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EJO

ISSN 1120-6721
Eur J Ophthalmol 2017; 00 (00): 000-000
DOI: 10.5301/EJO.5000952

ORIGINAL RESEARCH ARTICLE

A randomized study of the efficacy and safety of 0.1%
cyclosporine A cationic emulsion in treatment of
moderate to severe dry eye
Christophe Baudouin1-3, Francisco C. Figueiredo4, Elisabeth M. Messmer5, Dahlia Ismail6, Mourad Amrane6,
Jean-Sébastien Garrigue6, Stefano Bonini7, Andrea Leonardi8
1
Quinze-Vingts National Ophthalmology Hospital, Paris - France
2
Pierre et Marie Curie University, Paris 6, Vision Institute, INSERM UMR968, CNRS UMR7210, Paris - France
3
University of Versailles Saint-Quentin en Yvelines, Versailles - France
4
Royal Victoria Infirmary, Newcastle University, Newcastle upon Tyne - UK
5
Department of Ophthalmology, Ludwig-Maximilians-University, Munich - Germany
6
Santen SAS, Evry - France
7
Campus Bio Medico, Università di Roma, Rome - Italy
8
Department of Neuroscience, Ophthalmology Unit, University of Padua, Padua - Italy

ABSTRACT
Purpose: The SICCANOVE study aimed to compare the efficacy and safety of 0.1% cyclosporine A cationic emul-
sion (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 sig-
nificantly 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.
Keywords: Cationic emulsion, CsA, Cyclosporine, Dry eye disease, Severe keratitis

Introduction trinsic (e.g., autoimmune disease) or extrinsic (e.g., dry en-
vironment) factors, with particular prominence in women
Large epidemiologic studies have shown that the preva- and older individuals. Dry eye disease prevalence is likely to
lence of dry eye disease (DED) ranges between 5% and 35% increase with the aging of the population (1-4). Quality of
in certain populations, depending on the diagnostic criteria life is substantially reduced in patients with this debilitating
used (1). Dry eye disease can be initiated by numerous in- disease (5). The difficulty in making an accurate and timely
diagnosis and the absence of an accepted gold standard
DED treatment regimen add to the societal burden associ-
Accepted: February 20, 2017 ated with DED (6-8).
Published online: March 21, 2017 Dry eye disease is a complex, multifactorial disease result-
ing from a disturbance of the lacrimal functional unit and is
Corresponding author: accompanied by increased osmolarity of the tear film and
Christophe Baudouin, MD, PhD
Quinze-Vingts National Ophthalmology Hospital
inflammation of the ocular surface (9). Tear hyperosmolar-
28 rue de Charenton ity activates a cascade of inflammatory events at the ocular
75012 Paris, France surface that initiate surface epithelial damage (e.g., by apop-
cbaudouin@15-20.fr tosis, goblet cell loss, and mucin expression alteration), and

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International (CC BY-NC-ND 4.0). Any commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.wichtig.com

