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A comparative clinical trial of the efficacy of two different aqueous solutions of cyclosporine for the treatment of moderate-to-severe dry eye syndrome
  1. Leopoldo Baiza-Durán1,
  2. Javier Medrano-Palafox1,
  3. Everardo Hernández-Quintela2,
  4. Jaime Lozano-Alcazar3,
  5. J Félix Alaníz-de la O4
  1. 1Clinical Research Department, Laboratorios Sophia, S.A. de C.V. Guadalajara, Jalisco, México
  2. 2Asociación para Evitar la Ceguera en México, Hospital Dr. Luis Sánchez Bulnes. México D.F., México
  3. 3Fundación Hospital “Nuestra Señora de la Luz” I.A.P. México D.F., México
  4. 4Antiguo Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Unidad de Oftalmología, Guadalajara, Jalisco, México
  1. Correspondence to Dr Leopoldo Baiza-Durán, Laboratorios Sophia, S.A. de C.V., Av. Paseo del Norte 5255, Guadalajara Technology Park, C.P. 45010, Zapopan, Jalisco, México; drbvista{at}sophia.com.mx

Abstract

Objective To evaluate the efficacy and safety of two different concentrations of cyclosporine A (CsA) in aqueous solution compared to vehicle in patients with dry eye syndrome.

Design Multicentre, randomised, double-masked, vehicle-controlled, clinical trial.

Methods A total of 183 patients were enrolled and randomised to either CsA 1% (group A), CsA 0.05% (group B) or vehicle only (group C). The main objective was to evaluate the efficacy of CsA aqueous solution in the reduction of signs and symptoms in patients with moderate to severe dry eye disease.

Results An early (day 21) statistically significant improvement (p<0.05) was evident in four symptoms and three ocular signs in group A. An equivalent improvement in three symptoms and three ocular signs was demonstrated in group B. A significant improvement was identified in two symptoms and two ocular signs in group C. Comparing the three groups together, group A performed better in four symptoms than group B did with just one symptom. Group C did not show significant improvement. At day 42, group A showed improvement in four symptoms, while group B showed improvement in one symptom and one ocular sign.

Conclusions Cyclosporine A reduced complaints and improved major ocular signs in patients with moderate-to-severe dry eye disease. The group treated with the 0.1% cyclosporine A aqueous solution outperformed the other groups.

  • Dry eye
  • cyclosporine
  • keratoconjunctivitis sicca
  • comparative clinical trial
  • occular surface
  • cornea
  • medical treatment
  • cyclosporine 0.1%

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Introduction

Dry eye syndrome is a common and widespread ocular pathology. It is defined as ‘a disorder of the tear film due to tear deficiency or excessive evaporation that causes damage to the interpalpebral ocular surface and is associated with symptoms of discomfort.’1 Multiple factors are involved in the development of this ocular surface disease, encompassing diverse aetiologies, symptoms, and clinical findings.

Much of the pathophysiology of dry eye has been elucidated in the past years.2 It is now known that inflammation plays an important role in the development and persistance of ketratoconjunctivitis sicca. Although lubricants have long been the mainstay treatment,3 they have limited effect on their own. Control of ocular surface inflammation has greatly contributed to better treatment outcomes in patients with dry eye. The use of topical steroids for such purpose has clinical limitations due to their potential side effects. Consequently, the development of agents that could be used chronically without serious adverse effects was vital. That is where immunomodulatory agents such as cyclosporine A come into action. Cyclosporine A(CsA) inhibits T cell proliferation and prevents the release of pro-inflammatory cytokines by blocking the activity of calcineurin, a ubiquitous enzyme found in cell cytoplasm.4 Several basic and clinical studies have demonstrated the efficacy and safety of CsA in oleic emulsion for the treatment of dry eye.5–13

Nonetheless, currently available systems using oils to deliver CsA topically are poorly tolerated and provide a low bioavailability. These difficulties may be overcome through formulations aimed at improving the water solubility of CsA, facilitating tissue drug penetration, or using penetration colloidal carriers (micelles).14

In our study, we used CsA in aqueous solution with Sophisen, a patented drug carrier. This CsA–carrier association rendered a monodisperse, stable, micelle solution. This formulation is free of benzalkonium chloride.15

Patients and methods

This study was conducted according to the principles of the Declaration of Helsinki and was approved by the Local Research Ethics Committee and investigational site Institutional Review Board of each of the research centres. Informed consent was obtained from each patient. One hundred and eighty-three consecutive patients were evaluated in three of the most important ophthalmologic reference centres in Mexico City (Dr Luis Sánchez Bulnes' Hospital of the Asociación para Evitar la Ceguera en México, Hospital Nuestra Señora de la Luz, and Hospital Civil de Guadalajara). The mean age was 57.0±13 years, and 61% (112) were women. All patients were diagnosed with dry eye disease (DED), associated or not with Sjögren's syndrome. Both eyes were treated and included. Eligibility criteria are listed in table 1.

