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).
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.
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.
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.
Eur J Ophthalmol 2016; 26(4): 287 - 296
Article Type: ORIGINAL RESEARCH ARTICLE
Article Subject: Cornea
AuthorsAndrea Leonardi, Gysbert Van Setten, Mourad Amrane, Dahlia Ismail, Jean-Sebastien Garrigue, Francisco C. Figueiredo, Christophe Baudouin
- • Accepted on 18/02/2016
- • Available online on 07/04/2016
- • Published in print on 10/06/2016
This article is available as full text PDF.
Dry eye is one of the most common ophthalmic diseases, with a prevalence ranging from 5% to 35% (1). The term dry eye disease (DED) describes a multifactorial disease of the lacrimal functional unit that is associated with increased osmolarity of the tear film and inflammation of the ocular surface (2). Tear hyperosmolarity, resulting from reduced aqueous tear flow and/or increased evaporation, drives a vicious cycle of DED pathology. Tear hyperosmolarity causes apoptosis of cells of the conjunctiva and cornea while also triggering inflammatory cascades that contribute to further cell apoptosis and altered mucin production. This in turn exacerbates tear film instability, leading to more tear hyperosmolarity (3).
Individuals with DED experience eye symptoms including irritation, pain, dryness, foreign body sensation, and visual disturbance (1). The severe form of the disease is characterized by persistent and recurrent symptoms that are known to poorly correlate with the objective clinical findings (4-5-6-7-8). For instance, patients with severe DED may present with decreased symptoms of discomfort, potentially due to downregulation of corneal sensory receptors (7).
Treatment strategies for DED have largely been restricted to instillation of various artificial tear formulations, which typically provide only short-term relief from DED symptoms (9). Despite the fact that topical steroids have shown some promise for improving the signs and symptoms of DED, their potential benefit is limited by their known iatrogenic ocular side effects (such as intraocular hypertension and cataract) and are thus not recommended for long-term use (10, 11). A therapeutic approach that has received increased attention in recent years is inhibition of the inflammatory responses associated with DED through the use of anti-inflammatory compounds such as cyclosporine A (CsA). Restasis® (Allergan, Inc., Irvine, CA, USA), an anionic oil-in-water emulsion incorporating CsA (0.05%), was approved by the US Food and Drug Administration in 2003 to treat patients with keratoconjunctivitis sicca (12). In Europe, there is currently no medicinal product that has been approved for treatment of DED; however, Santen SAS (Evry, France) has developed a cationic emulsion formulation containing 0.1% (1 mg/mL) CsA (CsA CE) for the topical treatment of severe forms of immune-mediated ocular surface diseases such as DED. This product was registered in 2015 in the European Union for the treatment of severe keratitis in adult patients with DED that has not improved despite treatment with tear substitutes (13). In contrast with Restasis®, CsA CE is a cationic emulsion, the instillation of which results in a long-lasting presence of CsA in the tear film over the entire surface of the eye (14-15-16). The ocular bioavailability of CsA with the CsA CE formulation is, therefore, higher than with previous CsA formulations (16).
Patients with DED with severe keratitis have an increased risk of infection, vision loss, and impaired quality of life (1). Preclinical and clinical testing of CsA CE has demonstrated a positive benefit-risk ratio in this specific patient population. A phase III confirmatory trial was conducted in patients with severe DED to demonstrate the superiority of CsA CE over its vehicle in simultaneously improving signs and symptoms after 6 months of treatment. In addition, the overall ocular safety of CsA CE was assessed after 6 and 12 months of treatment.
Patients included in this study were male and female patients with severe DED aged 18 and older. Eligible patients were those having corneal fluorescein staining (CFS) graded 4 on the modified Oxford scale (from 0 to 5) (17), a Schirmer test score ≥2 mm/5 min and <10 mm/5 min (18), and an Ocular Surface Disease Index (OSDI) score ≥23 (19).
This study involved a 6-month, multicenter, randomized, double-masked, vehicle-controlled, parallel-group period, followed by a 6-month open-label follow-up period. The study was conducted in 50 centers in 9 European countries (France, Germany, Italy, Spain, Belgium, United Kingdom, Sweden, Austria, and the Czech Republic).
