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Journal Français d'Ophtalmologie
Volume 37, n° 8
pages 589-598 (octobre 2014)
Doi : 10.1016/j.jfo.2014.05.001
Received : 8 January 2014 ;  accepted : 9 May 2014
Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease – A randomised comparative study
Tolérance oculaire et efficacité d’une émulsion cationique chez des patients présentant un syndrome sec oculaire léger à modéré – étude randomisée comparative
 

M. Amrane a, , C. Creuzot-Garcher b, P.-Y. Robert c, D. Ismail a, J.-S. Garrigue a, P.-J. Pisella d, C. Baudouin e, f, g
a Santen SAS, 1, rue Pierre-Fontaine, 91058 Evry cedex, France 
b Service d’ophtalmologie, CHU de Dijon, 3, rue du Faubourg-Raines, 21000 Dijon, France 
c Service d’ophtalmologie, CHU Dupuytren, 2, avenue Martin-Luther-King, 87000 Limoges, France 
d Service d’ophtalmologie, CHU Bretonneau, 2, boulevard Tonnellé, 37000 Tours, France 
e Service d’ophtalmologie, Centre national d’ophtalmologie des Quinze-Vingts, institut de la vision, université Paris 6, 28, rue de Charenton, 75012 Paris, France 
f Hôpital Ambroise-Paré, AP–HP, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France 
g Université de Versailles Saint-Quentin-en-Yvelines, 55, avenue de Paris, 78000 Versailles, France 

Corresponding author.
Summary
Purpose

The purpose of this study was to compare the safety and efficacy of a new cationic emulsion (CE) with a formulation of polyvinyl alcohol and povidone (PVA-P) for the treatment of mild to moderate dry eye disease.

Methods

This was a multicenter, open-label, comparative study. Patients were randomised to receive CE (Cationorm®) or PVA-P (Refresh®) (1:1). The following objective criteria were assessed to compare the two eye drops: tear Break-up Time (TBUT), Schirmer's test, lissamine green staining (Van Bijsterveld score), corneal fluorescein staining (Oxford scale) and oculopalpebral examination, on D7 and D28 (end of study). At these visits, ocular symptoms and safety were also assessed.

Results

Seventy-nine patients were randomised: CE: 44 patients; PVA-P: 35 patients. At D28, improvement was significantly better for TBUT [CE: 1.7±2.4 s; PVA-P: 0.6±1.8 s; P =0.015] and for the Van Bijsterveld score [CE: −1.4±1.2; PVA-P: −0.9±1.2; P =0.046] in the CE group. The same applied for the palpebral erythema score (P =0.023), overall efficacy assessed by the investigators (P <0.001), and symptoms not related to eye drop instillation (P =0.021). Improvement was observed from D7. No difference was observed between the two treatments with regard to ocular safety.

Conclusion

These results suggest that in patients with mild to moderate dry eye, Cationorm®, in addition to its moisturizing and lubricating properties, also helps stabilize the tear film due to its oily component. This study demonstrates the benefit of this new pharmaceutical form for the treatment of mild to moderate dry eye disease.

The full text of this article is available in PDF format.
Résumé
Objectif

L’objectif de l’étude était de comparer la tolérance et l’efficacité d’une nouvelle émulsion cationique (EC) à une formulation d’alcool polyvinylique et povidone (APV-P) dans le traitement de la sécheresse oculaire légère à modérée.

Méthodes

Étude multicentrique, en ouvert, comparative. Les patients étaient randomisés pour recevoir EC (Cationorm®) ou APV-P (Refresh®) (1:1). La comparaison a porté sur des critères objectifs [temps de rupture du film lacrymal (TBUT), test de Schirmer, test au vert de lissamine (score de Van Bijsterveld), imprégnation cornéenne à la fluorescéine (échelle d’Oxford) et examen oculopalpébral], ainsi que sur les symptômes oculaires et la tolérance à j7 et j28 (fin d’étude).

