FormalPara Key Summary Points

Why carry out this study?

Dry eye disease (DED) affects patients’ health and quality of life (QoL), and the treatments available are limited.

The primary objective of this clinical investigation (Code: 051/SI) was to achieve a 50% reduction in conjunctival hyperemia index from baseline to study termination.

The secondary objectives included patient-reported outcomes, clinical performance measures, and safety.

What was learned from the study?

The clinical investigation’s results showed a 50% reduction in the conjunctival hyperemia index in 23% of the participants and a 26% reduction in the same index in 77% of the participants.

Although the primary endpoint was not completely met, these results demonstrate a significant reduction in the conjunctival hyperemia index.

The preservative-free solution with xanthan gum and desonide produced a significant improvement in the signs, symptoms, and QoL of patients with mild to moderate DED, along with a good safety profile after 1 month of treatment.

Introduction

As defined by the Tear Film and Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) and a clinical consensus on dry eye disease (DED), dry eye is a multifactorial symptomatic disease of the ocular surface characterized by a loss of homeostasis of the tear film caused by multiple factors that interact in a vicious cycle where tear film instability and hyperosmolarity lead to ocular surface inflammation, damage, and neurosensory abnormalities. Tear film instability arises from conditions that affect the ocular surface, and it manifests as early tear film break-up and tear film hyperosmolarity. As explained, tear hyperosmolarity results from tear film instability, but it may also be directly caused by conditions that cause reduced lacrimal secretion or excessive evaporation. Tear hyperosmolarity triggers a cascade of events in surface epithelial cells, leading to the release of inflammatory mediators and the ocular surface inflammation and damage characteristic of DED. This results in punctate epitheliopathy, further tear film instability, and early tear film break-up, which in turn exacerbates tear hyperosmolarity and complete the vicious circle that originates and perpetuates ocular surface damage. Reduced tear secretion also exposes the corneal epithelium to environmental conditions that cause inflammation and peripheral nerve terminal damage, which in turn lead to neurosensory abnormalities [1, 2]. DED is diagnosed by first performing triaging questions to discard conditions that mimic DED; if DED is suspected, the Dry Eye Questionnaire-5 (DEQ-5) or Ocular Surface Disease Index (OSDI) should be completed; if either of these questionnaires’ results is positive for DED, they should trigger further DED examinations, including tear break-up time (TBUT), tear film osmolarity evaluation, and ocular surface staining; if these tests detect ≥ one of three DED signs (reduced non-invasive break-up time, elevated or a large interocular disparity in osmolarity, or ocular surface staining) in either eye, disrupted tear film homeostasis is present and DED is confirmed [1, 3]. The questionnaires and tests mentioned herein were reported as reliable in diagnosing DED in the TFOS DEWS II Diagnostic Methodology report [3].

A meta-analysis by the TFOS DEWS II estimated that the prevalence of DED ranged from 5 to 50% for studies including symptoms with or without signs; rates based on symptom reporting were used because they were found to be more reliable than those based on signs which align with the fact that DED is essentially a symptomatic disease [4]. This meta-analysis confirmed that DED prevalence increases with age (between 2%, if based on self-reports of clinical diagnosis of DED, and 10.50%, if based on positive Schirmer tests, by decade), that women have higher prevalence (with a peak increase among 40–50 year olds but rates are not provided because they vary greatly) but this gender difference in prevalence only becomes significant with age, and that DED is more prevalent among Asian populations (odds ratio of 1.50–2.20 times over that of patients of European descent) [4]. Both the wide range of prevalence rates and demographic differences are explained by the various definitions used, the different populations studied, and the different parameters used to diagnose DED [4].

