all clinical findings, CE-based ATs represent a valuable treatment option for patients with various etiologies of DED including evaporative forms and would deserve evaluation of benefits in other surgical intervention types triggering DED.

Topical cyclosporine A cationic ophthalmic emulsion in paediatric vernal keratoconjunctivitis: pooled analysis of randomised NOVATIVE and VEKTIS trials.

BACKGROUND/OBJECTIVES: Cyclosporine A cationic ophthalmic emulsion (CsA CE) was evaluated in paediatric and adolescent patients with vernal keratoconjunctivitis (VKC) in the NOVATIVE (NCT00328653) and VEKTIS (NCT01751126) trials. The similarity of these studies permitted pooled assessment of the effect of CsA CE on corneal damage as well as safety and tolerability. SUBJECTS/METHODS: Pooled outcomes were assessed for the first 28 days of treatment. In NOVATIVE, 118 patients were randomised to 4 times daily (QID) CsA CE 0.05%, 0.1%, or vehicle eye drops. In VEKTIS, 169 patients were randomised to CsA CE 0.1% QID or twice daily (BID) or vehicle. For these analyses, treatment groups comprised: (1) pooled CsA CE 0.1% QID arms (high-dose; n = 96); (2) pooled CsA CE 0.05% QID arm from NOVATIVE and CsA CE 0.1% BID data from VEKTIS (low-dose; n = 93); and (3) pooled vehicle QID arms (vehicle; n = 98). RESULTS: Changes from baseline to day 28 (mean ± standard deviation) in corneal fluorescein staining (CFS) scores for CsA CE high-dose, low-dose, and vehicle groups were -1.6 ± 1.47 (95% CI: -0.9, -0.1; p = 0.0124 vs vehicle), -1.7 ± 1.39 (95% CI: -1.1, -0.3; p = 0.0015 vs vehicle), and -1.0 ± 1.55, respectively. Adverse events (AEs) of any type were reported in 37.5%, 34.4%, and 37.8% of the high-dose, low-dose, and vehicle groups, respectively. Most were mild or moderate in severity. CONCLUSIONS: CsA CE significantly decreased corneal damage and was safe and well tolerated in patients with VKC. These data support CSA CE as a treatment option for the management of VKC.

NOVATIVE: A Phase II/III, Multicenter, Double-masked, Randomized Study of Cyclosporine A 0.05% and 0.1% Ophthalmic Cationic Emulsion Versus Vehicle in Patients with Vernal Keratoconjunctivitis.

PURPOSE: This study evaluates the efficacy and tolerability of cyclosporine A cationic emulsion (CsA-CE) in patients ≥4 years of age with moderate-to-severe vernal keratoconjunctivitis (VKC). METHODS: This Phase II/III, multicenter, double-masked, dose-ranging study had 2 treatment periods: a 4-week, randomized, vehicle-controlled period in which patients received 0.05% CsA-CE, 0.1% CsA-CE, or vehicle eye drops 4 times daily (period 1) and a 3-month period in which patients received 0.05% CsA-CE or 0.1% CsA-CE 2 or 4 times daily (period 2). The primary efficacy end point was rating of subjective symptoms at day 28 in period 1 per the BenEzra scale. FINDINGS: All groups showed improvement in subjective VKC symptoms at day 28, without a statistically significant difference between 0.05% or 0.1% CsA-CE vs vehicle. Both CsA-CE doses produced statistically significant improvements in corneal fluorescein staining scores vs vehicle at day 28; improvements were evident as early as week 1 and continued through month 1. Progressive reduction in subjective itching was evident after week 1 and continued through month 1. Treatment for an additional 3 months further improved subjective symptoms and objective signs of VKC in both CsA-CE groups. Improvement was most notable with 0.1% CsA-CE in patients with severe keratitis. The safety and tolerability profile is favorable. IMPLICATIONS: Although treatment with 0.05% and 0.1% CsA-CE showed clinical efficacy in alleviating keratitis and itching as early as week 1, with sustained benefit through 1 month, the primary efficacy end point was not met. These findings informed the design of the Phase III trial of 0.1% CsA-CE (Vernal Keratoconjunctivitis Study). CLINICALTRIALS: gov identifier: NCT00328653.

Surgical management of an aortic root dilatation in a patient suffering from Hunter syndrome.