Table 1

Eligibility criteria

In patients with prior topical medication, a washout period was initiated with methylcellulose 0.5% at least eight times a day for 2 weeks. Thereafter, each subject was randomly assigned to one of three groups. Group A: CsA 0.1% aqueous solution, group B: CsA 0.05% aqueous solution, and group C aqueous vehicle only (Sophisen; Laboratorios Sophia, Guadalajara, Mexico). All patients were prescribed one drop twice daily in both eyes, along with a lubricant (benzalkonium chloride preserved methylcellulose 0.5%) at least eight times a day. In each research centre, all patients were evaluated by the same investigator during screening and follow-up visits (days 16, 21, 42, 70 and 98). Symptoms (dryness, burning, photophobia, tearing, ocular fatigue, and foreign body sensation) and signs (conjunctival hyperaemia, tear break-up time, ocular surface condition, Rose Bengal staining, fluorescein staining, and Schirmer 1 test) of dry eye syndrome were evaluated. Ocular symptoms, were graded using a 4-point scale ranging from 0=rarely to 3=always notice this symptom.16

Clinical signs were recorded as follows. Conjunctival hyperaemia: 0=absent, 1=less than 25% conjunctival surface (bulbar and tarsal); 2=25 to less than 100% conjunctival surface; 3=hyperaemia of the entire conjunctival surface. Corneal surface: 0=no staining, 1=punctate staining, 2=coalescent staining, without stromal involvement, 3=stromal involvement. FBUT: fluorescein tear break-up time. One drop of fluorescein was instillated in each eye, and break-up time was measured three times; the average of the three was recorded in seconds. Fluorescein staining was measured 1 min after instillation of a drop of topical anaesthetic; staining was registered using a standardised grading system of 0–3 for each of the five areas of the ocular surface.1 Rose Bengal staining was noted using the van Bijsterveld grading system.17 For the Schirmer 1 test with anaesthesia (basic secretory test) topical anaesthetic was instilled in the eye, and the excess was blotted from the inferior conjunctival cul-de-sac. The Schirmer's test strips were then draped over the lower eyelid for 5 min. The amount of wetting was recorded in millimetres.

The collected data were logged into Excel 2000 software (Microsoft Corporation, Redmond, Washington, USA) and analysed with SPSS statistical tools (SPSS, Chicago, Illinois, USA; 2002, v 10.0) and GB-STAT (Dynamic Microsystems, v 9.0). Simple correlations and linear regressions were made between the eyes to establish the validity of the use of information from one or both eyes. The following analyses were employed to compare differences both between and within groups: The Friedman test of rank bifactorial variance, ANOVA with Bonferroni's post-hoc method, repeated measurements ANOVA for continuous variables, and the Wilcoxon and Kruskal–Wallis tests for categorical variables. A p≤0.05 was considered statistically significant.

Results

Due to high correlation values between eyes (0.75–0.89; κ = 0.73–0.81) the analysis of both eyes of each patient is presented in a cumulative manner. If eyes were individually analysed, it did not significantly affect the results.

Single group analysis

Group A showed statistically significant improvement in symptoms such as dryness (p=0.041), tearing (p=0.05), and foreign body sensation (p=0.003); as well as signs: break-up time (p=0.0001), Schirmer test (p=0.0001; figure 1), and fluorescein staining (p=0.003) at or beyond day 21. In group B, early improvement was observed in photophobia (p=0.044), tearing (p=0.0001), and foreign body sensation (p=0.0001), corneal surface condition (p=0.049), Schirmer test (p=0.031, figure 1), and fluorescein staining test (p=0.016). Finally, in group C, significant improvement was observed (at or beyond day 21) in dryness (p=0.003), tearing (p=0.0001), foreign body sensation (p=0.022), and tear break-up time (p=0.041).

Figure 1

Schirmer test. Mean values±SE. Group A: CsA 0.1%; group B: CsA 0.05%; group C: vehicle.