Résultats

Soixante-dix-neuf patients ont été randomisés : EC, 44 patients ; APV-P, 35 patients. À j28, l’amélioration apportée par EC était significativement supérieure sur le TBUT [EC, 1,7±2,4s ; APV-P, 0,6±1,8s ; p =0,015] et le score de Van Bijsterveld [EC, −1,4±1,2 ; APV-P, −0,9±1,2 ; p =0,046]. Il en était de même pour le score de l’érythème palpébral (p =0,023), de l’efficacité globale par les investigateurs (p <0,001) et des symptômes non liés à l’instillation (p =0,021). Les améliorations étaient observées dès j7. Aucune différence n’a été observée dans la sécurité oculaire des deux traitements.

Conclusion

Ces résultats suggèrent que chez les patients présentant un œil sec léger à modéré, Cationorm®, outre ses propriétés hydratantes et lubrifiantes, permettrait également de stabiliser le film lacrymal grâce à sa composante huileuse. Cette étude montre l’intérêt de cette nouvelle forme galénique dans le traitement de la sécheresse oculaire légère à modérée.

The full text of this article is available in PDF format.

Keywords : Dry eye, Tear film, Cationic emulsion

Mots clés : Œil sec, Film lacrymal, Émulsion cationique


Introduction

Dry eye disease is one of the most common ophthalmic conditions, affecting at least 15% of people over 65 years old [1, 2]. Women are twice as likely to suffer from it as men [3]. Dry eye is a chronic disease with a significant impact on the quality of life of patients [4]. Dry eye disease falls into two major classes: evaporative dry eye due to an anomaly in the quality of the tears, with instability and excessive evaporation of the tear film; and aqueous-deficient dry eye due to a decrease in tear secretion by the lacrimal glands [2, 5, 6]. In both cases a cascade reaction is set up, creating a vicious circle in which ocular dryness becomes chronic and the symptoms self-sustaining [2, 5].

Thus, instability of the tear film plays a crucial role in the development and the self-sustaining nature of dry eye [2, 5]. However, the majority of existing treatments rely on the use of aqueous tear substitutes, such as saline solutions or aqueous polymer gels, designed to artificially compensate the water content of the tear film in order to temporarily restore the lubricating, hydrating and protective properties, without any real effect on the stability of the tear film or any anti-evaporative role [7, 8].

In order to meet this therapeutic need, research has focused on new formulations, such as emulsions [9]. These new ophthalmic formulations, based on oil droplets stabilized by a film of surfactants and dispersed in an aqueous phase, would help stabilize the tear film by the addition of lipids to the external lipid layer [10, 11, 12, 13]. More recently, the concept of cationic emulsions was introduced, that is to say emulsions whose oil droplets are positively charged in order to create an interaction between the emulsion and the negatively charged ocular surface by electrostatic attraction [13, 14, 15]. The bio-adhesive properties of these cationic emulsions should make it possible to supplement more sustainably the three layers of the tear film, especially the lipid layer, which prevents tears from evaporating, and the mucus layer, which enables protection and healing of the corneal epithelium [13].

This has led to the development of a new cationic emulsion that combines cetalkonium chloride (CKC), an extremely lipophilic quaternary ammonium, with droplets of mineral oils. This emulsion is hypotonic (around 200mOsm/kg) and contains glycerol, a tonicity-adjusting agent, combining the properties of osmocorrection and osmoprotection [16]. The product's viscosity is similar to that of tears (about 1.13 mm2/s) and thanks to the electrostatic attraction between the cationic emulsion and the ocular surface, the spreading upon instillation is optimal (surface tension of about 40 mN/m and spreading coefficient of about −10mN/m). Thus the physicochemical properties of this cationic emulsion help meet the expected anti-evaporative, osmotic and rheological properties [8, 13, 17, 18]. In contrast to benzalkonium chloride (BAK), used as a preservative in certain eye drops [19, 20], this CKC-containing emulsion has additionally demonstrated excellent ocular tolerability, without any detergent properties, as animal studies have shown [13, 21, 22]. Thus as CKC is used purely for its cationic properties, this emulsion is preservative-free and supplied in single-dose-container or multi-dose container.

