Clinical science

Efficacy and safety of 0.1% ciclosporin A cationic

Br J Ophthalmol: first published as 10.1136/bjophthalmol-2017-311801 on 15 March 2018. Downloaded from http://bjo.bmj.com/ on 3 July 2018 by guest. Protected by copyright.
emulsion in dry eye disease: a pooled analysis of two
double-masked, randomised, vehicle-controlled
phase III clinical studies
Andrea Leonardi,1 Elisabeth M Messmer,2 Marc Labetoulle,3
Mourad Amrane,4 Jean-Sébastien Garrigue,4 Dahlia Ismail,4 Maite Sainz-de-la-Maza,5
Francisco C Figueiredo,6 Christophe Baudouin7,8,9

►► Additional material is Abstract debilitating effects, both physically and psycholog-

published online only. To view Background/aim  To assess the treatment effect of ically, from ocular pain and irritative symptoms;
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​0.1% ciclosporin A cationic emulsion (CsA CE) versus difficulties performing basic activities of daily living
bjophthalmol-​2017-​311801). vehicle on signs/symptoms of dry eye disease (DED) in such as driving and using a computer; and visual
various subgroups (moderate-to-severe DED/severe DED/ problems such as blurry vision.2 3 Management of
For numbered affiliations see Sjögren’s syndrome (SS)/SS with severe DED). DED is complicated by the fact that it is driven by
end of article.
Methods  Pooled data were analysed from two similar a self-perpetuating vicious cycle of tear film insta-
phase III studies: SICCANOVE (moderate-to-severe DED) bility, hyperosmolarity and ocular surface inflam-
Correspondence to
Dr Andrea Leonardi, Giustiniani and SANSIKA (severe DED with severe keratitis). In both mation.4 5 Without treatment, DED can progress
2, 35128 Padova, Italy ; ​andrea.​ studies, patients aged ≥18 years received CsA CE 0.1% and increase in severity, becoming more refractory
leonardi@​unipd.​it (n=395) or vehicle (n=339) once daily for 6 months. to treatment and potentially leading to permanent
A composite responder efficacy endpoint (corneal ocular damage.4 6
Selected data have been Current treatment strategies typically rely on
fluorescein staining–Ocular Surface Disease Index (CFS–
presented in abstract/poster
format at the Annual Meeting OSDI) at month 6) was used to evaluate the efficacy of the use of artificial tears to lubricate and hydrate
of the Association for Research CsA CE in alleviating signs/symptoms of DED (response the ocular surface, but this approach provides
in Vision and Ophthalmology defined as improvement of ≥2 grades in CFS and only short-term symptomatic relief that does
(ARVO) 2016, 1–5 May, Seattle, ≥30% in OSDI (baseline to month 6)). Human leucocyte not address ocular surface inflammation, the
WA, USA (Poster A0080);
the European Association antigen-DR (HLA-DR) conjunctival expression was used principal underlying pathophysiological compo-
for Vision and Eye Research as a biomarker of ocular surface inflammation. nent of chronic DED. 7 8 Ciclosporin A (CsA),
(EVER) 2016 Congress, 5–8 Results  CsA CE–treated patients were significantly an anti-inflammatory agent, has shown signif-
October, Nice, France (Poster more likely to be CFS–OSDI responders than vehicle- icant benefits in moderate-to-severe DED and
S064); and the Medical Contact
treated patients in the overall (OR 1.66, 95% CI 1.11 has been the focus of increasing interest and
Lens and Ocular Surface
Association (MCLOSA) 2016 to 2.50; P=0.015), severe DED (1.80, 1.04 to 3.19; investigation in recent years.9 When applied
Annual Scientific Meeting, 25 P=0.038) and SS with severe DED (3.37, 1.20 to 11.19; topically as an oil-based formulation, CsA has
November, London, England. P=0.030) populations. The difference was not significant low bioavailability and is poorly tolerated10;
for CsA CE versus vehicle for the overall Sjögren’s however, in 2015, a cationic emulsion (CE)
Received 2 January 2018
Revised 14 February 2018 population (OR 1.77, CI 0.89 to 3.66; P=0.109). CsA formulation containing 0.1% (1 mg/mL) CsA
Accepted 20 February 2018 CE also significantly reduced median HLA-DR expression (CsA CE; Ikervis; Santen SAS, Evry, France) was