Hunter syndrome is a rare disease leading to glycosaminoglycan accumulation in tissues. Multiple organs are involved, but prognosis is mainly conditioned by cardiac and respiratory failures. Cardiac valvular impairment is quite common but aortic root dilatation is rarely described. This article covers a case of surgical root replacement due to aortic valve insufficiency and aortic root dilatation documented with magnetic resonance and computed tomography angiographies. Anatomic pathology reported both aortic valve and aorta with mucoid overload and elastic fibre depletion. These patients do have a risk of aortic root dilatation, which justifies periodic monitoring. Diagnosis must be made using indexed measures.

Thrombus of the Aorta and SARS-CoV-2 Infection: Cause or Trigger?

Objective: Coronavirus disease 19 is a well-established cause of rare arterial thrombosis. Nevertheless, the exact mechanism of arterial thrombosis remains to be elucidated. We herein report the case of a large floating thrombus of the aortic arch, its surgical management and histological analysis. Case: A 65-year-old patient presented to the emergency department with a suspected stroke. He was non-smoker, but presented cardiovascular risk factors, namely hypertension, type 2 diabetes and hyperlipidaemia. A computed tomography of the aorta revealed a large floating thrombus of the aortic arch, at the base of the brachiocephalic trunk, suspected to be the etiology of stroke. Therapeutic anticoagulation was immediately started. The decision was made to perform an open aortic replacement surgery because of the symptomatic thromboembolic event with recent cerebral infarction and the potential harmfulness of the thrombus due to its size. A mobile thrombus was observed at the base of the brachiocephalic trunk by echocardiography. It was attached to a small area of the upper aortic wall and had an irregular surface. Histology revealed a platelet-rich thrombus lying on an aortic atherosclerotic plaque without pronounced inflammation. No plaque ulceration was present but endothelial cell desquamation was observed consistent with plaque erosion. Conclusion: In our case, there was a thrombus lying on an atherosclerotic plaque with intact thick fibrous cap, but associated with a plaque erosion mechanism. The thrombus formation appeared more likely to relate to a very localized endothelial injury.

First-line latanoprost therapy in ocular hypertension or open-angle glaucoma patients: a 3-month efficacy analysis stratified by initial intraocular pressure.

BACKGROUND: Prospective, multicenter, randomized, double-masked trials have shown latanoprost instilled once daily to be at least as effective as and generally superior to timolol administered twice daily and to be as effective as other frequently prescribed prostaglandin analogues. This study prospectively assessed the efficacy of latanoprost monotherapy in a large cohort of treatment-naive patients with a broad range of baseline intraocular pressure (IOP) levels treated in actual clinical practice settings. METHODS: This prospective, open-label, multicenter, uncontrolled, phase IV study included treatment-naive ocular hypertension or open-angle glaucoma subjects initiating latanoprost once daily (evening). IOP levels were measured at baseline and after 1 and 3 months. The primary efficacy outcome was mean change in IOP from baseline to month 3. Analyses were stratified by baseline IOP: > or = 20 and <24 mmHg vs > or = 24 mmHg. RESULTS: Efficacy analyses (intent to treat) included 572 subjects: 20 to <24 mmHg group, N = 252; > or = 24 mmHg group, N = 320. Mean baseline IOP levels were 22.2 +/- 0.9 mmHg and 26.7 +/- 2.8 mmHg, respectively. At month 3, significant IOP reductions were seen in both groups (p < 0.0001, within-group differences); reductions were smaller in the 20 to <24 mmHg group (-6.3 +/- 2.4 vs -9.2 +/- 3.7 mmHg, respectively; -28.0 +/- 10.6% vs -34.1 +/- 11.9%, respectively). An IOP reduction of > or = 30% from baseline to month 3 was noted in 48.4% and 65.6% of subjects, respectively (p < 0.0001). At month 3, targets IOPs of < or = 18 mmHg were achieved by > or = 70% of subjects in both groups. Latanoprost was well tolerated with an adverse event profile similar to that reported in the literature. CONCLUSIONS: This "real world" study found once-daily latanoprost to be effective and safe in treatment-naive ocular hypertension or open-angle glaucoma patients. Patients with baseline IOP levels of 20 to <24 mmHg as well as > or = 24 mmHg benefitted from initial latanoprost therapy. TRIAL REGISTRATION NUMBER: NCT00647101.

Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease.

Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears.

Twelve-Month Results of Cyclosporine A Cationic Emulsion in a Randomized Study in Patients With Pediatric Vernal Keratoconjunctivitis.