Patients affected by DED commonly complain about a multitude of symptoms, such as dryness, burning, foreign body sensation, soreness, blurry and/or fluctuating vision, poor visual quality, and increased tearing [5]. However, the symptoms that patients experience and their clinical signs upon examination sometimes do not completely match. Discomfort is often felt in mild DED without signs of tissue damage, and in more severe disease, hyperalgesia can diminish because of corneal sensory neuron damage, resulting in an asymptomatic pattern that does not match the severity of the observed ocular surface injury [6, 7]. DED causes pain and irritation affecting ocular and general health (mood) and daily activities (reading, driving, and ability to work) [8, 9]. It also negatively affects overall quality of life (QoL). According to the Beaver Dam Offspring Study (BOSS), patients with DED had lower SF-36 (with considerably worse bodily pain and general health indices) and National Eye Institute Vision Function Questionnaire-25 (NEI-VFQ-25, worse in all subscales but most notably regarding ocular pain), and they were 64% more likely to experience depressive symptoms [10]. Moreover, women with DED tend to experience more mental health problems than women without DED (significant difference in perceived stress scale, p = 0.02, and general anxiety disorder, p = 0.038), and even after covariate adjustments, women with DED have higher risks of perceived stress, depression, and anxiety (odd ratios of 1.28, 2.64, and 5.81, respectively) [11].

The direct (medical care spending) and indirect (lost work productivity and worse QoL) economic burden and impact of DED are considerable. For example, the total annual cost of managing DED in the US has been estimated to be USD 3.84 billion [4]. Indirect costs are particularly problematic. In the Lifelines Dutch cohort, 8.30% of patients with DED had more impaired work functioning compared to those without (49.20% vs 41.10%, OR 1.21, 95% CI 1.10–1.32, corrected for demographics, smoking and 48 comorbidities), which was comparable to the impairment caused by rheumatoid arthritis. Among patients with more symptomatic DED, the work impairment was greater (59.10%) and comparable to that caused by depression [12, 13].

Although the treatments available for this condition are limited (tear substitutes, anti-inflammatory medications, surgery, dietary and environmental modifications, and complementary therapies) [4], patient satisfaction and QoL generally improve with DED treatment [14]. The treatment for this condition starts with ocular surface lubricants and devices such as artificial tears to protect the ocular surface and improve symptoms. However, as detailed by Pucker et al. in their Cochrane review, although artificial tears are generally considered safe and effective in providing relief and improving the QoL of patients, they can produce adverse reactions (blurred vision, ocular discomfort, and foreign body sensation) and do not treat the underlying etiology. Moderate-to-severe DED requires anti-inflammatory (tetracyclines, non-steroidal anti-inflammatory drugs, glucocorticoids) and even immunosuppressive drugs which directly address the underlying pathophysiology of DED. These active agents have varying degrees of efficacy and may be associated with more side effects than more basic treatments [15,16,17].

New ocular formulations containing low-dose, preservative-free topical low potency steroids with limited corneal penetration along with topical lubricants have sparked interest regarding alleviating the irritation linked to DED. These were found to have a rapid onset of action and elicited statistically significant improvements in DED parameters with no intraocular pressure (IOP) changes [18,19,20,21,22].

This article describes the findings of a post-market clinical investigation that aimed to assess the ocular performance, tolerance, and safety of a novel and preservative-free ophthalmic solution to treat ocular discomfort due to mild to moderate DED in the context of conventional clinical practice. Xanthan gum is a natural polymer that lubricates the ocular surface, and the low-dose of desonide sodium phosphate, which is a low potency topical corticosteroid with low ocular penetration and absorption, helps to reduce mild ocular irritation. Regarding the safety concern about using a corticosteroid as an ancillary product, many publications have shown the safety of topical steroids for ophthalmic use with a low side effect profile in multiple studies [23]. Our study formulation is indicated to relieve discomfort and eye irritation due to environmental factors (dust, heat, smoke, wind, air conditioning, and allergens), and, thanks to the ancillary substance, a very low concentration of a corticosteroid, desonide sodium phosphate, it can be useful in case of redness of the ocular surface, as for example in ocular dryness [24].

Methods

We present an observational, prospective, multicentric, post-market clinical investigation to collect routine data about the effect of daily instillation of an ophthalmic solution in patients suffering from DED at specified time points to compare the outcomes after 1 month of treatment versus baseline and not requiring additional patient visits or investigations. Given the design of this clinical investigation, no control group was planned. The clinical investigation involved three Italian centers with high clinical experience in the treatment of DED between May 2022 and August 2022: the Unità Operativa Complessa (U.O.C) di Oftalmologia at the Azienda Ospedaliera Universitaria Gaetano Martino in Messina, U.O.C. di Oculistica at the Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco in Catania, and U.O.C. di Oculistica della Azienda Ospedaliero Universitaria “Mater Domini” Catanzaro (Italy). The coordinating principal investigator, Prof. Pasquale Aragona at the U.O.C. “Gaetano Martino,” was selected to lead this study because of his extensive experience in DED, as exemplified by his involvement in 23 publications on DED in PubMed in the last 10 years. Drs. Giuseppe Giannaccare and Caterina Gagliano were also selected because of their extensive experience and publications on DED.