versus vehicle at 6 months (P=0.002). approved by the European Medicines Agency for
Conclusion  Pooled phase III data indicate CsA CE the treatment of severe keratitis in adults with
produced significant improvement in signs/symptoms DED that has not improved despite treatment
versus vehicle in patients with moderate-to-severe DED with tear substitutes. Compared with previ-
(especially in those with severe keratitis), including ously available formulations of CsA, CsA CE
patients with SS with severe DED. has a prolonged precorneal residence time and
improved bioavailability, allowing for once-
daily instillation.11–14 The efficacy and safety of
CsA CE were assessed in two double-masked,
Introduction randomised, parallel-group, vehicle-controlled
The Dry Eye Workshop II has recently proposed a phase III studies: SICCANOVE, in patients with
new definition of dry eye disease (DED): DED is moderate-to-severe DED; and SANSIKA, in
a multifactorial disease of the ocular surface char- patients with severe DED. Overall, CsA CE was
acterised by a loss of homeostasis of the tear film, well tolerated and efficacious in reducing corneal
To cite: Leonardi A, and accompanied by ocular symptoms, in which surface damage and ocular surface inflammation
Messmer EM, Labetoulle M,
tear film instability and hyperosmolarity, ocular in patients with moderate-to-severe DED.15–17
et al. Br J Ophthalmol Epub
ahead of print: [please surface inflammation and damage, and neurosen- Pooled data from the SICCANOVE and
include Day Month Year]. sory abnormalities play aetiological roles.1 DED SANSIKA studies were analysed to better under-
doi:10.1136/ affects 5%–50% of the population according to stand the magnitude of the treatment effect of CsA
bjophthalmol-2017-311801 worldwide surveys,2 and patients can experience CE, compared with vehicle, on signs and symptoms
Leonardi A, et al. Br J Ophthalmol 2018;0:1–7. doi:10.1136/bjophthalmol-2017-311801 1
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of DED in the overall DED population and in multiple patient
Table 1  Demographic and baseline characteristics of patients
subgroups defined by age, sex, menopausal status, disease
included in the pooled full analysis set
severity or duration and the presence or absence of Sjögren’s
syndrome (SS). CsA CE (n=395) Vehicle (n=339)
SANSIKA study (n, %) 154 (39.0) 91 (26.8)
SICCANOVE study (n, %) 241 (61.0) 248 (73.2)
Methods Mean age, years (SD) 58.7 (13.2) 59.5 (12.5)
Study design and participants Female, n (%) 331 (83.8) 291 (85.8)
Data for this pooled analysis were obtained from two Sjögren’s syndrome, n (%) 147 (37.2) 122 (36.0)
randomised, 6-month phase III clinical studies (EudraCT Severe DED, n (%) 193 (48.9) 126 (37.2)
numbers: 2007-000029-23 (SICCANOVE), 2011-000160-97 (CFS grade 4, OSDI ≥23)
(SANSIKA)) that evaluated the efficacy and safety of CsA CE HLA-DR data available, n (%) 94 (23.8) 74 (21.8)
in patients with moderate-to-severe DED.15 16 Both studies CFS, mean (SD)—SANSIKA study 4.00 (0.00) 4.00 (0.00)
were conducted in accordance with the principles of Good (n=154) (n=90)
Clinical Practice and with the ethical principles set out in the CFS, mean (SD)—SICCANOVE study 2.83 (0.71) 2.80 (0.72)
Declaration of Helsinki. All enrolled patients provided written (n=241) (n=248)
informed consent. Efficacy and safety methods and results OSDI, mean (SD)—SANSIKA study 61.4 (19.4) 58.8 (18.4)
from each study have been previously described15 16; the design (n=154) (n=91)
of both studies is outlined in online supplementary figure 1 and OSDI, mean (SD)—SICCANOVE study 44.41 (21.94) 41.96 (21.84)
briefly described below. (n=241) (n=248)
The SICCANOVE and SANSIKA studies were similar in CFS, corneal fluorescein staining; CsA CE, 0.1% (1 mg/mL) ciclosporin A cationic
design, allowing the data to be pooled for analysis. Both emulsion; DED, dry eye disease; HLA-DR, human leucocyte antigen-DR; OSDI, Ocular
were multicentre, double-masked, parallel-group, controlled Surface Disease Index.