multicenter. gels. including DED (31-33). which do not sufficiently address Participants the underlying pathogenesis of DED (22) and. suggesting that 0.025%. eye pain. signs of the disease (i. artificial tears (Larmabak® 0. screening visit. 4. included use of systemic or topical CsA. France) has been developed to score between 2 and 4 (scored on a modified Oxford scale). difficult-to-treat DED (34). pain. Two Subjects recruited into the study were requested to dis. emulsion) for up to 6 months. foreign body on inhibiting the important inflammatory component of DED sensation. During the 6-month treatment period. and fluctuating vision (1. and entered a 2-week washout pe- ity (10-13). therefore. ciples of Good Clinical Practice and with the ethical principles group. or use of topical cor- Methods ticosteroids or prostaglandins within 1 month before study entry. fungal). The ob. or photophobia) in at least one eye. if left untreated. double-masked.05%. The Efficacy assessments study design was discussed with and authorized by the Scien- tific Advice Working Party at the European Medicines Agency Efficacy was assessed only in the worse eligible eye. artificial tears.. patients instilled 1 For example. Contact lens wear was not allowed during the study. France. improve ocular delivery of CsA and enhance its immunomod. or inflammation not associated with cluding DED signs and symptoms. and month 6 (final visit. associated with severe. may not be an effective treatment in severe DED cases (23). The study was conducted at 61 23 with the protocol code NVG06C103. or sirolim- us within 6 months prior to study entry. infection caused an improvement in several secondary endpoints. green staining score ≥4 (scored with the Van Bijsterveld scale). detailed in the Declaration of Helsinki. de- in 2006. The change in © 2017 The Authors. eye dryness. and the study was conducted in accordance with the prin- This multicenter. Admin- early or mild DED without signs of tissue damage. study-eligible patients were randomized to corneal surface (3. Patients with chronic DED become trapped in this riod during which they administered 1 drop of unpreserved vicious cycle of inflammation and ocular surface damage.1% CsA CE DED during the 3-month period immediately preceding the should be investigated in further clinical studies (31).. controlled study compared a sterile ophthalmic cat. was to demonstrate surgery or ocular laser treatment within 6 months before the the superiority and examine the ocular tolerance and systemic date of study entry in eligible eyes or within 3 months prior to safety of 0. a corneal fluorescein staining (CFS) CE. randomized. Germany. sticky through the introduction of topical steroid pulse therapy and feeling. and a corneal and conjunctival lissamine diseases. randomiza- eign body sensation. These tion was stratified by the presence or absence of Sjögren syn- symptoms may correlate poorly or be discordant with clinical drome to mitigate any imbalance between treatment arms. Ikervis®. and the United Kingdom).2 Cyclosporine A cationic emulsion for dry eye this in turn promotes tear film instability and hyperosmolar. were assessed at month 1 (day 28 ± 3 days). corneal surface damage) (8. bacterial. 3.g. During the post lead to vision abnormalities and permanent damage of the washout period. Patients included in this study had persistent moderate to In addition. Efficacy and safety neal sensory receptors and corneal nerve damage) (8). (eligible eye). (viral. In the same eye cal formulations (22.7 log- 0. itching. Santen SAS. symptoms rely largely on topical instillation of artificial tears or lubricating gels (19-22). Evry.1% showed that corrected distance visual acuity (BCDVA) score >+0. SICCANOVE. can cause disease progression and provided by the sponsor up to 8 times daily. Because Sjögren syndrome is which can include eye irritation.9% unpreserved saline solution) which. Patients were also excluded if they had ocular jective of the current study. eye dryness. or ointments and punctual occlu- short-lived due to their rapid elimination via the nasolacrimal sion). and 0. 0. with a sever- anti-inflammatory agents such as cyclosporine A (CsA) in topi. Spain. 3-month. 4). tacrolimus. 14). Additional exclusion criteria moderate to severe DED. parallel.. They were required to have had one or more symptoms drainage system (24). patients also had to have a tear break-up time A 0. minimal symptoms of discomfort may be present in patients only the use of the sponsor-supplied unpreserved artificial with severe DED (potentially due to downregulation of cor. Published by Wichtig Publishing . co-primary efficacy endpoints (an objective [sign] and a sub- continue use of any topical ophthalmic treatment (including jective [symptom] parameter) were assessed. whereas istration of concomitant topical treatments was prohibited. sites located in 6 European countries (the Czech Republic. This study was regis- ionic emulsion of 0.1% (1 mg/mL) cyclosporine A cationic emulsion (CsA (TBUT) of ≤8 seconds.1% CsA (Santen SAS) with vehicle over a tered in the EudraCT database under number 2007-000029- 6-month treatment period. a Schirmer tear test (without anesthesia) score ≥2 mm/5 min ulatory benefits in moderate to severe ocular inflammatory and <10 mm/5 min.1% CsA CE compared with vehicle in patients with study entry in noneligible eyes. A previous phase II. day 168 ± 14 days). 15-18). in.1% CsA CE or its vehicle (drug-free cationic Patients with DED experience symptoms of discomfort.1% CsA CE had a comparable safety profile to the vehicle and MAR in eligible eyes or a history of ocular trauma. fined as the eye with the highest CFS score at baseline. Study design All enrolled patients provided written informed consent. for. burning or stinging.g. symptom relief achieved with artificial tears or severe DED that was refractory to conventional management lubricating gels are largely palliative and can be relatively (e. Italy. hyperalgesia can be observed in patients with drop of study drug once daily in both eyes at bedtime. More recent therapies have focused of ocular discomfort (e. their own artificial tears). blurred vision. 25-30). month 3 (day Current medical strategies to relieve DED-associated 84 ± 7 days). double-masked clinical study in dry eye with CsA The main exclusion criterion for this study was a best- at concentrations of 0. receive either 0.e. tears (up to 6 times daily) was permitted. ity score of ≥2 (graded on a 4-point scale).