Inter-group analysis

Improvement was greatest for group A compared with the other groups at different follow-up visits with regard to symptoms such as red eye (p=0.01 at day 70 vs group C, p=0.012 at day 98 vs group B and, p=0.008 at day 98 vs group C; figure 1), dryness (p=0.008 at day 21 vs group B), photophobia (p=0.015, p=0.011, and p=0.021 for days 16, 42, and 70, respectively), and for ocular fatigue (p=0.011 at day 16 vs group B, p=0.018 at day 16 vs group C, and p=0.001 at day 42 vs group B). The variables that were significantly better in group B (always compared with group C) were the ocular fatigue (p=0.017) and the ocular surface conditions (p=0.02). Group C did not show a significant improvement compared with the other groups. No clinical or statistically significant changes occurred with regard to the ocular health and safety variables evaluated. No serious adverse effects were reported in any of the groups during follow-up.

Discussion

The present findings confirm the beneficial effect of topical CsA on signs and symptoms of dry eye disease. This is the first report of such an effect for this agent to be formally demonstrated in a Hispanic population. Further, previous clinical studies of the topical use of CsA for dry eye syndrome used a castor oil-based emulsion while the present study used a micellated aqueous solution (US patent 6 071 958) that was previously characterised from an ultra structural point of view.15

It is important to emphasise that, in the present study, we observed improvement in the clinical manifestations of dry eye syndrome using both of the CsA concentrations and the vehicle. There are several possible explanations for this. First, the sustained use of methylcellulose as a coadjuvant treatment under supervision by an investigator could have increased the compliance of patients in applying the treatment. Alternatively, the vehicle (Sophisen) used as a placebo and used in the treatment formulations in groups A and B, may have had a positive effect as a lubricant or by some unknown means. Finally, it is evident that the greatest number of variables, in the earliest stages of the trial, and with greatest statistically significant differences occurred most clearly in group A, followed by group B and then group C. This suggests that CsA has a positive effect that is independent of the vehicle and the coadjuvant lubricant treatment and which is dependent on the concentration used.

The CsA concentration of 0.1% had the greatest effect on the burning symptom, even though this concentration itself might contribute to a burning sensation at the time of application.

CsA has been shown, in vivo, to increase the number of goblet cells in patients with dry eye syndrome (related or not to Sjögren's syndrome),18 to reduce the epithelial change,18 to reduce the presence of apoptotic markers,6 11 to modulate the presence of HLA DR,6 to reduce the number of activated lymphocytes,7 to downregulate interleukin 6 expression,8 and to allow greater inflammation control of the ocular surface. These effects may be related to the attenuation effects of inflammatory events that take place in the development and perpetuation of dry eye syndrome.

From a clinical point of view, the study by Gunduz and Ozdemir demonstrated that CsA in olive oil improved the time of lachrymal rupture and reduced the Rose Bengal staining in 15 patients with dry eye syndrome caused by Sjögren's syndrome, when compared with 15 other randomised patients assigned to a placebo group during the 2-month study period.13

A large-scale multicentre study of patients with moderate-to-severe dry eye syndrome (162 patients) showed that CsA emulsions in castor oil at high concentrations of 0.2% and 0.4% showed no additional benefits, while low concentrations of 0.05% and 0.1% were the most appropriate formulations.10 A follow-up clinical phase of the same study involving 877 patients with moderate-to-severe dry eye syndrome tested CsA emulsions concentrations of 0.05% and 0.1%, and a vehicle. This study lasted 6 months and confirmed the positive effect of CsA using both subjective and objective parameters.11

The findings in the present study suggest that an aqueous solution of CsA can have a therapeutic effect on both symptoms and signs and is safe in patients with moderate to severe dry eye syndrome. The 0.1% concentration appears to have a greater benefit than either the 0.05% concentration or the vehicle, when analysed independently. These observations support the idea that CsA could have an even more relevant role in the management of dry eye syndrome.13 19 20 Further comparative studies are warranted to determine whether the aqueous solution used in the present study is equivalent to the commercially available oil-based formulation.

Acknowledgments

The authors thank Anel De Luca, MD, for her invaluable help in writing this paper.

References

Footnotes

  • Competing interests LB-D and JM-P are employees of the Clinical Research Department of Laboratorios Sophia, S.A. de C.V., which manufactures and distributes the cyclosporine aqueous solution. The other authors have no competing interests.

  • Ethics approval This study was conducted with the approval of the Ethics Committees of the following hospitals: Hospital “Dr. Luis Sánchez Bulnes” of the Asociación para Evitar la Ceguera en México, I.A.P., México D.F., México; Fundación Hospital “Nuestra Señora de la Luz” I.A.P. México, D.F., México; and Antiguo Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Unidad de Oftalmología; Guadalajara, Jalisco, México.

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

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