The aim of this clinical trial was to compare the tolerability and efficacy of this cationic emulsion with the reference artificial tears containing polyvinyl alcohol and povidone in the treatment of patients with mild to moderate bilateral dry eye disease.

Methods
Study design

This comparative, open-label, randomised, multicenter, phase II clinical study was conducted in patients with mild to moderate dry eye disease, treated for at least 3 months. Following the positive opinion of the Ethics Committee of Île-de-France VII, the trial was conducted in 15 French study centres (ophthalmologists from private practice and hospitals) between September 2007 and February 2008, in compliance with Good Clinical Practices and the principles outlined in the latest version of the Declaration of Helsinki.

Given the difference in visual appearance of the study products (milky appearance of the cationic emulsion, as against the transparent comparator), a double-masked study has not been possible.

Patients

The included patients were men and women 18 years of age and over, who had given their written informed consent and whose dry eye disease had been under treatment for at least 3 months.

The diagnosis of mild to moderate dry eye disease [8, 23] was validated by the presence of at least two of the following bilateral dry eye symptoms [score1 on a 0 to 3-point scale (0=absent; 1=mild; 2=moderate; 3=severe)]: burning/stinging, eye dryness, itching, pain, sandy feeling/grittiness, sticky feeling, foreign-body sensation, photophobia; and the presence of at least three of the following four objective parameters in each eye:

mean tear film Break-up Time (TBUT) ≤10s [24];
Schirmer's test without anaesthesia ≤10mm/5min;
corneal fluorescein staining score>1 (Oxford scale [25]);
lissamine green staining total score ≥3 (Van Bijsterveld score [26]).

The main exclusion criteria were:

severe dry eye disease defined by the presence of at least one of the following criteria: need for at least 8 instillations/day of artificial tears, confluent superficial punctate keratitis>2 (Oxford scale [25]), conjunctival hyperaemia with a score>3 (McMonnies scale [27]), moderate or severe blepharitis, conjunctival chemosis ≥2 on a 0 to 4-point scale;
ocular inflammation (Tyndall score>0);
history of ocular allergy.

Study schedule

This clinical trial comprised four visits:

a screening visit preceding the stop of the treatment for dry eye of 7 to 10 days and its replacement by sodium chloride (Unilarm®, Europhta, Monaco);
an inclusion/randomisation visit;
two follow-up visits on D7 and D28 (end of study assessment).

Included patients were randomised either into the CE group (cationic emulsion) – Cationorm® preservative-free single-dose eye drops (Santen SAS ex-Novagali Pharma, Evry, France), or into the PVA-P group (polyvinyl alcohol/povidone) – Refresh® preservative-free single-dose eye drops (Allergan, Irvine, USA). These eye drops were instilled at the rate of one drop into each eye four times daily (morning, noon, afternoon and after dinner) over the 28 days of the study. At the time of the inclusion visit and follow-up visits (D7 and D28), patients were instructed not to use any eye drop within two hours before the visit. During the inclusion visit and final visit (D28), the study product was instilled at the end of the first evaluations and another series of evaluations was performed 30minutes after instillation in order to obtain data related to instillation.

At inclusion and at each of the follow-up visits, a set of assessments relating to objective efficacy was conducted. The TBUT and the lissamine green staining were assessed before and after instillation, at inclusion and at D28 and at the start of the consultation at D7, and Schirmer's test was measured at the start of each consultation. At the end of the study and after the last instillation, the investigator rated the global efficacy and global local treatment tolerance (scale from 0=very satisfactory to 3=unsatisfactory); and the patient assessed the comfort of use (“drops comfortable?” yes/no).

The objective signs were assessed by a slit-lamp examination and corneal fluorescein staining, before and after instillation at each study visit. Subjective ocular symptoms (before and after instillation) were assessed by the patient on a grading scale of 8 ocular symptoms used at the start of each visit and 30minutes after instillation at the consultations at inclusion and at D28.

Finally, ocular safety [visual acuity (VA) and intraocular pressure (IOP)] was assessed on D28 (in comparison with the values on inclusion) and systemic safety on D7 and D28.