In addition. complete responders (patients with CFS score of 0.Baudouin et al 3 CFS (sign) and the change in global score of ocular discom. The per improvement protocol (PP) population included patients from the FAS who  Co-responders = improvement of ≥2 did not have any major protocol deviations that could affect grades in CFS and ≥30% in OSDI efficacy analysis of the co-primary endpoints. For DED symptoms.76. or severe). VAS = VAS responders (patients with ≥25% improvement in VAS) and visual analogue scale. In addition. erythema or edema on the lid and ment groups (Tab. pain. temic CsA levels were determined by blood sampling at the Other efficacy assessments included the corneal and baseline and month 6 visits. In a subset of patients. the TBUT (at screening and each Ocular symptoms related to study treatment instillation visit) (9). foreign body sensation. the Ocular Surface Disease Index (OSDI) question. considered to be a clinically Planned responder analyses relevant change. burning or stinging. global evaluation (months 1. the If the answer was “yes. abnormal lashes. TBUT. The following ef- ficacy outcomes were analyzed for the FAS and PP datasets: In patients with CFS score of 2 at baseline 83 93 change from baseline in CFS score and global score of ocular   Complete responders = CFS score of 0 discomfort (VAS).  Complete responders = CFS score of 0 corresponding to a total decrease of 4. CFS = corneal fluorescein tor. a sample size of 205 patients per group was deemed necessary in order to detect a mean (±SD) CsA CE. n Vehicle. blurred vision. I). and study (all visits from baseline to month 6). and indicated its duration. sys- of these 8 individual symptom scores.25 ± 0. Other safety as- photophobia) was assessed using a VAS ranging from 0% to sessments included BCDVA and intraocular pressure (IOP) at 100%. and the investigator’s some ocular discomfort at instillation of the study treatment. the primary efficacy endpoints. I).9. OSDI. 37). Planned responder analyses evaluated the proportion of staining. mian gland obstruction. anterior cham- tificial tears was also monitored at each visit over the course ber inflammation. and the global ocular discomfort score was the mean baseline and at months 3 and 6. symptom) from baseline to month 6 were cytology at baseline and month 6 (39) in a subset of patients. and an additional improvement in VAS 25% decrease was anticipated in the active treatment group. The full analysis In patients with CFS score of 4 at baseline 43 42 set (FAS) included all patients from the safety population who  CFS responders = ≥2 grades had at least one posttreatment efficacy evaluation. OSDI = ocular surface disease index. Local ocular tolerance assessments the Schirmer tear test without anesthesia (at baseline and month 3 and 6 visits) (9). eye dryness. each symptom. and 6 visits)..05 in both 2-sided tests. [AUF] and percentage of cells) was measured by impression logue scale [VAS].e. conjunctival lissamine green staining score graded on the Van Bijsterveld scale (at baseline and each visit) (36. © 2017 The Authors. junctival epithelial cells (in arbitrary units of fluorescence fort unrelated to study treatment instillation (visual ana. with an anticipated dropout rate of 15%. Adverse events (AEs) were recorded throughout the itching.Responder analyses level and at 80% power. Published by Wichtig Publishing . With a 2-sided t test at 5% significance TABLE I . conjunctiva. were assessed by asking the patient whether he or she felt naire (at baseline and each visit) (38). n difference in CFS of 0. Based on Post hoc responder analyses these assumptions. Each symptom of ocular discomfort (i. a total sample size of 482 patients (241 per group) needed to be recruited into the study in order to In patients with CFS score ≥3 and OSDI 128 118 score ≥23 at baseline achieve a significance level of 0. the expression of the cell surface inflamma.29.1% cyclosporine A cationic emulsion. Tab.” the patient described the nature of percentage of responders in terms of ocular discomfort (pa. Slit-lamp percentage of complete responders in terms of CFS (patients examination was also used to assess the presence of meibo- with a CFS score of 0) were compared between the 2 treat. CFS was scored on a 7-point modified Oxford scale (0 = no staining and 7 = severe) slit. and lens opacification. CsA CE = 0.  CFS responders = ≥2 grades improvement Statistical analysis  OSDI responders = ≥30% improvement  Co-responders = improvement of ≥2 The safety population included all randomized patients grades in CFS and ≥30% in OSDI who received at least 1 dose of the study drug. the mean change in global score of oc- In patients with moderate to severe DED 241 248 ular discomfort (VAS) unrelated to instillation at month 6 for  Ocular discomfort responders = ≥25% the vehicle group was estimated as –3. sticky feeling. Safety assessments lamp examination of the cornea (35). Schirmer tear test. graded its severity on a 3-point scale (mild. of the study. tear film debris. The use of concomitant unpreserved ar.11 ± 2. and global evaluation of efficacy by the investiga- N reflects the number of patients included in the full analysis set. tients with ≥25% improvement in VAS from baseline) and the moderate. Sample size tory marker human leukocyte antigen–DR (HLA-DR) on con- The sample size calculation was based on a previous phase IIa study (31). 3. DED = dry eye disease. lissamine green staining.