studies conducted in Europe in which patients  ≥18 years
of age with DED were randomised to receive once-daily
CsA CE 0.1% (1 mg/mL) or its vehicle for 6 months. The Statistical analyses
SICCANOVE study included patients with moderate-to-se- CFS–OSDI responder rates were analysed with a logistic regres-
vere DED (in the same eye: ≥1 symptom of ocular discom- sion model (with ‘treatment’ and ‘pooled country’ as factors)
fort with a severity score  ≥2 (on a 4-point scale), tear using imputed data. Study effect was included as a fixed effect
breakup time ≤8 s, corneal fluorescein staining (CFS) score to account for the structure of the data set. The CFS–OSDI
between 2 and 4 (modified Oxford scale; 0 to 5), Schirmer responder rate was analysed in four patient populations: (1) all
test without anaesthesia  ≥2 mm/5 min and  <10 mm/5 min, DED patients (full analysis set (FAS); n=734), (2) severe DED
and corneal/conjunctival lissamine green staining score  ≥4 (n=319; patients with CFS grade 4 and OSDI  ≥23), (3) all
(van Bijsterveld scale)). 16 The SANSIKA study enrolled SS patients (n=269; patients with SS) and (4) SS/severe DED
patients with severe DED (CFS=4 (modified Oxford scale; (n=130; patients with SS and severe DED). Sensitivity analyses
0 to 5), Schirmer test without anaesthesia  ≥2 mm/5 min for CFS–OSDI responder rates were performed using the main
and  <10 mm/5 min, and Ocular Surface Disease Index logistic model on the per-protocol set, on the FAS (observed
(OSDI) score ≥23). 15 All patients who received active treat- data) and on the FAS by treatment received. Sensitivity analyses
ment or vehicle in the SICCANOVE and SANSIKA studies were also performed using the Cochran-Mantel-Haenszel test
were included in the pooled analysis. and controlling for pooled country.
CFS measurements (changes from baseline to month 6) were
analysed by age, sex, menopausal status, SS status and disease
Study assessments and endpoints duration in a subset of patients (n=629) who had CFS values at
Both studies included objective assessments of DED signs, such baseline and at month 6. The model was adjusted for treatment,
as CFS score and Schirmer test, as well as subjective assessments study, visit and treatment by study. HLA-DR data were analysed
of DED symptoms, such as OSDI and visual analogue scales, after logarithmic transformation using an analysis of covariance
which assessed patient symptoms (burning or stinging, foreign model with ‘treatment’ and ‘pooled country’ as fixed factors and
body sensation, itching, eye dryness, pain, blurred vision, sticky baseline score as a covariate. Because the data distribution for
feeling and photophobia). Efficacy was determined only in the HLA-DR expression was found to be log-normal, median, rather
analysis eye, defined as the worst eye meeting the entry criteria than mean, values were reported as a measure of location.
listed above. The primary efficacy endpoint in the pooled anal-
ysis was a composite responder efficacy endpoint (CFS–OSDI) Results
at month 6, defined as an improvement in both CFS (modi- Study population
fied Oxford scale) by ≥2 grades from baseline and OSDI score The pooled FAS (all DED patients) population included 734
by  ≥30%. Human leucocyte antigen-DR (HLA-DR) expres- patients (table 1), 395 CsA CE patients and 339 vehicle patients.
sion on conjunctival epithelial cells (as assessed by impression Most of the patients (84.7%) were women, 43.5% had severe
cytology) at baseline and at month 6 was evaluated to investigate DED and 36.6% had SS. Overall, demographic and baseline
the relationship between disease severity (CFS score) and ocular disease characteristics were well balanced across treatment
surface inflammation. groups.