Statistical analyses

The efficacy analyses were performed on an intent-to-treat (ITT) basis according to theoretical randomisation groups, and the tolerability analyses according to the treatment actually taken.

The significance level (α) was fixed at 5% bilaterally for all the study comparisons, with no adjustment for multiplicity for this phase II study. Similarly, the number of patients was not determined by statistical calculation but was set arbitrarily at 30 per group based on similar studies.

For all the clinical parameters measured in this study, descriptive statistics presented have been adjusted to the distribution of the variables.

Moreover, for analysing the change in the quantitative parameters between inclusion and D7 or D28, an analysis of variance model with GEE (generalized estimating equations) was used, allowing simultaneous analysis of both eyes of each patient, by modelling the corresponding covariance [28]. This model with one fixed factor (the treatment) has made it possible to estimate adjusted means (LS–means), confidence intervals and the P -value of the inter-group differences for the values observed at each visit, relative to the values on inclusion.

Post-hoc analyses were also conducted on the proportion of responders (a response being defined as an improvement of 30% or more in the symptoms unrelated to the instillation on D28) as well as an analysis integrating the parameter on Meibomian gland dysfunction (MGD or non-MGD) at inclusion.

Results
Initial patient characteristics

Seventy-nine patients with mild to moderate dry eye disease were randomised by the 15 participating study centres. The ITT population consisted of 44 patients randomised into the CE group and 35 into the PVA-P group. As a result of an error by one of the investigators, one patient randomised into the PVA-P group received a treatment batch intended for the CE group. Thus, 34 patients have actually been treated with Refresh® and 45 with Cationorm®.

The mean age of the patients was similar in both treatment groups (CE: 61.3±15.4 years; PVA-P: 61.9±12.5 years) with more women in the CE group (90.9% versus 80.0%). The percentage of patients with systemic medical history was similar in both treatment groups (CE: 54.5%; PVA-P: 60.0%), and arterial hypertension was the most common systemic history (15.9% versus 22.9%). Regarding medical and surgical ophthalmological history, differences were observed between the two groups of patients in cataract (CE: 18.2%; PVA-P: 5.7%) and phacoemulsification (13.6% versus 0%).

At baseline, the evaluations relating to dry eye were similar in both treatment groups, for Schirmer's test, lissamine green staining (Van Bijsterveld score), TBUT, and also for Corneal fluorescein staining (Oxford scale) (Table 1).

Regarding oculopalpebral slit-lamp examination, the characteristics at baseline were the same apart from the lens opacification (Table 2). For each eye, patients’ assessment of the eight symptoms unrelated to instillation was comparable in both treatment groups (Table 3).

Considering treatment compliance, the large majority of the patients did instill the study treatment four times a day for the 29 days of the study (D1 to D7: 95.5 versus 91.4%; D8 to D28: 79.1 versus 80.0%).

Clinical results
Tear film break-up time (TBUT)

At D0 (before instillation), the TBUT was 5.8±1.7s in the CE group and 5.9±1.7s in the PVA-P group. At D7 the improvement in the TBUT in comparison to D0 before instillation was similar in both treatment groups (Table 1). However, at D28 the mean TBUT continued to improve in the CE group reaching 7.4±3.0s before instillation, whereas in the PVA-P group, a plateau was reached between D7 and D28 (6.6±2.8 s; 6.5±2.8 s, respectively). The improvement in the TBUT at D28 before instillation was significantly greater for CE than for PVA-P (P =0.015, Table 1).

Lissamine green staining (Van Bijsterveld score)

At D0 (before instillation), the staining scores were 3.4±1.2 and 3.5±1.4 in CE and PVA-P groups, respectively. At D28 before instillation, the score was 1.9±1.3 in the CE group compared to 2.6±1.3 in the PVA-P group; the improvement was greater in the Cationorm® group than in the Refresh® group (P =0.046) (Table 1).

Schirmer's test (without anaesthesia)

At D0 (before instillation), the scores for Schirmer's test were 6.9±2.4 and 6.8±2.9 in CE and PVA-P groups, respectively. This test revealed an improvement in the lacrimal secretion from D7, which was regular during the study in both treatment groups, with a slightly greater improvement at D28 in the CE group to reach a mean value of 8.8±4.1, as against 8.1±4.7mm in the PVA-P group (Table 1), but without any statistical difference between the groups.