Patients initially underwent a 2-week washout period during which any ongoing ophthalmic treatments were stopped and unpreserved artificial tears (AT) were provided by the sponsor for use as frequently as required throughout the study (saline solution, Larmabak®, Théa, Clermont-Ferrand, France). Patients were randomized to receive one drop once daily at bedtime of CsA CE (Ikervis®) unpreserved single-dose cationic emulsion eyedrops (Santen SAS) or its vehicle for 6 months, according to a 2:1 allocation ratio. During the open-label phase (the last 6 months), all patients received CsA CE. Treatment efficacy and safety were assessed at the end of the 6-month randomized period; safety was also assessed at 12 months following the 6-month open-label period. Intermediate visits also occurred at months 1, 3, and 9.
All enrolled patients provided written informed consent, and the study was conducted in accordance with the principles of Good Clinical Practice and with the ethical principles set out in the Declaration of Helsinki. This study was registered under the following number in the EudraCT database: 2011-000160-97 with the protocol code number NVG10E117 (20).
Efficacy was only determined in the analysis eye, defined as the worst eligible eye.
The same eye (eligible eye) had to fulfill all the applicable aforementioned selection criteria (CFS of 4, Schirmer test score ≥2 mm/5 min and <10 mm/5 min, and OSDI score ≥23). The analysis eye was the eligible eye with the higher lissamine green staining score (17) at baseline. If both eyes had the same lissamine green staining score, the eye with the worse Schirmer test score at baseline was used. If both eyes had the same Schirmer test score, the right eye was used.
To assess the efficacy of CsA CE, both objective (signs) and subjective (symptoms) parameters were examined. Objective assessments included CFS, Schirmer test (without anesthesia), tear break-up time (TBUT) (18), lissamine green conjunctival staining using the Van Bijsterveld scale, tear film osmolarity, and human leukocyte antigen DR (HLA-DR) expression on the conjunctival cell surface by impression cytology (21-22-23). Subjective assessments included OSDI, visual analogue scale (VAS) of ocular discomfort, use of concomitant AT, investigator’s global evaluation of efficacy, and National Eye Institute Visual Function Questionnaire (NEI-VQF-25).
Safety was assessed by best-corrected distance visual acuity (BCDVA) and intraocular pressure (IOP) in both eyes, blood sampling for CsA levels, vital signs (blood pressure, pulse rate, and respiratory rate), ocular/systemic adverse events (AEs), and slit-lamp examination of both eyes.
The primary efficacy endpoint of this study was the combined CFS-OSDI responder rate at month 6. A CFS-OSDI responder was defined as a subject displaying an improvement of ≥2 grades in CFS from baseline and an improvement of ≥30% in OSDI from baseline. This endpoint was analyzed on the full analysis set (FAS) using imputed data with a logistic regression model (factors “treatment” and “pooled country”). The FAS comprised all patients randomized into the study who received any amount of the study drug and were analyzed according to randomized treatment (intention-to-treat principle). Missing data were imputed as follows. Patients who discontinued treatment before month 6 were considered nonresponders if discontinuation was due to lack of efficacy, lack of tolerance, or change in dry eye therapy. Patients who discontinued before month 1, or who did not discontinue before month 6 but for whom month 1, month 3, and month 6 evaluations were missing, were also considered as nonresponders. If the patient discontinued before month 6 due to a reason other than those specified above, a last observation carried forward (LOCF) procedure was used (carrying forward the month 3 or month 1 evaluation). The LOCF was also used if a patient did not discontinue before month 6 but for whom the evaluation was missing.
Sensitivity analyses were also performed for the primary efficacy endpoint using the primary logistic model on the per-protocol set (PPS), on the FAS using observed data only, and on the FAS considering the actual treatment received and using a Cochran-Mantel-Haenszel (CMH) test controlling for pooled country. The PPS excluded FAS patients with any major protocol deviation.
Further efficacy endpoints were analyzed on the FAS and the PPS. The CFS, OSDI, global VAS, and combined CFS-VAS responder rates and complete corneal clearing rate were analyzed using the logistic model described above. Analysis of CFS, OSDI, global VAS, and lissamine green score change from baseline was performed using a repeated-measures analysis of variance with the following fixed factors: treatment, visit, pooled country, and treatment by visit interaction. Schirmer test, TBUT, NEI-VQF-25, HLA-DR expression, and tear film osmolarity were analyzed using an analysis of covariance model with the fixed factors treatment and pooled country, and the corresponding baseline data as covariate. A supportive analysis was conducted using a CMH test stratified on pooled country. This test was also used to analyze the investigator global evaluation of efficacy.