Ocular and systemic adverse events were monitored
throughout the SICCANOVE and SANSIKA studies (baseline Co-responder analysis
visit through month 6 visit). Other safety assessments included Patients treated with CsA CE were more likely to be CFS–
best-corrected distance visual acuity (BCDVA), intraocular pres- OSDI responders than patients treated with vehicle (figure 1).
sure (IOP) and blood sampling of systemic CsA levels. In the FAS (all DED patients) population, 21.6% of CsA CE
2 Leonardi A, et al. Br J Ophthalmol 2018;0:1–7. doi:10.1136/bjophthalmol-2017-311801
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Figure 1  CFS–OSDI responder rates in the pooled analysis. *Statistically significant difference for CsA CE versus vehicle (P<0.05). Values represent
imputed data. The P values were calculated using a logistic regression model. CFS, corneal fluorescein staining; CsA CE, 0.1% (1 mg/mL) ciclosporin A
in a cationic emulsion; DED, dry eye disease; FAS, full analysis set; OSDI, Ocular Surface Disease Index.

patients achieved a CFS–OSDI response, compared with 13.1% of vehicle patients (P=0.109). However, statistical significance
of patients treated with vehicle (P=0.015). In the subgroup was reached in the subgroup of patients with SS with severe
of patients with severe DED at baseline, 29.5% of patients DED (23.4% for CsA CE patients vs 9.4% for vehicle patients;
with CsA CE achieved a CFS–OSDI response, compared with P=0.030).
18.3% of vehicle patients (P=0.038). In the overall SS group, The ORs for CFS–OSDI response for the individual
differences were not statistically significant: 19.2% of CsA CE and combined studies illustrate the same trends, favouring
patients achieved a CFS–OSDI response, compared with 11.6% CsA CE treatment over vehicle except in the overall SS

Figure 2  Pooled analysis and individual study results for the effect of CsA CE in improving both signs and symptoms (assessed by CFS–OSDI
responder rate) in (A) all patients, (B) patients with severe DED, (C) all patients with SS and (D) patients with SS and severe DED at baseline.
A response was defined as improvement of ≥2 grades in CFS and ≥30% in OSDI. CFS, corneal fluorescein staining; CsA CE, 0.1% (1 mg/mL)
ciclosporin A in a cationic emulsion; DED, dry eye disease; FAS, full analysis set; OSDI, Ocular Surface Disease Index; SS, Sjögren’s syndrome.
Leonardi A, et al. Br J Ophthalmol 2018;0:1–7. doi:10.1136/bjophthalmol-2017-311801 3
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Figure 3  Change from baseline in CFS score at month 6 by patient subgroup in the pooled analysis (n=629). Green boxes represent the estimate
of the difference between groups (least-squares means). Horizontal lines are 95% confidence limits. CFS, corneal fluorescein staining; CL, confidence
limit; CsA CE, 0.1% (1 mg/mL) ciclosporin A in a cationic emulsion; LCL, lower confidence limit; UCL, upper confidence limit; VEH, vehicle.

population (figure 2A–D). In the FAS (all DED patients) in reducing ocular inflammation from baseline to month 6
population (figure 2A), the OR and the 95% CI were 1.66 (P=0.002). Notably, while reductions in HLA-DR expression
(1.11 to 2.50), and in the subgroup of patients with severe DED, were observed with CsA CE for each CFS subgroup, and to a
the corresponding values were 1.80 (1.04 to 3.19) (figure 2B). lesser extent for vehicle with the CFS=2 and CFS=4 subgroups,
The OR and 95% CI in the SS/severe DED population also an increase in HLA-DR expression was seen among patients
favoured CsA CE treatment and indicated a three-times-greater receiving vehicle in the CFS=3 subgroup.