PURPOSE: To assess the safety and efficacy of cyclosporine A cationic emulsion (CsA CE) 0.1% eye drops in pediatric patients with severe active vernal keratoconjunctivitis (VKC). DESIGN: Multicenter, double-masked, randomized controlled trial 8-month safety analysis. METHODS: Of 169 patients (age range, 4-17 years) initially randomized in the 4-month VErnal KeratoconjunctiviTIs Study (VEKTIS), 142 entered the 8-month follow-up period during which CsA CE patients remained on their original regimen (CsA CE 4 times daily [QID, high-dose] or CsA CE twice daily [BID, low-dose] + vehicle BID) and vehicle patients were allocated to one of these 2 active regimens. Main outcome measures were safety, including treatment-emergent adverse events, and efficacy, including corneal fluorescein staining (CFS) score. RESULTS: Improvements in CFS score, rescue medication use, key VKC symptoms (photophobia, tearing, itching, and mucous discharge), and quality of life (QoL) assessed by QUICK questionnaire observed with CsA CE compared with vehicle during the 4-month evaluation period remained stable during the 8-month follow-up period, with the high-dose regimen continuing to provide greater benefits in most efficacy measures. CsA CE was well tolerated. Treatment-related treatment-emergent adverse events during the 12-month study were reported in 15 (20.8%) and 11 (15.7%) of the CsA CE high-dose and low-dose patients, respectively, most commonly instillation site pain (13.9% and 7.1%, respectively). Laboratory data, vital signs, slit lamp examination, best-corrected distance visual acuity, and intraocular pressure raised no safety concerns. CONCLUSIONS: Improvements in keratitis, symptoms, and QoL achieved after CsA CE treatment for 4 months remained stable over the 8-month follow-up period. CsA continued to maintain a favorable safety profile.

Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies.

BACKGROUND/AIM: To assess the treatment effect of 0.1% ciclosporin A cationic emulsion (CsA CE) versus vehicle on signs/symptoms of dry eye disease (DED) in various subgroups (moderate-to-severe DED/severe DED/Sjögren's syndrome (SS)/SS with severe DED). METHODS: Pooled data were analysed from two similar phase III studies: SICCANOVE (moderate-to-severe DED) and SANSIKA (severe DED with severe keratitis). In both studies, patients aged ≥18 years received CsA CE 0.1% (n=395) or vehicle (n=339) once daily for 6 months. A composite responder efficacy endpoint (corneal fluorescein staining-Ocular Surface Disease Index (CFS-OSDI) at month 6) was used to evaluate the efficacy of CsA CE in alleviating signs/symptoms of DED (response defined as improvement of ≥2 grades in CFS and ≥30% in OSDI (baseline to month 6)). Human leucocyte antigen-DR (HLA-DR) conjunctival expression was used as a biomarker of ocular surface inflammation. RESULTS: CsA CE-treated patients were significantly more likely to be CFS-OSDI responders than vehicle-treated patients in the overall (OR 1.66, 95% CI 1.11 to 2.50; P=0.015), severe DED (1.80, 1.04 to 3.19; P=0.038) and SS with severe DED (3.37, 1.20 to 11.19; P=0.030) populations. The difference was not significant for CsA CE versus vehicle for the overall Sjögren's population (OR 1.77, CI 0.89 to 3.66; P=0.109). CsA CE also significantly reduced median HLA-DR expression versus vehicle at 6 months (P=0.002). CONCLUSION: Pooled phase III data indicate CsA CE produced significant improvement in signs/symptoms versus vehicle in patients with moderate-to-severe DED (especially in those with severe keratitis), including patients with SS with severe DED.

Topical ocular 0.1% cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program.

