Real-world insights and outcomes related to ciclosporin A 0.1% cationic emulsion for the long-term treatment of dry eye disease in Germany: Country-level sub-analysis of the PERSPECTIVE study

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial, complex, and chronic ocular condition, requiring long-term treatment, which may be challenging to diagnose and treat in clinical practice [1‐6]. The condition is fairly common, with epidemiological data in Europe showing a prevalence ranging from 11 to 30% [4]. It is defined by the Tear Film Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles” [1]. Symptoms include ocular irritation, foreign body sensation, photophobia, eye pain, and impaired/blurred vision, as well as itching, burning/stinging, and/or scratching sensations, all of which can limit performance of daily tasks and quality of life [1, 2, 5].

DED is typically classified as either evaporative or aqueous deficient [1]. Meibomian gland dysfunction is one of the underlying causes of evaporative DED, whereas tear underproduction results in aqueous-deficient dry eye [1]. However, most people with DED display signs and symptoms in varying combinations that relate to both types of disease [1]. It is a progressive condition, resulting in inflammation and damage to the ocular surface, caused, in part, by increased osmolarity of the tear film [6]. Regardless of whether the underlying mechanism for DED is increased tear evaporation or aqueous deficiency, or both, the homeostasis of the ocular surface is disrupted and pro-inflammatory pathways are activated, causing ocular surface damage and neurosensory aberrations, leading to a vicious and self-perpetuating cycle of inflammation and worsening pathophysiology [1, 2, 7‐9]. DED is typically cyclical in nature with episodic worsening (or flares) of signs and symptoms occurring over time, including prolonged discomfort and ocular inflammation (usually indicated by the presence of eyelid and/or conjunctival hyperemia) [5]. If left untreated, DED may progress in severity and result in permanent ocular damage [5].

Once a diagnosis has been reached, management of DED focuses on restoring both the tear film and ocular surface homeostasis, treating the underlying pathophysiology, preventing symptomatic flares, and reducing complications [1, 2, 8]. Management of DED typically follows a stepwise approach, beginning with education on the disease and behavior modification (including diet, environment, lid hygiene, and application of warm compresses), as well as the use of tear substitutes or artificial tears (ATs) [8]. ATs protect and lubricate the ocular surface but do not tackle the underlying pathogenesis and inflammation associated with the condition. DED progresses in most cases, requiring the addition of topical anti-inflammatory treatments, such as corticosteroids or ciclosporin, to reduce inflammation and help improve quality of life [2, 3, 5, 8, 10‐17]. If DED progresses, it is advised by the TFOS DEWS II and German Ophthalmology Society (DOG) guidelines, and recent expert consensus recommendations, that anti-inflammatory treatments should be initiated as early as possible, when the ocular surface is likely to be responsive to therapy (such as when first-line ATs no longer adequately control symptoms) [4, 5, 8, 18]. Corticosteroids are effective at controlling inflammation, but their long-term use is associated with a risk of ocular complications, such as ocular hypertension (or glaucoma), cataracts, and infections [8, 19]. In contrast, topical ciclosporin A (CsA) is a widely used anti-inflammatory treatment that can be administered over the long term and is approved for the treatment of severe keratitis in patients with DED that has not improved despite treatment with ATs [20]. Topical CsA is available as either a 0.05% anionic or 0.1% cationic emulsion (CE); however, CsA 0.1% CE ophthalmic solution is the only commercially available treatment in Europe [20]. Clinical studies have established the efficacy and tolerability of CsA 0.1% CE and report a reduction in corneal surface damage and ocular surface inflammation with up to 24 months of follow-up [11‐15]. Three real-world studies have reported similarly improved outcomes with CsA 0.1% CE in patients with DED [5, 16, 21], including a recent real-world experience report from the UK which showed that patients with ocular surface inflammatory diseases (particularly those with DED) experience improved clinical outcomes with CsA 0.1% CE treatment and a reduced need for adjunctive steroids [16].

The 12-month real-world PERSPECTIVE study showed that, in routine clinical practice across Europe, CsA 0.1% CE was well tolerated and effective in controlling the signs and symptoms of severe keratitis in adults with DED that had not improved despite treatment with ATs [5]. This study was designed to reflect real-world clinical practice and specified that treatment should be prescribed in accordance with the approved label for CsA 0.1% CE, as judged by the study investigator, rather than specifying a formal threshold corneal fluorescein staining (CFS) score or the presence of any specific signs and symptoms of DED [5]. This large, multicenter, observational study reported that CsA 0.1% CE significantly reduced ocular surface damage and improved the severity and signs of DED from Week 4 through to Month 12, and provides insights into outcomes that ophthalmologists and patients may expect with this treatment [5].