Sample size calculations were based on the results of a previous phase III study performed in patients with moderate to severe DED (24). The expected CFS-OSDI responder rates at 6 months were 28% and 10% with CsA CE and its vehicle, respectively. Setting the risk α at 5% and the power at 90%, around 225 evaluable patients were needed (150 in the CsA CE group and 75 in the vehicle group) to detect a significant difference between groups. Accounting for nonevaluable patients (approximately 10%), a total of 252 patients were to be recruited.
The safety analysis set was used for reporting safety data; this included all randomized patients for whom there was any evidence they used study medication and for whom any follow-up data were available. Safety analyses were performed using the actual treatment received.
Among the 313 patients who were screened, 261 patients were randomized to receive treatment. A total of 245 patients, 154 in the CsA CE group and 91 in the vehicle group, were included in the full analysis set. The participant flow chart diagram from screening until the completion of the study is summarized in
Baseline demographic characteristics
|CsA CE (n = 154)||Vehicle (n = 91)||Total (n = 245)|
|CsA CE = 0.1% cyclosporine A cationic emulsion.|
|Data represent the full analysis set population.|
|Age, y||n = 154||n = 91||n = 245|
|Mean (SD)||60.8 (13.5)||62.1 (11.8)||61.3 (12.9)|
|Median (min, max)||61.7 (22.9, 87.6)||63.5 (32.7, 86.3)||62.5 (22.9, 87.6)|
|Sex||n = 154||n = 91||n = 245|
|Female, n (%)||126 (81.8)||83 (91.2)||209 (85.3)|
|Male, n (%)||28 (18.2)||8 (8.8)||36 (14.7)|
|Sjögren syndrome||n = 154||n = 91||n = 245|
|Number (%) of patients||58 (37.7)||34 (37.4)||92 (37.6)|
|Time since diagnosis, y||n = 153||n = 91||n = 244|
|Mean (SD)||8.8 (7.1)||9.7 (6.7)||9.1 (7.0)|
|Median (min, max)||6.2 (0.2, 31.5)||8.7 (0.2, 30.7)||6.8 (0.2, 31.5)|
Patient flow during the SANSIKA study. aReason for nonretention was major breach to good clinical practice. bDuring the study, 3 patients were dispensed the incorrect treatment: 1 patient randomized to 0.1% cyclosporine A cationic emulsion (CsA CE) received vehicle and 2 patients randomized to vehicle received CsA CE. One patient did not take any study medication and was excluded from the full analysis set (FAS). Thus, the FAS consists of 245 patients: 154 in the CsA CE group and 91 in the vehicle group. AE = adverse event; SAF = safety analysis set; TEAE = treatment-emergent adverse event (defined as an event that started on or after the date of the first study drug dose).
The results presented below are limited to the double-masked comparative study period.
CFS-OSDI responder rate
This analysis shows no statistically significant difference in the CFS-OSDI responder rate between treatment groups at 6 months (
Responder rates in key efficacy variables after 6 months of randomized treatment with CsA CE or vehicle
|CsA CE (n = 154)||Vehicle (n = 91)||p Valuea|
|CFS = corneal fluorescein staining graded on a scale from 0 to 5; CsA CE = 0.1% cyclosporine A cationic emulsion; OSDI = Ocular Surface Disease Index questionnaire; VAS = global visual analogue scale assessment of ocular discomfort.|
|Data represent imputed data on the full analysis set population. Values are n (%).|
|a p Value for treatment effect in the logistic regression model.|
|CFS-OSDI response (improvement ≥2 grades [CFS] and 30% [OSDI])|
|Responders||44 (28.6)||21 (23.1)||0.326|
|CFS response (improvement ≥2 grades)|
|Responders||80 (51.9)||41 (45.1)||0.346|
|OSDI response (improvement ≥30%)|
|Responders||61 (39.6)||36 (39.6)||0.939|
|VAS response (improvement ≥30%)|
|Responders||48 (31.2)||34 (37.4)||0.302|
|CFS-VAS response (improvement ≥2 grades [CFS] and 30% [VAS])|
|Responders||35 (22.7)||19 (20.9)||0.744|
|Complete corneal clearing (CFS = 0)|
|Yes||10 (6.5)||4 (4.4)||0.428|
To detect a potential treatment effect on patients showing a marked improvement in CFS over 6 months, a post hoc analysis of the primary efficacy endpoint was undertaken that increased the threshold for improvement of CFS to 3 grades instead of 2 (
Corneal fluorescein staining (CFS)-Ocular Surface Disease Index (OSDI) response rates after 6 months of randomized treatment with 0.1% cyclosporine A cationic emulsion (CsA CE) or vehicle in patients showing a marked improvement in CFS of 3 grades or higher and at least 30% improvement in OSDI. Data represent the imputed data according to the randomized treatment group and the full analysis set population. Comparison between groups was performed using a logistic regression model.