Corneal fluorescein staining (Oxford scale)

At D0 (before instillation), the mean staining scores were 1.6±0.5 and 1.7±0.5 in CE and PVA-P groups, respectively. At D28 before instillation the score improved in both groups to reach 1.0 ± 0.6 in the CE group compared with 1.2±0.8 in the PVA-P group, without any statistical difference between groups (results based on the treatments actually taken, Table 1).

Changes in the oculopalpebral examinations

An improvement in the erythema score for the eyelids and eyelid margins was observed from D7 in patients actually treated with Cationorm®, in contrast to those treated with Refresh® (−0.21±0.64 and +0.04±0.27, P =0.015, respectively). The improvement was maintained in the CE group with a significant difference compared with the control group at D28 before instillation (P =0.023) (Table 2).

The scores at D7 and D28 for oedema of the eyelids and eyelid margins, Meibomian gland obstruction, conjunctival chemosis, conjunctival erythema and debris in the tear film decreased compared to the initial scores in both treatment groups, with no significant difference between the groups (Table 2).

Initial oculopalpebral examinations (5minutes after instillation) revealed hyperaemia in both eyes of three patients in the CE group and one patient in the PVA-P group. These clinical signs improved in both groups at D28; in two patients in the CE group in particular, the examinations were normal at D28, although these patients had McMonnies scores of 2 and 3 at baseline (D0).

Changes in ocular symptoms

The scores for the patient-assessed symptoms unrelated to instillation improved significantly in both treatment groups from D7. The improvement was always greater in the group actually treated with CE as compared to the PVA-P group (Table 3), but only reached a statistically significant difference for the “sensation of ocular dryness” symptom at D28 (P =0.037). However, as regards the total score (sum of the scores for the 8 symptoms), the improvement was significantly greater in the CE group at D7 [−2.7±2.5 (−35.5%) versus −1.6±2.0 (−21.1%), respectively, P =0.020] and at D28 [−3.7±3.2 (−48.7%) versus −2.3±2.3 (−30.3%), respectively, P =0.021].

The scores for the subjective ocular symptoms related to CE instillation were similar to those of the patients in the PVA-P group. Thus, the total score for the eight ocular symptoms at D28 did not show any difference after instillation of the study product between the two treatment groups.

Global treatment efficacy

The assessment by the investigators of the global efficacy was favourable for the cationic emulsion (P <0.001) with a satisfactory or very satisfactory result for 81.4% of patients (35 patients out of 43), versus 40.0% for the control group (14 patients out of 35).

Ocular tolerability and safety

In both treatment groups, the great majority of patients judged the treatment to be comfortable [Cationorm®: 97.7% (42 patients out of 43); Refresh®, 91.4% (32 patients out of 35)]. Local tolerability was considered by investigators to be satisfactory or very satisfactory for the large majority of patients [CE: 97.7% (42 patients out of 43); PVA-P 91.4% (32 patients out of 35)].

No difference was observed in ocular safety of the two study products. Thus, the mean corrected visual acuity at D28 was unchanged in both groups, and the IOP was stable (CE: +0.2±1.6 mm Hg; PVA-P: +0.5±1.2 mm Hg). The number of patients with at least one adverse event (AE) was small (CE: 3 patients; PVA-P: 2 patients). One patient in the CE group stopped the treatment due to a bilateral palpebral oedema and stinging, possibly treatment-related according to the investigator.

Post-hoc analyses

The proportion of responders (patients with an improvement of 30% or more in the symptoms unrelated to the instillation at D28) was significantly greater in the CE group, with 43.6% of responders at D28, as against 24.4% in the control group (P =0.045).

The efficacy analysis, depending on the absence or presence of Meibomian gland dysfunction (MGD) has involved respectively 89 eyes in the non-MGD subgroup (56.3%) and 69 MGD eyes (43.7%) graded from mild (n =54, 78.3%) to moderate (n =15, 21.7%).