The clinical investigation candidates were recruited by competitive enrollment at the involved clinical investigation sites.

Candidates were eligible if they could be certified as having mild to moderate DED and qualified as eligible research participants according to international regulations:

  • were adults who provided their informed consent to participate and were able to comply with the protocol requirements and

  • had a diagnosis of mild to moderate DED with ocular discomfort in one or both eyes defined as the presence of conjunctival hyperemia > 1.50 assessed by OCULUS Keratograph 5 M, scoring of ocular surface staining with fluorescein (≥ 6) using the National Eye Institute (NEI) scale (total score per single eye range 0–33 adding the score of cornea and conjunctiva), tear film break-up time with fluorescein (TFBUT, recorded as the average of three measurements) seconds, symptom assessment in dry eye (SANDE) questionnaire ≥ 40, and subject able to meet the requirements of the clinical investigation plan, according to the investigator.

The candidates were excluded if they did not have ocular or systemic comorbidities that could confound the results and were not receiving medications that could interact and did not have a history of hypersensitivity to the components of the formulation under study:

  • had undergone any ocular surgery in the 3 prior months;

  • had corneal injuries or traumatic abrasions, glaucoma, or ocular hypertension;

  • had ocular infections or clinically significant inflammation;

  • had Sjögren's or Stevens-Johnson syndrome (ocular cicatricial pemphigoid);

  • were taking medications that could interfere with tear gland secretion or received topical or systemic corticosteroids in the 4 weeks preceding the clinical investigation;

  • had a known or potential hypersensitivity and/or history of allergic reactions to one of the components of the topical medical device;

  • had a history of pathologies associated with corneal thinning;

  • had evidence of severe or uncontrolled systemic disease or any other significant disorders that, in the opinion of the investigators, did not allow participation in the clinical investigation or could compromise the results;

  • had participated in other research studies within the previous 30 days.

Due to the observational, non-interventional, and post-market design of this study, the participants were assigned to receive the study formulation as part of current clinical practice and no additional invasive or burdensome diagnostic or monitoring procedures outside of normal clinical practice were required. Since the study aimed to confirm the performance and safety of an already marketed medical device and was designed accordingly, the study’s findings were not negatively affected by following standard clinical practice procedures and tests.

The participants were to attend three visits, as shown in the clinical investigation flowchart (Table 1), from inclusion to two follow-up visits in the span of 30 days. The investigators performed all the evaluations on both eyes of each participant. The clinical investigation’s participants instilled one drop of study formulation from single-dose containers (0.30 ml each) in the conjunctival fornix, three times a day in the affected eye for 30 days, and they were followed for a maximum of 34 days.

Table 1 Flowchart of the procedures performed at each visit during the clinical investigation
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The primary objective of this clinical investigation was to record a 50% reduction in conjunctival hyperemia index as assessed by OCULUS Keratograph 5M at the study termination visit [visit 3, the 30th day (± 4) from the first instillation] compared to baseline. The secondary objectives were changes in intensity and frequency of dry eye symptoms per the SANDE questionnaire, the NEI-VFQ-25, clinical performance (reduction in corneal and conjunctival staining with fluorescein using the NEI, evaluation of TFBUT, evaluation of compliance by counting single dose containers and boxes), safety of the product by performing investigator global assessment of safety (IGAS), evaluation of reported adverse events, and of IOP.

The study formulation is a medical device (XanterDES® SIFI S.p.A.) consisting of eyedrops without preservatives with a physiologic pH and hypotonic osmolarity (~ 240 mOsmol). It contains xanthan gum (0.20%), desonide sodium phosphate (0.025%), and excipients with a physiologic pH (7.00–7.60). The preservative-free formulation eliminates the potential of allergic and toxic reactions to chemical preservatives [17]; xanthan gum helps relieve eye discomfort and irritation due to environmental elements like dust, heat, smoke, wind, air conditioning, and allergens; desonide assists the formulation to alleviate minor irritations in the ocular surface [17, 20].