the model was fitted to the change from baseline at days 28.5%) patients with Sjögren syndrome in the CsA FAS population. Missing data for the primary ef- ficacy variables were imputed using the last observation car- ried forward method. logistic regression and Van Elteren tests). All post hoc analyses were conducted exclusively in the and 88 (35. and the baseline score of the parameter as a co- variate.39 [95% CI -3. 84. and visit.007). all efficacy results present- ed here were assessed in the FAS population. respectively. 2A). respectively. 1 . of 58. Co-primary efficacy endpoints sistent moderate to severe DED were randomized. CE and vehicle groups. and per protocol (PP) population baseline. Sjögren syndrome status. Demographic and baseline (p = 0. The safety population. 2.9%) p = 0. Where appropriate. with no significant differ- treatment arms were balanced with respect to proportion ence between groups (difference of -0. CsA CE = 0.010) and a Van (84. Simi- characteristics were also comparable between the 2 treat. and 492 pa- tients were treated with either CsA CE (242 patients) or vehicle In patients with moderate to severe DED. Fig.1%]). Table I outlines the various responder analyses performed in these subsets of patients.4 Cyclosporine A cationic emulsion for dry eye The co-primary efficacy endpoints were analyzed at month 6 using an analysis of covariance (ANCOVA). score of 2 at baseline. -0. A total of 82 patients withdrew from the study improved in both treatment groups between baseline and early (Fig.59) and As a result of the randomization and stratification process. 489. Published by Wichtig Publishing .34) groups. for secondary outcomes. Post hoc analyses Post hoc analyses were performed on 3 subsets of pa- tients: 1) patients with a CFS score ≥3 and OSDI score ≥23 at Fig. and the majority of female patients were There were noticeable improvements in the mean postmenopausal (294 patients [60. and as a conse- quence. A total of 177 change in global ocular discomfort (VAS) score from base- (36.21 ± 19.1% cyclosporine A cationic emulsion. A total of 495 patients diagnosed with per.05 ± 0. and 347 patients. line to month 6 in both the CsA CE (-12. the main ANCOVA model was fitted as described above. II). Sjögren status. 2) patients with a CFS score of 4 (defined as patients included 492. We did not perform any multiplicity adjustments because the co-primary endpoints were expected to be simultaneously significant for the study to be considered positive.11]. vehicle (-11. 2A).06) was statistically significant 96.808.8% in the CsA CE group and dence interval [CI] -0. For param- eters analyzed using repeated-measures models. full analysis set (FAS). of patients with Sjögren syndrome. p = 0. AE = adverse with severe keratitis) at baseline. a chi-square test was used to determine per. 2B).8]. the data were found to be log-normally distributed. which included treatment.. This study was conducted between September 2007 and September 2009. lar results were also seen with ordinal logistic regression ment groups (Tab. however. the overall mean compliance rates CE (-1.2 years.94) (Fig. and 3) patients with CFS event.Patient flow diagram for the SICCANOVE study.82 ± 0.5. improvements were greater with CsA During the study.39. 2. and 168 with fixed effect terms for treatments. and ANCOVA was used for comparisons of means. and secondary anal- yses were performed at months 1 (day 28) and 3 (day 84) to detect a potential early effect of the treatment. reporting of median values was preferred over re- porting of mean values.5%) and 413 female (odds ratio [95% CI] 1. Efficacy results Results Unless otherwise specified. and the corresponding baseline score as covariates. were relatively high and numerically comparable between The adjusted treatment difference of -0.82 ± 18. © 2017 The Authors.009) in favor of the CsA CE treatment (Fig.g. 1).98) than with vehicle (-0. Additional secondary analyses were performed to show robustness of the primary results (e. there were 89 (36. The 76 male (15. For the exploratory HLA-DR parameter.9% in the vehicle group).22 (95% confi- the 2 treatment groups (96.5%) patients included in the study had an average age Elteren test (p = 0.2%) patients had a prior diagnosis of Sjögren syndrome. and either Patient demographics confirmed or supported by analyses performed in the PP population.11. CFS scores (250 patients). month 6. centage differences between treatment groups.53 [1.

Data represent the full analysis set (FAS) with missing data imputed by the last observation carried forward method.1 (19.83 (0. Published by Wichtig Publishing .92) over vehicle (-0.7 (1.Demographics and baseline characteristics in the full analysis set All patients (N = 489) CsA CE (n = 241) Vehicle (n = 248) Age.9 (1.5) CFS score. 47. n (%)  White 483 (98.0) 3 (1.9) 88 (35. s. mean (SD) .6 (12.7)  Median 59.2)a 43. 3.0)b OSDI score. 4.8) 245 (98.3) 59 (24.6 (2. mean (SD) . 90 20.2 (12.8 (1.8) 238 (98.1% cyclosporine A cationic emulsion. 2.72) Lissamine green staining score. b Assessed in 245 patients.8 (12.2) 89 (36. VAS = visual analogue scale. B) Mean change from baseline in corneal fluorescein staining (CFS) and visual analogue scale (VAS) scores.0 60.80 (0. TBUT = tear break-up time. mean (SD) . A total of 241 patients and 248 patients in the CsA CE and vehicle groups.002).0   Min.Change from baseline in the co-primary endpoints after 6 months of randomized treatment with 0.0 57. a Assessed in 238 patients.1) 160 (64.9) 40 (16.0 (21.9) 58.0) 1 (0.1% cyclosporine A cationic emul- sion (CsA CE) in patients with moderate to severe dry eye disease.7 (1. p = 0.71) 2.70.5) 36 (14. © 2017 The Authors.9) 4. n (%)  Yes 177 (36.2) 2 (0. with improvements maintained through month 3 was significantly greater with CsA CE (-0.2)   Female/postmenopausal 294 (60.7) Global ocular discomfort score (VAS). These Signs results suggest that treatment with CsA CE resulted in im- proved signs of moderate to severe DED after 1 month of The mean change in CFS score from baseline to month 1 treatment.Baudouin et al 5 TABLE II .8) 152 (63. 90 21.8) CsA CE = 0.5)  No 312 (63. (A.2) Schirmer tear test (mm/5 min). mean (SD) .0) 42.4 (22. CFS = corneal fluorescein staining. n (%)   Female/premenopausal 119 (24. 87 Sex/menopausal status. Fig. mean (SD) . mean (SD) . respectively. respectively.4) TBUT. which was confirmed by logistic regression and Van Elteren test. OSDI = Ocular Surface Disease Index. 44. y   Mean (SD) 58. Similar results favoring CsA CE (-0.6 (2. Secondary efficacy endpoints (-0. The statistical comparison shown reflects the results of an analysis of covariance model.8)   Asian 1 (0. 5. max 20.7)   Male 76 (15.1) 146 (60.5) 60 (24. 2 .4) Sjögren syndrome.52. were analyzed.8 (20.77) than with ­vehicle and month 6.6) 148 (59.8) 57.6) 3.030) were observed at month 3.1) Ethnicity.8)   Black 5 (1.1) 5.2) 0 (0. p = 0.