At Day 28, the improvement in the TBUT was greater with CE than with PVA-P for eyes with MGD (+2s versus +0.5 s, P =0.0349) (Table 4). In the non-MGD subgroup, the improvement in the TBUT in the CE group was also greater than that obtained with PVA-P (+1.4s versus +0.6s). As regards the lissamine green staining, the eyes with MGD treated with CE showed a slightly greater improvement in the Van Bijsterveld score than the non-MGD group, whereas improvement was identical in both subgroups of eyes treated with PVA-P. The improvement observed for the MGD eyes was significantly greater in the CE group than the PVA-P group (P =0.0268, Table 4). The change in the total symptom score (score from 0 to 24) confirmed these results, with a significantly greater improvement in the MGD eyes treated with CE in comparison with those treated with PVA-P (P =0.0046), and as in the case of the previous signs, a similar tendency was observed in non-MGD eyes. As in the general study population, there was no difference between the treatments in both subgroups for the corneal fluorescein staining (Table 4).

Discussion

The choice of selection and evaluation criteria in this comparative clinical study relied on the main tests carried out in usual practice and used in clinical trials. The selection criteria chosen were similar to the criteria used to diagnose patients with mild to moderate dry eye disease in accordance with the recommendations of the International Task Force (ITF) of the Delphi panel on dry eye [5, 8, 23]. The study treatments were evaluated with the recommended and commonly-used tests [Schirmer's test, Break-up Time (TBUT), corneal fluorescein staining, lissamine green staining and slit-lamp examination], supplemented by patient assessment of the eight symptoms associated with the disease, as well as an assessment of treatment satisfaction by patients and investigators [29, 30]. The assessment time for dry eye treatments other than anti-inflammatories and secretagogues is usually relatively short [29]. Thus, clinical trial duration of 28 days was regarded as sufficient for comparing artificial tears and a new cationic emulsion (CE) that was expected to be more effective overall and faster-acting in treating dry eye [13].

This cationic emulsion was compared with reference artificial tears containing polyvinyl alcohol and povidone (PVA-P) in the treatment of patients with mild to moderate bilateral dry eye disease that had been treated for at least three months. Therefore, in order to obtain baseline inclusion values under identical conditions for all patients, this treatment was discontinued and replaced by a sodium chloride treatment lasting 7 to 10 days. Patients were then included in the study and randomised into one of the two treatment groups (CE/PVA-P). However, given the difference in appearance of the study products, this clinical trial was conducted in an open-label fashion, thus exposing the assessment of the less objective criteria to possible bias.

The inclusion and exclusion criteria corresponding to a mild to moderate dry eye disease were validated for all patients [5]. The initial characteristics of the study population are in agreement with literature data, with a predominance of women and patients over the age of 50 [1, 6]. The initial characteristics were similar for both groups, apart from the percentage of women and the number of patients with cataract, which were higher in the CE group. In addition, compliance was good and comparable in the two groups during the trial treatment period.

After 28 days of treatment, tear secretion as assessed by Schirmer's test had increased in both groups to reach values close to the threshold of normality [31]. Measurement of the TBUT before instillation showed a moderate improvement in both treatment groups on D7, but a significantly greater improvement was observed at D28 in the CE group. Thus, the integrity of the tear film at the end of the study was further enhanced in patients treated with the cationic emulsion, with a mean value (7.4s) closer to the minimum normal threshold (10s) [24]. This result corroborates the results observed with mineral oils, which allow a thicker film to form [17] and could thus reinforce the lipid layer necessary for the control of evaporation and the stabilisation of the tear film [13]. The lissamine green staining showed a decrease in the Van Bijsterveld score as soon as D7. At D28, this improvement continued, reaching a 41% decrease in the pre-instillation score in patients treated with the cationic emulsion, a significantly greater improvement than that observed with PVA-P. This improvement in corneal and conjunctival lesions was also significantly greater in the CE group after instillation. This improvement observed with the lissamine green dye, which theoretically stains dead cells or cells not covered by mucus and therefore exposed to desiccation [32], suggest that the cationic emulsion has a protective action on the ocular surface.