To detect a difference of 50% at the end of the clinical investigation compared to baseline in conjunctival hyperemia index with a 5% significance level and 88% power (one-sample t-test), 27 subjects were required. Considering a 10% dropout, a sample size of 30 participants was required. The dropout rate and effect size used in the sample size calculation were based on the clinical and research experience of the principal investigators.

Statistical analyses were performed with SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were summarized depending on the nature of the analyzed variables. For quantitative variables, arithmetic mean, standard deviation (SD), median, and minimum and maximum (range) values were used, and for qualitative variables, frequency and percentage were taken for each modality. Missing data were not considered for percentage calculations. Differences in endpoints between baseline and different time points were assessed using paired t-tests for normally distributed data, while the Wilcoxon signed-rank test was used for non-normal data. A p-value ≤ 0.05 was considered statistically significant. In addition, 95% confidence intervals were calculated for primary and secondary endpoints. If both eyes were affected by dry eye, the statistical analysis was performed considering the eye with worse conjunctival hyperemia at baseline, i.e., the “worse eye.” If the level of conjunctival hyperemia at baseline was the same in both eyes, then the right eye was considered for statistical purposes. The performance analysis was done on the intention-to-treat (ITT) population, and the results were confirmed in the per protocol population (PP). Safety endpoints were analyzed in the safety population.

This clinical investigation was conducted to fully comply with Medical Device Regulations (MDR) for the post-market clinical follow-up of class 3 medical devices and in compliance with the latest version of the Declaration of Helsinki (October 2013), ICH-GCP Guidelines, international standard ISO 14155:2020 (‘Clinical Investigation of Medical Devices for Human Subjects—Good Clinical Practice’), and the Regulation (EU) 2017/745 of the European Parliament and of the Council of April 5, 2017, on medical devices. The participant’s privacy and personal data were also protected according to Regulation (EU) 2016/679 of April 27, 2016, on the protection of persons regarding the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). This clinical investigation was approved by the institutional review boards of the Interagency Ethics Committee of Messina, University Hospital “G. Martino” (Via Consolare Valeria, 1–98125, Messina, Italy) on February 15, 2022 (protocol number 21–22 from January 28, 2022), the Ethics Committee Catania 1, University Hospital Policlinic "G. Rodolico—San Marco" (Via S. Sofia, 78–95123, Catania, Italy) on March 21, 2022 (protocol number 67/2022/PO of the EC Register of Opinions), and the Ethics Committee of the Calabria Region (Sec. Area Centro, Viale Tommaso Campanella, 115–88100, Catanzaro, Italy) on March 17, 2022, protocol number 62 of March 17, 2022).

All the study participants provided their informed consent to participate in this clinical investigation. According to local requirements and the corresponding regulations, the investigators discussed the possibility of participating in the study with the patients and provided all the necessary information necessary for the prospective participants to comprehend the full nature and purpose of the study, including possible risks as well as the right to discontinue participation in the study at any stage, without affecting their relationship with the investigator or care. The informed consent form was then reviewed, discussed, dated, and signed by participants and investigators before any study-related procedure was initiated.

Results

As shown in Fig. 1, 31 participants were screened and 30 were enrolled and included in the ITT and safety population at the clinical centers in Messina and Catania. The average treatment duration was 30.07 ± 1.83 days for patients in the ITT population. Most participants attended the 14 ± 2 day (visit 2) and 30 ± 4 day (visit 3) follow-up visits (90% and 86.60%, respectively); 26 patients completed the clinical investigation according to the clinical investigation plan. Almost three-quarters (70%, 21/30) of the participants were women. The average age was 61.50 ± 14.60 (range, 32–81) years (Table 2). All patients were affected by DED characterized by conjunctival hyperemia (mean 1.95 ± 0.37), mean total NEI score of 15.06 ± 6.43, mean TFBUT of 4.07 ± 1.65, and mean on total SANDE of 71.78 ± 14.16.