Corneal fluorescein staining
There was a statistically significant improvement in CFS score over time (main effect of time: p<0.001) in patients receiving either CsA CE or vehicle (
Change in corneal fluorescein staining (CFS) over 6 months of randomized treatment with 0.1% cyclosporine A cationic emulsion (CsA CE) or vehicle. Data represent mean CFS values ± standard error of the full analysis set population. Sample size at baseline and months 1, 3, and 6: 154, 149, 140, and 132, respectively, with CsA CE, and 91, 88, 89, and 83, respectively, with vehicle. Comparison between groups was performed using a repeated-measures analysis of variance.
The likelihood of CFS improvement by at least 3 grades within 6 months of treatment (post hoc analysis) was approximately 3 times higher with CsA CE than with vehicle (odds ratio 3.3, 95% CI 1.6, 7.0), with 35.6% of the patients reaching grade 1 or less in the CsA CE group compared with 14.5% in the vehicle group (p = 0.001).
The effect of treatment on inflammation at the conjunctival cell surface was determined by using HLA-DR expression as a biomarker. The decrease in the level of HLA-DR expression from baseline quantified in arbitrary units of fluorescence (AUF) was greater with CsA CE than with vehicle (
Change in human leukocyte antigen DR (HLA-DR) expression over 6 months of randomized treatment with 0.1% cyclosporine A cationic emulsion (CsA CE) or vehicle. Data represent median HLA-DR expression values of the full analysis set population. Comparison between groups was performed using an analysis of covariance model, after logarithmic transformation.
Tear film osmolarity
A trend of improvement in both groups was found without statistical difference between groups.
Following experts’ recommendations, tear film osmolarity was analyzed post hoc in patients with baseline levels >308 mOsm/L (considering the worst value between both eyes), a threshold known to be indicative of DED (25). A total of 55 patients met this criterion, 34 (22.1%) in the CsA CE group and 21 (23.1%) in the vehicle group, and the mean osmolarity value was similar between these subgroups. Although there was an improvement in the worst tear film osmolarity over time in both subgroups, the CsA CE subgroup showed a significantly greater change from baseline at month 6 than the vehicle subgroup (p = 0.048), with the mean and median values of worst tear film osmolarity in the CsA CE subgroup lower than 308 mOsm/L, whereas they remained slightly higher than this threshold in the vehicle subgroup (
Change in worst tear film osmolarity between both eyes in patients with >308 mOsm/L at baseline over 6 months of randomized treatment with 0.1% cyclosporine A cationic emulsion (CsA CE) or vehicle. Data represent mean values ± standard error of a subgroup of the full analysis set population. Means were adjusted for baseline values using an analysis of covariance model with “treatment” and “pooled country” as fixed factors and the baseline data as covariate. aOsmolarity ranges taken from Lemp et al (25).