The results of corneal fluorescein staining and Schirmer's test, while not statistically significant, do also indicate an improvement in the quality of the tear film. These results are in agreement with those observed in other tear film studies [33, 34].

The cationic emulsion would thus act on all levels of the tear film and would ensure a better protection of the ocular surface. This result is supported by the investigators’ overall perception of efficacy.

In both treatment groups, almost all the patients judged the treatment comfortable.

Patients’ assessment of the symptoms unrelated to instillation is in agreement with these clinical results, even though it is less objective in the case of this open-label study, since an important improvement is observed in both treatment groups from D7, and this is always greater in the CE group on D7 and on D28. This decrease in the total score for the eight symptoms after one week of treatment with the cationic emulsion (−35.5%) was equivalent to that obtained with the reference artificial tears after 28 days of treatment (−30.3%).

An assessment of the number of responder patients was also conducted. The proportion of responders was defined a posteriori, a response being considered as an improvement of 30% or more in the symptoms unrelated to eye drop instillation at D28. This value was chosen by analogy to the value used in other therapeutic domains and considered as clinically relevant for calculating the proportion of patients responding in respect of the symptoms or pains of a disease or condition (for example, fibromyalgia, cancer, arthritis, bowel disorder, etc.). At D28, the greater rate of responders in the CE group than in the control group bears out the objective results observed in this study.

Furthermore, obstruction of Meibomian glands causes disturbances in the tear film, with repercussions on certain characteristics of dry eye disease [5, 35, 36]. A post-hoc efficacy analysis including the MGD factor (eyes with or without mild to moderate Meibomian gland dysfunction), confirmed the efficacy results for the cationic emulsion as regards the signs and symptoms of dry eye disease. The significantly greater efficacy of the cationic emulsion on TBUT and lissamine green staining, compared with PVA-P, in the MGD subgroup, back up the data suggesting that the cationic emulsion may act on the tear film.

Thus, in the context of dry eye disease with keratitis and associated with MGD, the oil-in-water cationic emulsion could prove especially useful, since in addition to its lubricating properties, its oily component could serve to stabilise the tear film when the external lipid layer is defective [13].

Ocular safety was good and no difference was observed between the two products, with VA and IOP being stable in both treatment groups. The number of patients with at least one adverse event was low in both treatment groups. The cationic emulsion thus showed good tolerability and safety of use, equal to those of the reference treatment, during the 28 days of the study treatment.

Conclusion

In this clinical trial the integrity of the tear film was further strengthened in patients treated with Cationorm® with a greater improvement of the lissamine green staining score. This result was accompanied by an improvement of ocular symptoms experienced by the patients. In addition, Cationorm® preservative-free proved to be safe and well tolerated in these patients.

The results of this study suggest that in patients with mild to moderate dry eye, Cationorm® could be particularly useful because in addition to its lubricating and moisturizing properties, it would also stabilize the tear film through its oily component. This cationic emulsion provides a new therapeutic alternative for patients with mild to moderate dry eye, particularly among those with Meibomian gland dysfunction.

Disclosure of interest

M.A., D.I. and J.-S.G. are employees of Santen SAS.

C.CG., P.-Y.R. and P.-J.P. were investigators of the study.

C.B. was coordinating investigator of the study.


Acknowledgements

The authors would like to thank Maëva Deniaud for statistical advice and Robert Campos-Oriola for help in medical writing.

The authors also thank the investigators of the study: Dr Yvon Arnoux, Dr Nina Besnaïnou, Dr Marie-Noëlle Boudouard, Dr Anne Chrétien-Malinchoni, Dr Gérard Decroix, Dr Olivier Dussueil, Dr François Hanoun, Dr Philippe Jacquelin, Dr Anne-Marie Parienté, Dr Marcel Sauvourel, Dr Jean-Paul Vounatsos.


 This study was presented at the Congress of the European Society of Ophthalmology (SOE) in 2011 in Geneva, Switzerland and at the 1st Conference on the Tear Film and Ocular Surface in Asia (TFOS ASIA) in 2012 in Kamakura, Japan.

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