PURPOSE: The objective of this study was to report the evaluation of efficacy and safety of cyclosporine A cationic emulsion (CsA CE) 0.1% for the treatment of severe keratitis in adults with dry eye disease (DED) in a French early-access program. METHODS: Patients with DED and severe keratitis (corneal fluorescein staining [CFS] score of 3-5 on the Oxford scale and/or the presence of corneal lesions [filaments or ulcers]) were enrolled in a compassionate use program (Authorization for Temporary Use [ATU]) for once-daily CsA CE, which was approved by French health authorities prior to its registration. Efficacy and safety at 1, 3, 6, and 12-month follow-up visits were evaluated. RESULTS: The ATU cohort (n=1,212; mean age =60.5 years; 79.5% female; 98.1% with severe keratitis; 74.5% with corneal lesions) consisted of 601 CsA-naïve patients and 611 patients treated previously with other CsA formulations. The primary DED etiology was Sjögren's syndrome (48.7%). Clinical benefit could be discerned among 548 evaluable patients from months 1 to 12: keratitis improvement, 44.8% at month 1 and 42.1% at month 12; keratitis stabilization, 47.2% and 45.7%, respectively; symptom improvement, 47.2% and 48.6%; and symptom stabilization, 44.8% and 45.0%. Corneal clearing (CFS score =0) increased from 4.8% (month 1) to 11.4% (month 12). No unexpected safety concerns were identified; instillation site pain (10.2%) and eye irritation (7.8%) were the most common adverse events. CONCLUSION: The French ATU cohort provides supportive data on the clinical benefit of CsA CE in improving/stabilizing symptoms and corneal damage in DED patients with severe keratitis in real-world clinical practice.

Persistence of Efficacy of 0.1% Cyclosporin A Cationic Emulsion in Subjects with Severe Keratitis Due to Dry Eye Disease: A Nonrandomized, Open-label Extension of the SANSIKA Study.

PURPOSE: Results from a 6-month double-masked and a 6-month open-label study (SANSIKA) established the efficacy and safety of once-daily 0.1% cyclosporin A cationic emulsion (CsA CE) in severe keratitis due to dry eye disease (DED). This article presents results from the Post-SANSIKA study, a 24-month extension of SANSIKA assessing the sustained efficacy of CsA CE after treatment discontinuation. METHODS: Time to relapse (corneal fluorescein staining [CFS] score ≥4 [modified Oxford scale]) was assessed after treatment discontinuation in patients from the SANSIKA study who had CFS improvement from a score of 4 to ≤2 after 6 or 12 months of treatment with CsA CE. FINDINGS: Of 62 patients who achieved a CFS score ≤2 at the end of the SANSIKA study, 38 did not relapse and 24 (39%) relapsed during the 24-month period after CsA CE discontinuation; the latter (relapse) group comprised 35% of patients initially treated with CsA CE for 12 months in SANSIKA versus 47% of those treated for 6 months only. Patients spent the most time during the extension study at CFS scores of 1 or 2 (median duration of 8.5 weeks and 14.7 weeks per year, respectively), indicating marked improvement, and less time at scores of 3, 4, or 5 (median time, 2.0 weeks, 0 weeks, and 0 weeks per year). Of 23 patients eligible for safety analysis (ie, patients who received the study treatment at least once), 12 (52.2%) reported a total of 26 ocular adverse events (AEs). Among these, 5 ocular AEs, reported in 5 patients (21.7%), were considered related to study treatment: 3 events of mild instillation site pain in 3 patients (13.0%) and eye discharge and foreign body sensation, each reported in 1 patient (4.3%). Only 1 systemic AE (nasal congestion), reported in 1 patient (4.3%), was considered related to study treatment. None of the AEs led to treatment discontinuation. IMPLICATIONS: The majority of patients who discontinued CsA CE after experiencing DED improvement in the SANSIKA study did not experience a relapse in this 24-month follow-up study; these patients spent the most time at CFS scores consistent with marked improvement. CsA CE had a favorable safety/tolerability profile over 2 years. Treatment for up to 12 months with CsA CE provides sustained improvements in patients with severe keratitis due to DED. EudraCT registration no. 2012-002066-12.

Starr-Edwards aortic valve: 50+ years and still going strong: a case report.

The advent of the Starr-Edwards mechanical valve marked the beginning of the modern era for heart valve replacement. Nowadays, this valve has been supplanted by lower profile bileaflet mechanical prostheses that are considered to have better haemodynamics, lesser risk of thrombo-embolic complications, and longer durability without structural prosthesis failure. These assumptions often lead physicians to face with the question of systematically replacing functional Starr-Edwards valves in patients undergoing redo operations on other valves. We report the case of a 67-year-old patient who recently underwent mitral valve replacement for symptomatic rheumatic valve disease with an excellent outcome. During the operation, the Starr-Edwards valve in the aortic position implanted 51 years earlier was found to still functioning normally hence was left in place, thereby breaking a new longevity record for a valve prosthesis.

Relevance of Lipid-Based Products in the Management of Dry Eye Disease.

Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air-water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed.

Correlation Between the Inflammatory Marker HLA-DR and Signs and Symptoms in Moderate to Severe Dry Eye Disease.