Other efficacy analyses
The CFS, OSDI, VAS, and CFS-VAS responder rates and complete corneal clearing rate at month 6 are presented in
Secondary efficacy assessments: change from baseline after 6 months of randomized treatment with CsA CE or vehicle
|CsA CE (n = 154)||Vehicle (n = 91)||p Value|
|CI = confidence interval; CsA CE = 0.1% cyclosporine A cationic emulsion; OSDI = Ocular Surface Disease Index questionnaire; VAS = global visual analogue scale assessment of ocular discomfort.|
|Data represent the full analysis set population. Global VAS assessment was measured on a 0%-100% scale. Because the patient was asked to rate each ocular symptom by placing a vertical mark on a 100-mm horizontal line, data were recorded in mm rather than % (with 1 mm = 1%).|
|a Adjusted means were obtained using a repeated-measures analysis of variance model with the following fixed factors: treatment, visit, pooled country, and treatment by visit interaction.|
|b Values obtained at screening are considered baseline values.|
|c The p value of the nonparametric Cochran-Mantel-Haenszel test was considered instead of the analysis of covariance p value because the distribution of the residuals was not normal (as evaluated by the Shapiro-Wilk test).|
|Baseline||n = 154||n = 91|
|Mean ± SD||61.4 ± 19.4||58.8 ± 18.4|
|Median (min, max)||62.5 (25.0, 100.0)||58.3 (25.0, 100.0)|
|Change at month 6||n = 131||n = 82|
|Mean ± SD||-14.4 ± 21.1||-13.3 ± 18.8|
|Adjusted mean (95% CI)a||-13.6 (-17.0, -10.0)||-14.1 (-18.6, -9.5)|
|Median (min, max)||-14.6 (-79.2, 45.6)||-13.6 (-60.4, 32.5)||0.858|
|Global VAS assessment (mm)|
|Baseline||n = 145||n = 85|
|Mean ± SD||55.6 ± 20.6||54.5 ± 18.5|
|Median (min, max)||55.1 (5.0, 98.0)||52.5 (16.9, 92.5)|
|Change at month 6||n = 120||n = 75|
|Mean ± SD||-13.0 ± 22.7||-10.5 ± 21.6|
|Adjusted mean (95% CI)a||-12.1 (-16.1, -8.2)||-11.2 (-16.3, -6.1)|
|Median (min, max)||-11.1 (-59.8, 66.6)||-10.4 (-59.5, 38.5)||0.766|
|Schirmer test, mm/5 min|
|Screeningb||n = 154||n = 91|
|Mean ± SD||3.7 ± 2.0||3.9 ± 2.2|
|Median (min, max)||3.0 (2.0, 9.0)||3.0 (2.0, 9.0)|
|Change at month 6||n = 141||n = 82|
|Mean ± SD||2.2 ± 5.7||1.5 ± 4.3|
|Median (min, max)||1.0 (-7.0, 32.0)||1.0 (-5.0, 19.0)||0.604c|
Change in Schirmer test (
Lissamine green conjunctival staining, TBUT, and NEI-VFQ-25 data (
Other efficacy assessments: change from baseline after 6 months randomized treatment with CsA CE or vehicle
|CsA CE (n = 154)||Vehicle (n = 91)||p Value|
|CI = confidence interval; CsA CE = 0.1% cyclosporine A cationic emulsion; NEI-VFQ-25 = National Eye Institute Visual Function Questionnaire; TBUT = tear break-up time.|
|Data represent the full analysis set population.|
|a Data presented do not include data from patients for whom investigators were not able to perform the lissamine green examination correctly.|
|b Adjusted means were obtained using a repeated-measures analysis of variance model with the following fixed factors: treatment, visit, pooled country, and treatment by visit interaction.|
|c The p value of the nonparametric Cochran-Mantel-Haenszel test was considered instead of the analysis of covariance (ANCOVA) p value because the distribution of the residuals was not normal (as evaluated by the Shapiro-Wilk test).|
|d Means were adjusted for baseline values using an ANCOVA model with the fixed factors treatment and pooled country and the baseline data as covariate.|
|Lissamine green staininga|
|Baseline||n = 134||n = 79|
|Mean ± SD||4.5 ± 2.1||4.6 ± 2.2|
|Median (min, max)||4.0 (0.0, 9.0)||5.0 (0.0, 9.0)|
|Change from baseline at month 6||n = 114||n = 71|
|Mean ± SD||-1.7 ± 2.1||-1.5 ± 2.2|
|Adjusted mean (95% CI)b||-1.7 (-2.1, -1.267)||-1.4 (-1.9, -0.9)||0.411|
|Median (min, max)||-2.0 (-6.0, 4.0)||-1.0 (-9.0, 5.0)|
|Baseline||n = 154||n = 91|
|Mean ± SD||3.3 ± 1.6||3.5 ± 1.7|
|Median (min, max)||3.0 (1.0, 7.3)||3.0 (0.0, 8.5)|
|Change from baseline at month 6||n = 131||n = 83|
|Mean ± SD||0.8 ± 2.1||0.3 ± 1.8||0.298c|
|Median (min, max)||0.5 (-5.0, 8.7)||0.0 (-4.5, 7.8)|
|Tear film osmolarity, mOsm/L|
|Baseline||n = 57||n = 34|
|Mean ± SD||308.1 ± 20.9||305.6 ± 15.5|