probability of response over vehicle in this patient population
(OR 3.37; 1.20 to 11.19) (figure 2D). Safety findings
Drug-related treatment-emergent adverse events (TEAEs) were
Corneal fluorescein staining reported in 35.9% of CsA CE patients and 20.3% of vehicle
Improvements in CFS score at month 6 favoured CsA CE over patients in the pooled analysis (online supplementary table
vehicle in the overall population (treatment difference –0.303; 1). Drug-related TEAEs were mostly ocular in nature, with
95% confidence limit (CL) –0.464 to –0.142) (figure 3). A no reported incidence of serious systemic events. The most
significant treatment effect in favour of CsA CE was observed frequently reported ocular TEAEs deemed possibly related to
in most patient subgroups in the pooled analysis. Clinical benefit CsA CE treatment were instillation site pain (12.1%), eye irrita-
with CsA CE was most notable in elderly patients (65–74 tion (10.1%) and instillation site irritation (5.1%). Two patients
years of age: treatment difference –0.568, 95% CL –0.897 to experienced serious drug-related ocular TEAEs: one patient in
–0.239;  ≥75 years of age: –0.569,  –1.085 to –0.053), female the CsA CE group had severe corneal epithelial erosion that
patients (–0.349, –0.527 to –0.171) and menopausal patients resolved without sequelae, and one patient in the vehicle group
(–0.433, –0.638 to –0.228). Treatment with CsA CE also had decreased BCDVA; both discontinued therapy. Overall, study
produced improvements in CFS score regardless of SS status (SS discontinuation due to drug-related ocular TEAEs was reported
–0.288, –0.559 to –0.017; no SS –0.321, –0.520 to –0.123). in 9.3% of CsA CE patients and 5.9% of vehicle patients.
There were no clinically significant changes in blood pressure,
Ocular surface inflammation and relationship to DED severity pulse rate or respiratory rate in either treatment group during the
For the 168 patients with HLA-DR data at baseline and month 6, 6-month course of the studies; BCDVA and IOP also remained
baseline HLA-DR expression values were directly proportional stable. At baseline, five patients presented with a serum CsA
to CFS score, indicating that patients with more severe DED value greater than the upper limit of quantification (5.0 mg/mL;
had increased ocular inflammation. Figure 4 shows change in ie, CsA levels that could be reliably quantified); these patients
HLA-DR expression in median arbitrary units of fluorescence were already receiving systemic CsA at a stable dose (as allowed
according to baseline CFS score subgroups (CFS=2, 3 or 4). by the study protocols). At the month 6 visit, 35 patients had
Overall, CsA CE was significantly more effective versus vehicle a detectable serum CsA level that was below the upper limit
4 Leonardi A, et al. Br J Ophthalmol 2018;0:1–7. doi:10.1136/bjophthalmol-2017-311801
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of quantification (ie, CsA levels that could be detected but not chronic inflammatory diseases (eg, fibromyalgia, rheumatoid
reliably quantified), and 11 patients had a quantifiable serum arthritis).22
value; the latter values were considered negligible (highest value The results for CFS change from baseline in this pooled anal-
0.206 ng/mL). ysis were consistent with those obtained in both studies; a mean
treatment difference between CsA CE and vehicle of –0.303 (95%
CL –0.464 to –0.142) was observed for the overall patient popu-
Discussion
lation in the pooled analysis, as compared with a mean treatment
This analysis of pooled data from the SICCANOVE and SANSIKA
studies provides a representative estimation of the efficacy and difference of –0.22 (95% CI –0.39 to –0.06) and –0.35 (95% CI
safety of CsA CE in the treatment of moderate-to-severe DED. –0.671 to –0.021) in SICCANOVE and SANSIKA, respectively;
CsA CE was statistically superior to vehicle in improving both all results were statistically significant.15 16 According to the
signs and symptoms of DED in the overall patient population logarithmic nature of the modified Oxford scale, these findings
(especially in those with severe keratitis) and in patients with SS/ correspond to 30%–50% more punctate epithelial damage of
severe DED, and there was a trend towards greater benefits in the cornea in the vehicle group versus the treatment groups. The
the overall Sjögren’s population; CsA CE also demonstrated a improvement observed with CsA CE, particularly in the more
safety profile consistent with ophthalmic CsA use. severe populations, supports the primary goal for treatment of
Results in this pooled analysis were generally consistent with moderate-to-severe DED─namely, to maintain and protect the
those in the SANSIKA study, which used the composite CFS– ocular surface.23
OSDI response rate as its primary signs and symptoms endpoint. CsA CE also improved signs and symptoms (as assessed by