Purpose: To investigate correlations of the inflammatory HLA-DR marker with clinical signs and symptoms commonly used to assess dry eye disease (DED) severity. Methods: Baseline data were collected from three clinical studies conducted on moderate to severe DED patients. Characteristics of DED were analyzed and correlations were performed in 311 patients. Data were analyzed after treatment with 1 mg/mL cyclosporine (CsA) and vehicle. We quantified HLA-DR by flow cytometry in impression cytology specimens. Results: We found HLA-DR significantly increased with diagnosis of Sjögren syndrome (P < 0.0001) and meibomian gland disease (P = 0.0223). The strongest significant correlation was seen with the corneal fluorescein staining (CFS, r = 0.30, P < 0.0001). Significant negative relationships were also found with Schirmer's test (r = -0.20, P = 0.0003) and tear break-up time (TBUT, r = -0.13, P = 0.0226). Correlations were statistically significant with total Ocular Surface Disease Index and visual analog scale scores (r = 0.12, P = 0.0426, and r = 0.14, P= 0.0176, respectively). We found HLA-DR arbitrary units of fluorescence were statistically reduced after CsA treatment compared to vehicle (P = 0.022 and P = 0.021 in two studies). Conclusions: In clinical research on DED, discrepancy is often observed between symptoms and signs. We found HLA-DR correlated significantly with CFS clinical signs and to a lower extent Schirmer's test and weakly with TBUT and symptom reporting questionnaires. HLA-DR was reported to be useful for monitoring anti-inflammatory efficacy treatments in DED, which was confirmed with the reduction of HLA-DR while on CsA treatment. Its expression by conjunctival cells has the potential to serve as a biomarker, bridging signs and symptoms in clinical research in DED, but there is still a need for additional validation studies.

One-Year Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease.

PURPOSE: The SANSIKA study evaluated the efficacy/safety of 0.1% (1 mg/mL) cyclosporine A cationic emulsion (CsA CE) for treating dry eye disease (DED) with severe keratitis. The double-masked phase demonstrated that CsA CE was effective in reducing corneal damage and ocular surface inflammation, and was well-tolerated over 6 months. Here we report efficacy and safety findings of SANSIKA's open-label extension (OLE). METHODS: In this multicenter, double-masked, phase III study, patients with severe DED (corneal fluorescein staining [CFS] grade 4, modified Oxford scale) were randomized to once-daily CsA CE (Ikervis®) or its vehicle for 6 months, followed by 6-month open-label, once-daily CsA CE (CsA CE/CsA CE and vehicle/CsA CE groups). RESULTS: A total of 177 patients completed the OLE. Efficacy results reiterated the double-masked phase: CsA CE reduced CFS score and human leukocyte antigen-antigen D related expression, improved corneal clearing, and produced continuous improvements in global symptom scores (ocular surface disease index [OSDI], visual analogue scale). The CFS-OSDI response rates (≥2 CFS points, ≥30% OSDI improvement vs baseline) at 12 vs 6 months were 39.1% vs 28.6%, respectively, for CsA CE/CsA CE and 38.0% vs 23.1% for vehicle/CsA CE. Cyclosporine A CE's safety profile was similar to the initial 6 months. The most common treatment-related treatment-emergent adverse event was instillation site pain (7.8%, CsA CE/CsA CE group; 19.0%, vehicle/CsA CE group). No unexpected safety signals were observed; systemic CsA levels were undetectable/negligible in all patients except 2 previously treated with systemic CsA. CONCLUSIONS: In this 12-month study, once-daily CsA CE was well-tolerated and showed reductions in ocular surface inflammation and improvements in signs/symptoms in DED patients with severe keratitis.

A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye.