favor of CsA CE (p = 0. pression was -21.17 ± 1. Use of artificial tears during the study (monitored at each Mean changes from baseline to month 6 for Schirmer tear visit) was comparable between treatment groups. At baseline. p = 0. In this subpopulation.66) and TBUT (1.7% and 39.3 at month 1. were 40. the percentage which improved to a significantly greater extent in the vehi. were reduced after 6 ly. and 50.12 seconds for vehicle).7% at month 6.95 mm/5 min for CsA CE vs 1. Additionally.334 AUF for the CsA CE and lated to study medication [VAS]). However. the median change from baseline in HLA-DR ex- The percentage of responders (ocular discomfort unre. respectively. reported for the co-primary endpoint (CFS). 4).2% and 42.Human leukocyte antigen DR (HLA-DR) expression at baseline and after 6 months of randomized treat- ment with 0. ence in global VAS score (co-primary endpoint) was not sta- tistically significant. This (VAS) showed improvement of all symptoms in both treat. of responders in CFS. These response discernible difference was observed between the treatment rates indicate that although the mean between-group differ. -2. vehicle: n = 48) and at month 6 (CsA CE: n = 30. adjusted on cen- ter effect.3%) than in and vehicle groups.5 vs -1.8% vs 68. groups with respect to percentage of cells expressing HLA-DR. Median changes from baseline are from patients evaluable at baseline and at month 6 in the safety population (CsA CE: n = 24. in favor of CsA CE at month 6 (p = 0. were not statistically different between the 2 groups. vehicle: n = 36). respectively (Fig.05. Analyses of cell surface HLA-DR expression were per- The percentage of complete CFS responders (CFS score of formed in 89 patients (41 and 48 patients from the CsA CE 0) was numerically higher in the CsA CE group (8. respective.000 AUF for the CsA CE and Symptoms vehicle groups.048).76 mm/5 min for vehicle. subset represented 50% of the overall study population (n ment groups between baseline and month 6. and -2. and the difference be- provement in VAS. with 128 and 118 patients in the CsA CE and vehicle cal difference between groups. respectively). defined as percentage im.0% at months of treatment with CsA CE. was statistically higher in the CsA CE group mean change in OSDI score from baseline to month 6 favored than in the vehicle group at month 6 (Fig.876 AUF and -1. In a separate analysis. = 246).6 Cyclosporine A cationic emulsion for dry eye Fig. Post hoc analyses were performed on a subset of pa- Analyses of the 8 individual ocular discomfort symptoms tients with CFS score ≥3 and OSDI score ≥23 at baseline.98 seconds for CsA CE vs 1. mean changes in corneal and conjunctival the CsA CE group (-11. though numerically higher in the CsA CE group.13 ± Impression cytology 2.2 at month 6. The percentages post hoc analyses). test (1. The statis- tical comparison shown reflects an analysis of covariance on the rank- transformed value. satisfactory by investigators was slightly. respectively). supporting results and 62. 63. In patients evaluable at baseline and month 6. more patients in the CsA CE group than in Post hoc analyses the vehicle group experienced a clinically relevant reduction in ocular discomfort. 48. 3). not statistically significant.9% vs 62.5% at month 1.2%) at month 6 (p = 0. At month 6.572 AUF and 37.048) was observed. The percentage of patients for nificantly) greater in the CsA CE group than in the vehicle at whom treatment efficacy was classified as satisfactory or very all time points: -1. a statistically significant higher in the CsA CE group than in the vehicle group at each overall treatment effect (from a repeated measures model) in visit: 73.0% at month 6. As the data distribution was found to be log-normal.1% and 46.7 at month 3. but not significantly.038). dicative of conjunctival inflammation.1% cyclosporine A cat- ionic emulsion (CsA CE) or vehicle. This demonstrates that HLA-DR levels.1 vs -1. Published by Wichtig Publishing . but was lissamine green staining scores were numerically (but not sig. AUF = arbitrary units of fluorescence.5% at month 3. with no statisti. except for stinging/burning. © 2017 The Authors. vehicle groups. defined as patients with ≥2 grades of cle group (p = 0. median values are presented for patients present at baseline (CsA CE: n = 41.0 in the vehicle group). the median cell the vehicle group (5. vehicle: n = 31). surface HLA-DR expression was comparable between treat- ment groups (44.2% vs 59. no month 3. in- of responders in the CsA CE and vehicle groups. 3 .4 vs -2. The between-group difference for the improvement.1% at month 1.17). groups.8 vs -9. showed a statistically significant difference tween groups was found to be statistically significant (p<0.