The SANSIKA study found a CFS–OSDI response rate of CFS–OSDI response) in patients with SS, although the superi-
28.6% in the CsA CE group and 23.1% in the vehicle group ority over vehicle was statistically significant only in the subset
(P=0.326).15 Although statistical significance was not achieved of patients with both SS and severe DED. These findings are of
for CsA CE compared with vehicle in SANSIKA, it should importance, given that DED in patients who have SS, an auto-
be noted that statistical significance was achieved when the
immune form of aqueous-deficient dry eye, is typically more
threshold for improvement of CFS was increased from 2 grades
severe and difficult to treat than in patients without SS.24 25 A
to 3 grades in a post hoc analysis.15 Lack of statistical significance
clear association between ocular surface inflammation (HLA-DR
for the primary endpoint in the SANSIKA study may have been
due to the marked improvement seen with the vehicle, which expression as assessed by conjunctival impression cytology) and
is an unpreserved cationic oil-in-water nanoemulsion that can DED severity was also observed,26 and CsA CE significantly
have a beneficial effect on DED symptoms through improved reduced HLA-DR expression compared with vehicle at month
lubrication and hydration.14 18 Discordance between signs and 6 (overall treatment difference: P=0.002). This effect of CsA
symptoms of DED has been a challenge in the conduct of DED CE on HLA-DR likely derives from CsA CE’s anti-inflammatory
studies.19–21 In this respect, the composite endpoint provides a properties,26–28 and results from this pooled analysis support the
useful joint assessment of signs and symptoms in such a multi- use of HLA-DR expression level as a biomarker to monitor treat-
faceted disease; this approach has also been proposed in other ment response in patients with DED.

Figure 4  Pooled analysis of the relationship between CFS score and HLA-DR expression (as assessed by impression cytology). AUF, arbitrary units of
fluorescence; CFS, corneal fluorescein staining; CsA CE, 0.1% (1 mg/mL) ciclosporin A in a cationic emulsion; HLA-DR, human leucocyte antigen-DR.
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Limitations of this pooled analysis include differences in honoraria from, Alcon Pharma GmbH, Dompé, Pharm-Allergan GmbH, Santen GmbH,
entry criteria for the two studies (moderate-to-severe DED for Shire, Théa Pharma GmbH, TRB Chemedica AG, Ursapharm and VISUfarma and was an
investigator in the SICCANOVE study. ML is a consultant for, or has received a research
SICCANOVE vs severe DED for SANSIKA), which may limit grant from, Alcon, Allergan, Bausch & Lomb, Dompé, Santen and Théa and was an
comparability of the results. However, it should be noted that investigator in the SICCANOVE and SANSIKA studies. MA is an employee of Santen
when applying the ODISSEY algorithm for establishing the SAS. J-SG is an employee of Santen SAS. DI is an employee of Santen SAS. MS-d-l-M
severity of DED,29 both populations are categorised as predom- is a consultant for Santen and was an investigator in the SICCANOVE and SANSIKA
studies. FCF is a consultant for, or has received a research grant from, Allergan, Théa
inantly having severe disease (86.5% in SICCANOVE and 98%
and Santen and was an investigator in the SICCANOVE and SANSIKA studies. CB is a
in SANSIKA at baseline).30 Interestingly, from a geographical consultant for, or has received a research grant from, Alcon, Allergan, Santen and Théa
perspective, the two studies were conducted in Europe in the and was a clinical investigator in the SICCANOVE and SANSIKA studies.
same countries (Spain, France, UK, Italy, Czech Republic and Patient consent  Detail has been removed from this case description/these case
Germany) and many of the same clinical centres, with the excep- descriptions to ensure anonymity. The editors and reviewers have seen the detailed
tion that SANSIKA also recruited patients in Austria and Belgium. information available and are satisfied that the information backs up the case the
Moreover, the recruitment was conducted over multiple months authors are making.
for both studies (18 months for SICCANOVE and 10 months Ethics approval  Both studies described in our article were conducted in
for SANSIKA) in order to avoid biases from seasonal and weath- accordance with the principles of Good Clinical Practice and with the ethical
principles set out in the Declaration of Helsinki. All enrolled patients provided written
er-related conditions.31 informed consent. The studies were registered under the following numbers in the
In conclusion, the combined efficacy and safety data from this EudraCT database: 2011-000160-97 and 2007-000029-23.
pooled analysis suggest that CsA CE—a novel formulation of Provenance and peer review  Not commissioned; externally peer reviewed.