|Median (min, max)||305.0 (276.0, 366.0)||303.5 (275.0, 339.0)|
|Change from baseline at month 6||n = 40||n = 30|
|Mean ± SD||-3.3 ± 28.3||-5.8 ± 18.0||0.763b|
|Median (min, max)||-3.0 (-61.0, 118.0)||-7.5 (-38.0, 39.0)|
|NEI-VFQ-25 composite score|
|Baseline||n = 98||n = 55|
|Mean ± SD||71.9 ± 15.74||74.0 ± 13.4|
|Median (min, max)||72.9 (11.9, 96.4)||75.8 (43.0, 96.6)|
|Change from baseline at month 6||n = 73||n = 46|
|Mean ± SD||5.2 ± 8.9||4.8 ± 9.9|
|Adjusted mean (95% CI)d||4.1 (1.9, 6.2)||4.0 (1.3, 6.6)||0.945|
|Median (min, max)||4.7 (-15.7, 32.3)||5.0 (-21.2, 24.7)|
A summary of the treatment-emergent AEs (TEAEs) recorded during this study can be found in supplementary
Blood sampling revealed that 4 patients treated with CsA CE had measurable CsA levels that were below the upper limit of quantification (≤5 ng/mL), which is considered negligible. Three patients treated with CsA CE had CsA concentrations >5 ng/mL, but these patients were receiving systemic CsA treatment (allowed according to the clinical protocol provided that the treatment remained stable throughout the course of the study). There were no remarkable changes in BCDVA, IOP, or vital signs. No differences were detected between treatments using slit-lamp examination. Safety analyses over 12 months were performed on the 154 patients who received any amount of CsA CE treatment during this time period. Of these patients, 114 (74%) completed the 6-month open-label phase and were thus exposed to CsA CE for 12 months. The safety profile of CsA CE over 12 months was similar to the 6-month treatment profile (supplementary
The primary objective of this study was to demonstrate the superiority of CsA CE over vehicle in simultaneously improving signs (CFS) and symptoms (OSDI) in patients with severe DED, defined as patients with CFS score of 4 on the modified Oxford scale, Schirmer test score ≥2 mm/5 min and <10 mm/5 min, and OSDI score ≥23, after 6 months of treatment. Although treatment with CsA CE over 6 months was associated with a significant increase in the CFS-OSDI responder rate, a substantial improvement was also observed in patients receiving vehicle treatment, and no statistical difference was detected between groups. Further efficacy analyses revealed a similar trend of improvement in both signs and symptoms of DED in patients treated with either CsA CE or vehicle. For instance, the OSDI improvement in both groups after 6 months was 14 points on average, which can be considered clinically relevant since it is above the minimal clinically important difference described by Miller and colleagues in 2010, which ranges between 7.3 and 13.4 in severe disease (26).
The fact that the superiority of CsA CE over vehicle did not reach statistical significance in the primary endpoint, nor in most of the other efficacy endpoints, may be explained by the ability of the vehicle to improve DED symptoms on its own (5, 27). The vehicle, an unpreserved cationic oil-in-water nanoemulsion, increases the retention time of nanodroplets on the ocular surface by interacting electrostatically with the negatively charged components of the tear film. This property improves drug delivery but also enhances film hydration, lubrication, and stability (14, 16, 28). Additionally, efficacy endpoints assessing a concomitant improvement in both signs and symptoms may have been affected by the well-documented weak correlation between signs and symptoms in DED (4, 6, 7). The subjective nature of symptom severity and decreased corneal sensation in severe DED may explain the difficulty in reaching statistical significance in the primary endpoint (6, 29).
Due to the variable and multifactorial nature of the disease, the required length of treatment may vary between individual patients with DED (7, 18), which may also contribute to the difficulty of efficacy evaluation using the combined signs and symptoms endpoint. However, it should be noted that preclinical evaluations of CsA CE demonstrated maximal corneal and conjunctival CsA penetration at the concentration and posology used in this study (14).