56. © 2017 The Authors.1% cyclosporine A cationic emulsion (CsA CE) or vehicle in a subset of patients with a corneal fluorescein staining (CFS) score ≥3 and an Ocu- lar Surface Disease Index (OSDI) score ≥23 at baseline.1% cyclo- sporine A cationic emulsion (CsA CE) or vehicle according to corneal fluorescein staining (CFS) scores at baseline. were analyzed. provement in OSDI) was similar in the CsA CE and vehicle Additional post hoc analyses were performed on patients groups.049.Baudouin et al 7 Fig.002.Post hoc analysis of the re- sponder rates after 6 months of randomized treatment with 0. 4). 5). DR AUF at baseline: 48.Post hoc analysis of the per- centage of co-responders in both signs and symptoms of dry eye disease after 6 months of random- ized treatment with 0.047). Fig. Patients with the co-responders in both signs and symptoms (p = 0. respectively. but the percentage of co-responders (patients with with CFS score of 4 (defined as DED patients with severe kera- ≥2 grades of improvement in CFS and ≥30% improvement in titis) at baseline. for changes in CFS (p = 0. 4 . The 127.343 (n = 41).003. Data represent the full analysis set. Fig. In this patient population. or 4 at baseline. lissamine green staining The percentage of co-responders was significantly higher in (p = 0.77 (1. A total of 128 patients and 118 patients in the CsA CE and vehicle groups. and cally greater with CsA CE than with vehicle (p = 0.624 (n = 13) in patients with CFS scores of 2. 6A). This co-responder analysis was also per. statisti- (p = 0. respectively. The statistical comparisons shown reflect the re- sults of chi-square tests.003). and 4. Fig. with 43 and 42 patients OSDI) in both signs and symptoms was significantly higher in the CsA CE and vehicle groups.009). percentage of responders in OSDI (patients with ≥30% im. Published by Wichtig Publishing . cal superiority of CsA CE over vehicle was observed at month 6 formed in patients with CFS score of 2. and percentage of with CFS score of 4 at baseline (Fig.749 (n = 34). Ocular Surface Disease Index responders were defined as patients with ≥30% im- provement in OSDI. 3. 5). Co-responders were defined as patients who met both these criteria. 5 . 6B). Corneal fluorescein staining responders were defined as patients with ≥2 grades of improve- ment in CFS score. percentage the CsA CE group than in the vehicle group for the patients of responders in CFS (p = 0. The statistical comparisons shown reflect the re- sults of chi-square tests. Fig.1 (0. A total of 85 patients. Co-responders were defined as those having ≥2 points improvement in CFS score and ≥30% improvement in Ocular Surface Disease Index score. presented with in the CsA CE group than in the vehicle group at month 6 a CFS score of 4 at baseline. mean changes (SD) in CFS scores were -1. Schirmer tear test score (p = 0.0) in the vehicle group and statisti.011. Fig.97) in the CsA highest CFS score at baseline also had a higher value of HLA- CE group and -0. 3. respectively.