Fig. 1
figure 1

Patient disposition. ITT intention to treat, PP per protocol

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Table 2 Demographic characteristics of the clinical investigation’s participants
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In the ITT population (n = 30), the instillation of the study formulation was associated with a significant reduction in ocular hyperemia (Fig. 2). A significant decrease in redness scores (RS) was recorded from baseline (visit 1, screening, enrollment, and start of treatment) to the study termination visit (visit 3; mean − 0.51 ± 0.51; p ≤ 0.0001) and from visit 1 to visit 2 [14th day (± 2) from the first instillation; mean, − 0.36 ± 0.42; p ≤ 0.0001], considering changes from baseline (visit 1: mean 1.95 ± 0.37) to the study termination visit (mean 1.44 ± 0.55) and also considering changes from baseline (visit 1: mean 1.95 ± 0.37) to visit 2 (1.58 ± 0.46) (Table 3). Almost a quarter (23%) of the participants showed a 50% reduction in the conjunctival hyperemia index, while 77% of them showed a reduction of approximately 26% in this index. Although these results demonstrate a significant reduction in conjunctival hyperemia index, the primary endpoint of this clinical investigation, consisting in a decrease of 50% in ocular hyperemia, was not completely met.

Fig. 2
figure 2

Evolution of the clinical investigation’s primary endpoint and key secondary endpoints 2 weeks and 1 month versus baseline: **p ≤ 0.0001, x: p = 0.0035, °p = 0.001, °°p = 0.0005. NEI National Eye Institute, RS redness scores, SANDE symptom assessment in dry eye, TFBUT tear film break-up time with fluorescein

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Table 3 Assessment of conjunctival hyperemia (ITT and PP population)
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Regarding the secondary endpoint of clinical performance (Fig. 2), the assessment of corneal and conjunctival staining with fluorescein showed that in the ITT population, the study formulation significantly reduced corneal and conjunctival staining with fluorescein: there was a significant decrease in total NEI scores comparing baseline/visit 1 values ( mean 15.06 ± 6.43) to those of the study termination visit (mean 10.76 ± 6.78; mean delta between the two visits -4.30 ± 6.44; p = 0.0010). The total score for the cornea and the conjunctiva from baseline to the study termination visit was also reduced (mean − 2.06 ± 3.09; p = 0.0010 and mean − 2.36 ± 3.95; p = 0.0027, respectively) considering changes from baseline (mean 15.06 ± 6.43) to visit 2 (mean 10.53 ± 6.91). Regarding the TFBUT evaluation in the ITT population and as shown in Fig. 2, the study formulation significantly increased TFBUT from baseline to the study termination visit (mean 1.51 ± 2.10; p = 0.0005) considering a TFBUT mean basal value (visit 1) of 4.07 (± 1.65), mean value at visit 2 of 5.25 (± 2.53), and mean value at the study termination visit of 5.58 (± 2.39).

Compliance with treatment was good for all participants (n = 30) since they correctly used the study formulation during the study period (30 days).

The patient outcomes in the ITT population reported via the SANDE questionnaire showed that the administration of the study formulation reduced the intensity and frequency of dry eye symptoms (Fig. 2). There was a significant decrease in the total SANDE score from visit 1 to visit 3: mean – 26.06 ± 18.86; p ≤ 0.0001. The corresponding mean severity score and frequency scores in the same time frame were − 26.70 ± 18.38; p ≤ 0.0001 and mean − 25.30 ± 22.26; p ≤ 0.0001, respectively. The QoL questionnaire showed that administration of the study formulation could improve QoL by eliciting a significant amelioration in the reported visual function assessed using the NEI-VFQ-25 by evaluating its 12 subscales and optional items and determining the mean changes from visit 1 to visit 3 (Supplementary Materials Table S1).

As shown in Table S1, administration of the study formulation improved the QoL of the participants, as reported by the significant improvement in their visual function assessed by NEI-VFQ-25. Other parameters assessed with the NEI-VFQ-25 were general health, mean 4.86 ± 17.22, p = 0.2339; general vision, mean 11.31 ± 13.10, p = 0.0014; ocular pain, mean 15.00 ± 21.65, p = 0.0020; near activities, mean 11.81 ± 10.69, p = 0.0003; distance activities, mean 7.10 ± 11.30, p = 0.0135; social functioning, mean 2.08 ± 11.10, p = 0.4120; mental health, mean 12.72 ± 20.10, p = 0.0073; role difficulties, mean 7.18 ± 18.72, p = 0.1023; dependency, mean 1.97 ± 10.97, p = 0.4298; driving, mean 9.46 ± 18.19, p = 0.0236; color vision, study termination visit: mean 5.00 ± 16.13, p = 0.1344; peripheral vision, mean 4.00 ± 13.84, p = 0.1615.