There was a clear trend of greater improvement in patients receiving once-daily CsA CE compared with vehicle in most efficacy assessments. The superiority of CsA CE over vehicle reached statistical significance with regard to improvement in the quality of the corneal surface (CFS score) and the reduction of ocular surface inflammation (HLA-DR expression). The benefit of CsA CE treatment over vehicle in reducing corneal staining (CFS) over time was evident as early as month 3, and the difference between groups at month 6 of 0.35 represents, on average, 50% more corneal staining in the vehicle group compared with the CsA CE group, which is considered clinically relevant. A significant decrease in HLA-DR expression (quantified in AUF) was evident in the CsA CE group even after only 1 month of treatment. Conversely, vehicle treatment had almost no effect on this inflammatory biomarker over 6 months. The effect of CsA CE in this respect is most likely associated with the well-established anti-inflammatory properties of CsA (21, 23, 30-31-32-33-34-35). In this study, HLA-DR expression was also assessed using percentage of HLA-DR+ cells. The results showed no difference between groups due to the fact that this analysis cannot discriminate a population with a high fluorescence expression from another with a low fluorescence.
Post hoc data analyses provided further support for the superiority of CsA CE over vehicle in the treatment of DED. When considering patients showing a marked improvement in CFS of 3 grades instead of 2 (as was specified in the primary efficacy endpoint), there was a statistically significant difference in the CFS-OSDI responder rate between treatment groups. Additionally, when considering tear film osmolarity in the subgroup of patients who had a baseline value greater than the commonly accepted threshold indicative of DED (25), the CsA CE subgroup showed a significantly greater improvement than the vehicle subgroup.
The CsA CE was generally found to be well-tolerated in most patients, with no systemic findings that could suggest systemic absorption of cyclosporine. Apart from brief instillation site pain, which was more common in patients treated with CsA CE, there were no clear trends for an increased incidence of any ocular TEAE with either treatment. Furthermore, no detrimental effects on visual acuity, IOP, or vital signs were observed.
In conclusion, in the present study, CsA CE (Ikervis®)—a novel formulation of unpreserved single-dose cationic emulsion of cyclosporine 0.1%—was well-tolerated and effective in improving corneal surface damage and ocular surface inflammation. These benefits were achieved with a single daily instillation, which, compared with other DED treatments that require multiple instillations for efficacy, may reduce patient burden and improve quality of life (1). This study confirms the positive benefit-risk ratio of once-daily administration of Ikervis® in the treatment of severe keratitis in patients with severe DED.
The authors thank Pr. Françoise Brignole-Baudouin and Luisa Riancho for analyses and interpretation of HLA-DR results; Maëva Deniaud (MD Stat consulting) for statistical and methodology advice; Pr. Michael Lemp for help in study design; Scinopsis for medical writing support; and Chameleon Communications International for medical copyediting support.
Eudra CT A Multicenter, Randomized, Double-masked, 2 Parallell arm, Vehicle Controlled, 6-month Phase III Trial With a 6 Month Open Label Treatment Safety Follow-up Period to Evaluate The Efficacy and Safety of Cyclokat® 1mg/mL (Ciclosporin/Cyclosporine) Eye Drops, Emulsion Administered Once Daily in Adult Patients With Severe Dry Eye Disease (DED). Available at https: //www.clinicaltrialsregister.eu/ctr-search/trial/2011-000160-97/DE.Accessed October 5 2015.
Eudra CT A Phase III, Multicenter, Randomized, Controlled, Double-Masked Trial of NOVA22007 (Ciclosporin 0.1%) Ophthalmic Cationic Emulsion versus Vehicle in Patients with Moderate to Severe Dry Eye Syndrome. Available at https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-000029-23+. Accessed October 5, 2015.
- Leonardi, Andrea [PubMed] [Google Scholar] 1, * Corresponding Author (email@example.com)
- Van Setten, Gysbert [PubMed] [Google Scholar] 2
- Amrane, Mourad [PubMed] [Google Scholar] 3
- Ismail, Dahlia [PubMed] [Google Scholar] 3
- Garrigue, Jean-Sebastien [PubMed] [Google Scholar] 3
- Figueiredo, Francisco C. [PubMed] [Google Scholar] 4
- Baudouin, Christophe [PubMed] [Google Scholar] 5, 6, 7
Department of Neuroscience, Ophthalmology Unit, University of Padua, Padua - Italy
St. Eriks Eye Hospital, Stockholm - Sweden
Santen SAS, Evry - France
Royal Victoria Infirmary, Newcastle University, Newcastle upon Tyne - UK
Quinze-Vingts National Ophthalmology Hospital, Paris - France
UPMC University, Paris 6, Vision Institute, INSERM UMRS968, CNRS UMR7210, Paris - France
University of Versailles Saint-Quentin en Yvelines, Versailles - France
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