TEAE = treatment-emergent adverse event.2%] in the vehicle group).5) 6 (2. In patients with a CFS score of 2 at baseline (n = 176). Published by Wichtig Publishing .2) was reported for 39 patients (16.4) 0 between groups (24 patients [9. The number of patients ocular TEAE. Data represent the full analysis set. SAE = serious adverse event. Systemic TEAEs were experienced by 56 (23. systemic CsA levels © 2017 The Authors.a n (%)   Eye irritation 39 (16.1) 6 (2.028).0) 41 (16. n (%) reporting treatment-related ocular TEAEs was numerically high.7% and 10. n (%) 103 (42. The most common treat- ment-related TEAE in the CsA CE group was eye irritation.1) 4 (1.7) 5 (2. compared with the vehicle group (p CsA CE Vehicle = 0. n (%) 1 (0.0%]).9%] in the CsA CE group and 18 Any severe ocular TEAE 84 (34.4) cally higher in the CsA CE group (84 patients [34.1) 1 (0. 6 . Systemic CsA levels were measured in 184 patients (85 ate in intensity and were considered unrelated to the study and 99 from the CsA CE and vehicle groups.2) patients who withdrew due to an ocular TEAE was comparable Any ocular SAE. treatment (severe epithelial erosion of the cornea) was report. while those in B reflect the results of a chi-square test. TABLE III -Treatment-emergent adverse events reported in >2% of a significantly greater percentage of patients in the CsA CE patients (safety population) group exhibited complete corneal clearing (defined as a CFS score of 0) at month 6. III).8%) patients in the CsA CE and vehicle groups.” or “possibly” related by the study investigator. which Any severe treatment-related 87 (36.8) groups. The majority of systemic TEAEs were mild or moder. a Treatment-related TEAEs summarized here were deemed “definitely. n (%) the vehicle group (66 patients [58.   Lacrimation increased 10 (4.0) shown).7%]) than in the vehicle group (40 patients [16.1%) and 72 (28. In the 85 patients who received CsA CE.2) er in the CsA CE group (176 patients [78. “probably.0) 7 (2. respectively).0) 28 (11. respec- tively. CFS responders were defined as those having ≥2 points improvement in CFS score. Of the 83 and 93 patients in the CsA CE and vehicle (n = 242) (n = 250) groups with a CFS score of 2 at baseline.4) Ocular treatment-emergent AEs (TEAEs) were reported in   Instillation site irritation 22 (9.1%).6%) and 67 (26. The only treatment- related serious ocular TEAE designated as definitely related to CsA CE = 0. but the incidence of severe ocular TEAEs was numeri-   Meibomianitis 6 (2. A total of 43 patients and 42 patients in the CsA CE and vehicle groups. treatment. the number of   Conjunctival hyperemia 6 (2. respectively (Tab.9) 18 (7.0) patients [7.1% cyclosporine A cationic emulsion.5) 3 (1.4) Adverse events TEAE.8% Any ocular TEAE.” ed in the CsA CE group and resolved without sequelae.8) demonstrated complete corneal clearing. respectively.6) 67 (26.4) ate ocular TEAEs was comparable between groups (data not   Eyelid erythema 9 (3. respectively. The incidence of mild or moder.7) 40 (16.8%) patients in the CsA CE and vehicle   Eye pain 17 (7. Any ocular TEAE leading to 24 (9. The statistical comparisons shown in A reflect the results of an analysis of covariance model.1% cyclosporine A cationic emulsion (CsA CE) or vehicle in a subset of patients with CFS score of 4 at baseline.9%]).9%]) compared with study discontinuation. were analyzed. however.6) 103 (42.8 Cyclosporine A cationic emulsion for dry eye Fig. Any treatment-related ocular 92 (38. 21.Post hoc analysis of the mean change in baseline in corneal fluorescein staining (CFS) score (A) and CFS responder rate (B) after 6 months of randomized treatment with 0.