The study formulation had a good safety profile according to the IGAS score. In the ITT population, 62.96% of the participants had point scale 1 (very good safety), 25.93% had point scale 2 (good safety), 7.41% had point scale 3 (moderate safety), and only one participant (3.70%) had point scale 4 (poor safety). Three adverse events (AEs) occurred during the clinical investigation in the safety population (n = 30). They were observed in a 70-year-old woman and consisted of grade 1 (mild) conjunctival hyperemia, eye pain, and eye burning, all related to the study formulation. No serious AEs or deaths were reported. The study formulation did not affect the IOP (Table 4) in the ITT population (visit 1 to visit 3: mean 0.43 ± 1.61, p = 0.1517).

Table 4 IOP assessments in the ITT population
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Discussion

During the observational period (30 days), the 30 participants with DED were characterized by conjunctival hyperemia with mean of 1.95 ± 0.37, mean NEI total score of 15.06 ± 6.43, and mean SANDE score of 71.78 ± 14.16 received the study formulation for 30.12 ±1.83 days. Our data coincide with those of metanalyses and reports showing major risk factors, including older age and female gender [1, 4, 10, 25, 26]. Although the underlying pathophysiologic mechanisms through which these risk factors influence individual vulnerability to develop DED are complex, older age has been associated with a reduction in tear secretion that occurs with aging in either sex, especially > 50 years old, because of meibomian gland dropout [1, 4]. The higher prevalence in women is explained by the hormonal effects of sex steroids on the ocular surface and lacrimal glands, particularly the use of hormones for contraception, infertility, and hormone replacement therapy [10, 25, 26].

Although there was a statistically significant reduction in conjunctival hyperemia and a significant reduction in eyelid and conjunctival inflammation, the primary endpoint consisting of a reduction of 50% in eye hyperemia was not fully met: after 1 month of treatment, only 23% of the participants treated with the study formulation showed a 50% reduction in conjunctival hyperemia. The remaining 77% of the participants had their hyperemia reduced by approximately 26%. This is clinically significant considering other studies which indicate that the therapeutic approaches for DED generally elicit no better than 20% symptom improvement in 30 days [3, 27]. Failure to completely meet the primary endpoint may be related to the relatively short treatment period and the small sample size. Nevertheless, 30 days of treatment with the study formulation elicited a statistically significant reduction in conjunctival hyperemia in terms of RS (visit 1 to visit 3: mean − 0.51 ±0.51; p ≤ 0.0001), which aligns with a recent systematic review that showed that 1 month of regular treatment alleviates the symptoms of DED [28]. Additionally, the results of our clinical investigation were generally positive and confirmed the performance and safety of the medical device.

Furthermore, ocular dryness, which accompanies tear deficiency and changes tear properties, often results in corneal epithelial barrier dysfunction and superficial epithelial lesions that can be verified by the analysis of changes in corneal and conjunctival staining scores (NEI score) [29]. After the treatment period with the ophthalmic solution, we observed a statistically significant reduction of corneal and conjunctival staining with fluorescein (total score NEI mean – 4.30 ± 6.44), implying that the treatment improved the health and integrity of the ocular surface.

In particular, tear film stability is an important aspect of the tear film changes that occur in DED as it is linked to the health of the ocular surface [30]. TBUT is commonly used to assess the elapsed time between the end of a complete blink and the appearance of the first break in the tear film [31], indicating its ability to protect the ocular surface’s epithelium. The study formulation was able to significantly increase TFBUT. These results suggest that the instillation of the study formulation improved the integrity of the tear film by reducing its evaporation rate. Notably, the xanthan gum in the study formulation gives it a pseudoplastic behavior that favors the normal rheology of the tear film. It has a high water affinity and can thus increase viscosity, and it has antioxidant properties which may alleviate the oxidative stress in the ocular surface of patients with DED. This component also has mucoadhesive properties that can benefit the formation of the mucus layer of the tear film and increase the corneal residence time of the tear film. Studies comparing xanthan gum-based formulations to other formulations for DED have found that the first improved DED more than carboxymethylcellulose or similarly to polyethylene glycol/propylene glycol-based formulations [27, 32]. The study formulation also significantly reduced corneal and conjunctival fluorescein staining, as demonstrated by the significant decreases in NEI values, and improved symptoms as demonstrated by the SANDE scores.

