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Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies
  1. Andrea Leonardi1,
  2. Elisabeth M Messmer2,
  3. Marc Labetoulle3,
  4. Mourad Amrane4,
  5. Jean-Sébastien Garrigue4,
  6. Dahlia Ismail4,
  7. Maite Sainz-de-la-Maza5,
  8. Francisco C Figueiredo6,
  9. Christophe Baudouin7,8,9
    1. 1 Department of Neuroscience, Ophthalmology Unit, University of Padua, Padua, Italy
    2. 2 Department of Ophthalmology, Ludwig-Maximilian University of Munich, Munich, Germany
    3. 3 Department of Ophthalmology, Bicêtre Hospital, APHP, Paris-Sud University, Le Kremlin Bicêtre, France
    4. 4 Santen SAS, Evry, France
    5. 5 Institute Clinic of Ophthalmology, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
    6. 6 Department of Ophthalmology, Royal Victoria Infirmary, Newcastle University, Newcastle upon Tyne, UK
    7. 7 Quinze-Vingts National Ophthalmology Hospital, Paris, France
    8. 8 Vision Institute, INSERM UMRS968, CNRS UMR7210, UPMC University, Paris, France
    9. 9 University of Versailles Saint-Quentin en Yvelines, Versailles, France
    1. Correspondence to Dr Andrea Leonardi, Giustiniani 2, 35128 Padova, Italy ; andrea.leonardi{at}


    Background/aim To assess the treatment effect of 0.1% ciclosporin A cationic emulsion (CsA CE) versus vehicle on signs/symptoms of dry eye disease (DED) in various subgroups (moderate-to-severe DED/severe DED/Sjögren’s syndrome (SS)/SS with severe DED).

    Methods Pooled data were analysed from two similar phase III studies: SICCANOVE (moderate-to-severe DED) and SANSIKA (severe DED with severe keratitis). In both studies, patients aged ≥18 years received CsA CE 0.1% (n=395) or vehicle (n=339) once daily for 6 months. A composite responder efficacy endpoint (corneal fluorescein staining–Ocular Surface Disease Index (CFS–OSDI) at month 6) was used to evaluate the efficacy of CsA CE in alleviating signs/symptoms of DED (response defined as improvement of ≥2 grades in CFS and ≥30% in OSDI (baseline to month 6)). Human leucocyte antigen-DR (HLA-DR) conjunctival expression was used as a biomarker of ocular surface inflammation.

    Results CsA CE–treated patients were significantly more likely to be CFS–OSDI responders than vehicle-treated patients in the overall (OR 1.66, 95% CI 1.11 to 2.50; P=0.015), severe DED (1.80, 1.04 to 3.19; P=0.038) and SS with severe DED (3.37, 1.20 to 11.19; P=0.030) populations. The difference was not significant for CsA CE versus vehicle for the overall Sjögren’s population (OR 1.77, CI 0.89 to 3.66; P=0.109). CsA CE also significantly reduced median HLA-DR expression versus vehicle at 6 months (P=0.002).

    Conclusion Pooled phase III data indicate CsA CE produced significant improvement in signs/symptoms versus vehicle in patients with moderate-to-severe DED (especially in those with severe keratitis), including patients with SS with severe DED.

    • ocular surface
    • tears
    • treatment medical

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

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    • Contributors MA, J-SG, DI and CB contributed to the initial study design. MA, DI and CB wrote the protocol and its amendments. MA, DI and CB reviewed the data quality prior to database lock. AL, EMM, ML, MS-d-l-M, FCF and CB contributed to the acquisition of data. AL, MA, J-SG, DI and CB contributed to the analysis and interpretation of data. MA and DI wrote the first draft of the manuscript with medical-writing assistance (funded by Santen). AL, EMM, ML, MA, J-SG, DI, MS-d-l-M, FCF and CB participated in the drafting and critical revision of the manuscript. All authors had full access to the data in the study and were required to approve the manuscript for submission and publication. AL made the final decision to submit the manuscript for publication. AL is the guarantor of this work and, as such, takes responsibility for the fidelity of the trial to the protocol and the completeness and accuracy of the data.

    • Funding The SICCANOVE and SANSIKA studies were sponsored by Santen SAS (Evry, France), which also provided funding for editorial development of this manuscript.

    • Competing interests AL is a consultant for, or has received a research grant from, Allergan, Alcon, MediVis, Santen, SIFI and Théa and was an investigator in the SICCANOVE and SANSIKA studies. EMM is a consultant for, or has received speaker honoraria from, Alcon Pharma GmbH, Dompé, Pharm-Allergan GmbH, Santen GmbH, 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 grant from, Alcon, Allergan, Bausch & Lomb, Dompé, Santen and Théa and was an investigator in the SICCANOVE and SANSIKA studies. MA is an employee of Santen SAS. J-SG is an employee of Santen SAS. DI is an employee of Santen SAS. MS-d-l-M 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 and Santen and was an investigator in the SICCANOVE and SANSIKA studies. CB is a consultant for, or has received a research grant from, Alcon, Allergan, Santen and Théa and was a clinical investigator in the SICCANOVE and SANSIKA studies.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval Both studies described in our article were conducted in 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 informed consent. The studies were registered under the following numbers in the EudraCT database: 2011-000160-97 and 2007-000029-23.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The authors thank Professor Françoise Brignole-Baudouin and Luisa Riancho for analyses and interpretation of HLA-DR results; Maëva Deniaud (MDSTAT Consulting) and Professor Bruno Scherrer for statistical and methodology advice; Lening Zhang of Santen for statistical support; Professor Michael Lemp for help in study design. The authors also wish to thank all of the investigators involved in the SICCANOVE and SANSIKA studies (see supplementary appendix for a complete list of names).

    • Correction notice This article has been corrected since it was published Online First. The Correspondence to address has been changed to "Giustiniani 2, 35128 Padova, Italy".

    • Presented at Selected data have been presented in abstract/poster format at the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) 2016, 1–5 May, Seattle, WA, USA (Poster A0080); the European Association for Vision and Eye Research (EVER) 2016 Congress, 5–8 October, Nice, France (Poster S064); and the Medical Contact Lens and Ocular Surface Association (MCLOSA) 2016 Annual Scientific Meeting, 25 November, London, England.

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