0. between the treatment groups with respect to percentages There were no changes in BCDVA or IOP over the course of cells expressing HLA-DR.Baudouin et al 9 were below the lower limit of detection (<0. for the global score of ocular discomfort as a co-primary end. 37).9%. and the oily phase els were assessed. the CsA CE group than in the vehicle group.2%. 0. had a smaller effect. flammation. following congresses: 2011 European Society of Ophthalmol- © 2017 The Authors. Two groups of patients were ocular discomfort) in patients with moderate to severe DED.5% for CsA CE and 16.1. once-daily instillation of CsA CE (Ikervis®) er tear test. with a CFS score of 2) tant. only 4 patients (4. Results ob- cally significant during the 6-month period in favor of CsA CE. month 6 cant CFS improvement observed from as early as month 1. 29.2 ng/mL). before by the ability of the cationic emulsion vehicle to improve DED the cycle of ocular inflammation and injury that can poten- symptoms (36. thus.e. statically with the negatively charged components of the tear with findings consistent with the expected safety profile of film (31). syndrome (47%) who were unresponsive to treatment prior centage of responders as determined by ocular discomfort to participation in this study.. and the inflammatory status of individual cells does not necessar- The percentage of patients experiencing ocular discom.050 ng/mL) in 70 Cytology impression/median cell surface AUF analysis in- patients (82. lubrication. This innovative formulation increases the tially lead to permanent and irreversible corneal damage is retention time of the nanodroplets on the ocular surface and established (8. 14).5% for CsA CE and may have identical results for percentages of cells expressing 30. ily correlate with the overall number of cells expressing HLA- fort related to study treatment instillation decreased in both DR. Among the patients for whom systemic CsA lev- the emulsion droplets allows rehydration. severe 2. and OSDI score. the cationic emulsion enhances film CsA. DR expression at month 6. This 4) and presented a higher percentage of responders in CFS result was reinforced by the results obtained in the lissamine and co-responders in both signs (CFS) and symptoms (OSDI) green staining test. the majority of patients experienced mild and ority of CsA CE in reducing DED-associated conjunctival in- transient (≤15 minutes) ocular discomfort at study treatment flammation may result from the intrinsic anti-inflammatory instillation. replenishes the lipid layer (31. No discernible difference was observed gible: 0. IOP. Secondary study objectives.. ment is considered to be a more reliable assessment of ocular inflammation because an individual cell’s binding of a marker Local ocular tolerance may vary based on the degree of inflammation present. where the overall difference was statisti. Despite this. vehicle: moderate 2. ­properties previously identified for CsA (27. as this subgroup using VAS) was observed in both treatment groups. we also investigated the potential for pa- in the CsA CE group at month 6.7%). At month 6. Published by Wichtig Publishing . Cyclosporine A CE was well-tolerated in most patients.e. Median cell surface AUF measure- of the study (data not shown). whereas the vehicle treatment tients (4. Indeed. but this had a high proportion of patients diagnosed with Sjögren improvement was numerically greater with CsA CE.1. the percentage of complete responders (i.8% HLA-DR compared with another patient with lower-grade in- for vehicle). 41).e. In conclusion.4%) and below the lower limit of quantification dicated that treatment with CsA CE significantly reduced HLA- (0.10 ng/mL) in 11 patients (12. a patient with a relatively high level of inflammation treatment groups between baseline (54.9%). indicating an early effect of the study drug. CFS) and a symptom (i. systemic CsA levels were quantifiable but negli.0%. but between-treatment differ. The clinical efficacy of CsA CE over vehicle The co-primary objective of this study was to demon. AUF.e. and the difference between statistical improvements in CFS (and in lissamine green stain- CsA CE and vehicle was statistically significant as early as af. improvements in these measures were consistently in favor The data in this study were presented as posters at the of CsA CE.. but negligible. In addition.0% for vehicle) and month 6 (40. 40. of DED following 6-month treatment with CsA CE. to completely recover after 6 months of treatment with CsA The absence of a significant between-group difference CE. The per. with signifi- ences were not statistically significant. which represented an impor. including changes in Schirm. was more pronounced in the most severely affected patients. tients with mild DED at baseline (i... but the same 2 individuals would be expected enced moderate or severe ocular symptoms (CsA CE: moder.e. (patients with ≥25% decrease in VAS) was significantly greater In this study. all showed improvements was well-tolerated and effective for the treatment of moderate numerically in favor of CsA CE. There were no detrimental effects on visual acuity. In the remaining 4 pa. 42-47). and stability: the aqueous medium of or vital signs. Overall. 15-17) and to successfully treat the disease in its early stages. selected: patients with a CFS score ≥3 and OSDI score ≥23 at A significant improvement in CFS was observed with CsA baseline and patients with a CFS score of 4. hydration. therefore improves the drug delivery by interacting electro. strate the superiority of 1 mg/mL CsA CE over vehicle in terms who were at risk of irreversible damage of the ocular surface of effect on both a clinical sign (i. TBUT. In-depth analyses focused on subsets of patients with ei- Discussion ther mild DED or severe DED (i. It is important relation between signs and symptoms in DED (8. severe 0%). the HLA-DR results suggested that the superi- In addition. to have clearly distinct profiles based on median cell surface ate 13. tained for the subgroup of patients with severe keratitis (CFS Improvement in global score of ocular discomfort (assessed score of 4) were particularly noteworthy. Both groups had CE after 6 months of treatment. ing and Schirmer tear test for patients with a CFS score of ter 1 month.1. with CFS score of 0 at month 6) was significantly greater in point could be explained by the well-documented weak cor.2 ng/mL. both ends of the disease severity spectrum). CsA levels (below 0. and 0. and at higher risk of infection. clinically relevant response. to severe DED during the 6 months of the study. few patients in both groups experi.7%) had quantifiable.

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The authors thank Scinopsis for medical writing support and Chame. Pflugfelder SC. The association between symptoms of discom- international coordinator in the SICCANOVE study. Shell JW. DEWS. Geneva. 2007. 7. Saudi J Ophthalmol. Topical cyclosporine: are all indications justified? Br 4. and D.45(Suppl 2):S211-S220. Oculus Optikgeräte.146(3):350-356.54(3):321-338.5(2): demiology Subcommittee of the International Dry Eye Work.10 Cyclosporine A cationic emulsion for dry eye ogy meeting. Santen.138(3): 444-457. DEWS. Spain.2012:604204. J Fr Ophtalmol.26(4):287-296. 2012. 2007. Recent developments on dry J Ophthalmol. © 2017 The Authors. Ophthalmic Epidemiol. BioMed Research In. Paterson A. Pflugfelder SC. Dana MR. Diagnostic 25. Lemp MA. Antho. et al. 0. and Santen and has also received research grants from Alcon. Nichols JJ. 2004. Lipid-containing eye drops. 2008.

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