PURPOSE: The SICCANOVE study aimed to compare the efficacy and safety of 0.1% cyclosporine A cationic emulsion (CsA CE) versus vehicle in patients with moderate to severe dry eye disease (DED). METHODS: In this multicenter, double-masked, parallel-group, controlled study, patients were randomized (1:1) to receive CsA CE (Ikervis®) or vehicle for 6 months. The co-primary efficacy endpoints at month 6 were mean change from baseline in corneal fluorescein staining (CFS; modified Oxford scale) and in global ocular discomfort (visual analogue scale [VAS]). RESULTS: The mean change in CFS from baseline to month 6 (CsA CE: n = 241; vehicle: n = 248) was significantly greater with CsA CE than with vehicle (-1.05 ± 0.98 and -0.82 ± 0.94, respectively; p = 0.009). Ocular discomfort improved similarly in both groups; however, the percentage of patients with ≥25% improvement in VAS was significantly higher with CsA CE (50.2%) than with vehicle (41.9%; p = 0.048). In a post hoc analysis of patients with severe ocular surface damage (CFS score 4) at baseline (CsA CE: n = 43; vehicle: n = 42), the percentage of patients with improvements of ≥2 grades in CFS score and ≥30% in Ocular Surface Disease Index score was significantly greater with CsA CE (p = 0.003). Treatment compliance and ocular tolerability were satisfactory and as expected for CsA use. CONCLUSION: Cyclosporine A CE was well-tolerated and effectively improved signs and symptoms in patients with moderate to severe DED over 6 months, especially in patients with severe disease, who are at risk of irreversible corneal damage.

Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial.

PURPOSE: The SANSIKA study was conducted to assess the treatment effect of 0.1% cyclosporine A cationic emulsion (CsA CE) eye drops on signs and symptoms of patients with severe dry eye disease (DED). METHODS: This was a multicenter, randomized, double-masked, 2-parallel-arm, 6-month phase III study with a 6-month open-label treatment safety follow-up. Patients with severe DED with corneal fluorescein staining (CFS) grade 4 on the modified Oxford scale were randomized to receive once-daily CsA CE (Ikervis®) or its vehicle. RESULTS: A total of 246 patients were randomized. The proportion of patients achieving ≥2 grades improvement in CFS and a 30% improvement in symptoms (Ocular Surface Disease Index [OSDI]) by month 6 was 28.6% with CsA CE vs 23.1% with vehicle (p = 0.326) (primary endpoint). Assessment of corneal damage showed greater improvement with CsA CE over vehicle in mean adjusted CFS change from baseline to month 6 (-1.764 vs -1.418, p = 0.037). There was a reduction in ocular surface inflammation assessed by human leukocyte antigen DR expression in favor of CsA CE at month 6 (p = 0.021). The mean OSDI change from baseline was -13.6 with CsA CE and -14.1 with vehicle at month 6 (p = 0.858). The main adverse event was instillation site pain (29.2% vs 8.9% in the CsA CE and vehicle groups, respectively), and it was mostly mild. CONCLUSIONS: CsA CE was well-tolerated and effective in improving corneal damage and ocular surface inflammation and confirmed the positive benefit-risk ratio of this new formulation of CsA for the treatment of severe keratitis in DED.

Efficacy and safety of a cationic emulsion in the treatment of moderate to severe dry eye disease: a randomized controlled study.

PURPOSE: To evaluate the efficacy and safety of a preservative-free cationic emulsion (CE) with a 0.18% hyaluronate sodium (HS) solution in patients with moderate to severe dry eye disease (DED) with keratitis or keratoconjunctivitis. METHODS: Eighty-five patients were randomized (1:1) in this multicenter, prospective, reference-controlled, parallel-group, investigator-masked study to receive CE (n = 44) or HS (n = 41). Clinical signs and symptoms were assessed over 3 months. The primary efficacy endpoint was noninferiority of CE to HS in change from baseline of ocular surface staining (OSS) score at 1 month. RESULTS: In the per protocol (PP) set and full analysis set (FAS), CE showed a similar and noninferior (p<0.0001) improvement in OSS scores compared with HS at 1 month (PP: -2.5 ± 1.3 vs -1.9 ± 1.6; FAS: -2.2 ± 1.5 vs -2.0 ± 1.8 for CE vs HS). Other clinical signs of DED similarly improved in both groups. In the FAS, global symptoms score of ocular discomfort was significantly better with CE compared with HS at 1 month (-14.8 ± 17.3 vs -7.6 ± 14.2; p = 0.0469), including greater alleviation of itching (-14.8 ± 21.2 vs -1.7 ± 19.7; p = 0.0100) and eye dryness (-21.9 ± 28.3 vs -8.4 ± 21.4; p = 0.0016). Similar trends were observed at 3 months for itching and eye dryness. Investigator global efficacy assessment and quality of life scores for eye pain and driving favored CE at 3 months. Incidence of adverse events was low in both treatment groups. CONCLUSIONS: CE was similar to HS with regards to safety and efficacy for objective signs but was superior to HS in improving DED symptoms in patients with moderate to severe DED.