The treatment also significantly improved the participants’ QoL, particularly their NEI-VFQ-25 scores. Notably, the NEI-VFQ-25, a thorough visual function questionnaire that assesses vision-specific QoL, was used in this study since it is recommended to assess DED symptomatology by the TFOS DEWS II and patients with DED typically present poorer NEI-VFQ-25 scores for general health and vision; ocular pain; short- and long-distance vision activities; vision-related social function, mental health, role difficulties, and dependency; and driving [3]. This questionnaire is suited for capturing the overall impact of ocular diseases on QoL, considering especially and simultaneously physical and psychologic health [3]. The results of a large (n = 750) cross-sectional survey among people affected by DED in the United States and Canada showed that DED negatively affects patients’ QoL, their daily activities, mood, and their ability to work. In addition, Slosen et al. explained that discomfort symptoms are directly correlated with disease severity in over three-quarters (79%) of the patients with severe DED, seriously impacting their QoL [9]. Fortunately, ophthalmic solutions and other DED treatments have been found to improve DED symptomatology and patient QoL [14]. In line with these considerations, after 30 days of treatment, the study formulation improved the participant’s QoL, as reported by the significant improvement in their reported general visual function, ocular pain, and near activities per NEI-VFQ-25.

This clinical investigation had some limitations, including the biases typically associated with observational designs (selection and information bias, confounders) [33] and absence of a control arm. However, a control arm was not considered necessary because this was a non-interventional, observational, post-market clinical investigation that only collected data from normal clinical practice, did not require any additional patient visits nor investigations, and was conducted to fully comply with MDR regulations for the post-market clinical follow-up of medical devices. Although no mitigation measures are considered necessary for the present study and no future studies for this specific study formulation are considered necessary, in accordance with MDR regulations, there is a post-marketing surveillance plan to monitor the safety of this medical device that is already on the market.

Another weakness of this study is that the effectiveness and safety data reported herein may be affected by the relatively short treatment period. In fact, the failure to meet the primary endpoint could have been related to the short treatment period, even though there is good evidence that DED symptoms are alleviated by artificial eye drops in 1 month of treatment [28]. Nevertheless, this clinical investigation confirms the performance (redness score changes between visits 1 and 2 and between visits 3 and 1 were statistically significant, p = 0.0001) and safety of an innovative xanthan gum-based artificial tear formulation that includes a very low dosage of desonide. The low corticosteroid concentration has an ancillary action to the xanthan gum to treat this inflammatory disease without the risk of increasing IOP and the formation of cataracts that are associated with higher corticosteroid concentrations as reported in a systematic review by Musleh et al. [22]. Several studies using low-potency steroids in low doses have found that these agents in combination with other elements alleviate DED without affecting IOP or causing other steroid-related side effects [18, 19, 21, 22]; furthermore, as shown in a recent randomized controlled study, the long-term (6-month) instillation of artificial tear formulations containing low-dose steroids also alleviated DED symptoms, improved TFBUT, and reduced corneal and conjunctival damage and inflammatory markers, and it did not alter IOP either [34]. Also, the combination of agents in preservative-free solutions has been found to be more beneficial to patients than single-agent artificial tears in a recent systematic review of the literature [28]. Another strength of this clinical investigation’s design is that, due to its observational nature, it did not require additional patient visits or investigations other than those performed per standard of care. Thus, the balance between benefits and risks for the study formulation seems favorable since it significantly improved signs and symptoms in patients with mild to moderate DED after 1 month of treatment with a good safety profile.

Conclusion

This study showed that the formulation containing xanthan gum 0.2%, with lubricant and hydrating properties, and sodium desonide phosphate 0.025%, a low-concentration and low-potency corticosteroid as ancillary substance, improves ocular surface conditions producing a significant improvement in the signs, symptoms, and QoL of patients with mild to moderate DED. This medical device also showed a good safety profile after 1 month of treatment.