unpreserved single-dose cationic emulsion of ciclosporin  0.1%—
Open Access  This is an Open Access article distributed in accordance with the
has a favourable safety and tolerability profile and is efficacious Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
in improving both signs and symptoms of DED in patients with permits others to distribute, remix, adapt, build upon this work non-commercially,
moderate-to-severe DED (especially those with severe keratitis), and license their derivative works on different terms, provided the original work
including patients with SS with severe DED. is properly cited and the use is non-commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/​4.​0/
Author affiliations © Article author(s) (or their employer(s) unless otherwise stated in the text of the
1
Department of Neuroscience, Ophthalmology Unit, University of Padua, Padua, Italy article) 2018. All rights reserved. No commercial use is permitted unless otherwise
2
Department of Ophthalmology, Ludwig-Maximilian University of Munich, Munich, expressly granted.
Germany
3
Department of Ophthalmology, Bicêtre Hospital, APHP, Paris-Sud University, Le
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Consulting) and Professor Bruno Scherrer for statistical and methodology advice;
9 Labbé A, Baudouin C, Ismail D, et al. Pan-European survey of the topical ocular use of
Lening Zhang of Santen for statistical support; Professor Michael Lemp for help in
cyclosporine A. J Fr Ophtalmol 2017;40:187–95.
study design. The authors also wish to thank all of the investigators involved in the
10 Lallemand F, Felt-Baeyens O, Besseghir K, et al. Cyclosporine A delivery to the eye: a
SICCANOVE and SANSIKA studies (see supplementary appendix for a complete list
pharmaceutical challenge. Eur J Pharm Biopharm 2003;56:307–18.
of names).
11 Lallemand F, Daull P, Benita S, et al. Successfully improving ocular drug delivery using
Contributors  MA, J-SG, DI and CB contributed to the initial study design. MA, DI the cationic nanoemulsion, novasorb. J Drug Deliv 2012;2012:1–16.
and CB wrote the protocol and its amendments. MA, DI and CB reviewed the data 12 Lallemand F, Schmitt M, Bourges JL, et al. Cyclosporine A delivery to the eye: a
quality prior to database lock. AL, EMM, ML, MS-d-l-M, FCF and CB contributed comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm
to the acquisition of data. AL, MA, J-SG, DI and CB contributed to the analysis 2017;117:14–28.
and interpretation of data. MA and DI wrote the first draft of the manuscript with 13 Daull P, Lallemand F, Philips B, et al. Distribution of cyclosporine A in ocular tissues
medical-writing assistance (funded by Santen). AL, EMM, ML, MA, J-SG, DI, MS-d- after topical administration of cyclosporine A cationic emulsions to pigmented rabbits.
l-M, FCF and CB participated in the drafting and critical revision of the manuscript. Cornea 2013;32:345–54.
All authors had full access to the data in the study and were required to approve 14 Daull P, Lallemand F, Garrigue JS. Benefits of cetalkonium chloride cationic oil-in-
the manuscript for submission and publication. AL made the final decision to submit water nanoemulsions for topical ophthalmic drug delivery. J Pharm Pharmacol
the manuscript for publication. AL is the guarantor of this work and, as such, takes 2014;66:531–41.
responsibility for the fidelity of the trial to the protocol and the completeness and 15 Leonardi A, Van Setten G, Amrane M, et al. Efficacy and safety of 0.1% cyclosporine
accuracy of the data. A cationic emulsion in the treatment of severe dry eye disease: a multicenter
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Funding  The SICCANOVE and SANSIKA studies were sponsored by Santen
16 Baudouin C, Figueiredo FC, Messmer EM, et al. A randomized study of the efficacy
SAS (Evry, France), which also provided funding for editorial development of this
and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to
manuscript.
severe dry eye. Eur J Ophthalmol 2017;27:520–30.
Competing interests  AL is a consultant for, or has received a research grant 17 Baudouin C, de la Maza MS, Amrane M, et al. One-year efficacy and safety of 0.1%
from, Allergan, Alcon, MediVis, Santen, SIFI and Théa and was an investigator in the cyclosporine A cationic emulsion in the treatment of severe dry eye disease. Eur J
SICCANOVE and SANSIKA studies. EMM is a consultant for, or has received speaker Ophthalmol 2017;27:678–85.

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