Since the PERSPECTIVE study included various European patient populations and allowed patients to enter the study if judged by the investigating clinician to have severe keratitis and DED (which may differ based upon a combination of factors), it may include a diverse and heterogenous study population [5]. For example, although the approved label for CsA 0.1% CE states that it should be used in the treatment of severe keratitis and DED, no formal threshold for CFS score (using the Oxford Grade Scale) is stipulated in the licensed indication, and the literature in this area does not clearly define the way in which disease severity should be graded [1, 4, 7, 8, 18, 20]. Therefore, in routine clinical practice, ophthalmologists may evaluate the severity of keratitis and DED using a combination of CFS score, other signs (e.g., eyelid and/or conjunctival erythema), patient-reported symptoms, and quality of life factors [5]. This approach reflects the complex and multifactorial nature of the disease. While the approach in the PERSPECTIVE study may be reflective of routine clinical practice across Europe, it may also present challenges when comparing outcomes against those from randomized controlled trials (RCTs) examining CsA 0.1% CE use in a homogenous and stringently selected group [5], or when translating findings to real-world practice in varied healthcare settings.

To extrapolate and investigate the findings to a single healthcare system with a more homogenous patient population, the current sub-analysis examined efficacy, tolerability, and safety data from ophthalmology clinics that participated in the PERSPECTIVE study in Germany [5]. This can provide more precise insights into treatment patterns, outcomes, and clinical decision-making related to CsA 0.1% CE in Germany, and will detract from any differences between real-world approaches in the management of DED between countries based on the healthcare system and providers, reimbursement criteria, variations in access to healthcare, local guidelines, and/or variations in physician assessments and evaluation of disease severity. This sub-analysis will also provide an opportunity to explore the areas of commonality and contrast between the data from Germany and other regional data regarding treatment outcomes achieved, and the patient populations considered by the treating physicians to have disease of sufficient severity to warrant CsA 0.1% CE treatment, in routine clinical practice. To our knowledge, this sub-analysis includes the largest cohort of patients treated for DED in Germany.

The PERSPECTIVE study comprised a 12-month, European, prospective, non-interventional, multicenter, observational study of adults (≥ 18 years of age) with severe keratitis and DED, currently treated with ATs. In line with the European Medicines Agency (EMA) requirements, the study was registered under the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP^®) European Union electronic Register of Post-Authorisation Studies (EU PAS Register) (EU PAS Register Number: EUPAS22376). All patients included were required to provide written informed consent prior to their enrollment. The centers/institutions are listed alongside the relevant investigator in the PERSPECTIVE Germany study group section at the end of this article. The current sub-analysis examined PERSPECTIVE study data collected from 20 ophthalmology clinics in Germany. The study methodology was previously reported [5], but the key elements are included below.

Data were collected between 11 April 2017 and 14 November 2019 during routine appointments at participating ophthalmology clinics in Germany at baseline and then following CsA 0.1% CE initiation at Week 4, 12, and 24, and Month 12. Attendance at baseline and Month 12 was mandatory for inclusion in the study, and data were reported for patients choosing to attend interim study visits. Baseline measures were recorded under AT treatment, and the eye with the highest baseline CFS score (Oxford Grade Scale; Grade 0–V) was chosen as the study eye. Variables were documented for each eye separately at baseline and subsequent study visits. In cases where the CFS score was equal in both eyes at baseline, the right eye was selected as the study eye. As the study was conducted in a routine clinical practice setting, all study medications (CsA 0.1% CE, ATs, or corticosteroids) were prescribed and reimbursed, or paid for, in accordance with local healthcare arrangements. No medication was supplied by the study sponsor.

Of the 501 patients enrolled in the PERSPECTIVE study, 236 patients were enrolled in Germany (Fig. 1). Of these, 69.9% were female, and the mean age was 60.8 (SD 15.8; range 19.9–93.2) years. Table 1 summarizes the baseline patient and clinical characteristics. The main reasons reported for initiating CsA 0.1% CE treatment were insufficient control of keratitis or DED with prior medication (72.9%) and progression of keratitis or DED (28.4%). Physicians were allowed to provide more than one reason for initiating CsA 0.1% CE treatment.

This sub-analysis of patients who were enrolled in the PERSPECTIVE study from Germany examined the effectiveness, tolerability, and safety of CsA 0.1% CE treatment in a real-world setting. The inclusion and exclusion criteria were reflective of the patient group defined in the approved CsA 0.1% CE label [5], and all study medications (CsA 0.1% CE, ATs, or corticosteroids) were prescribed in accordance with local healthcare arrangements. No major differences were observed in patient demographics between the overall study population (across Europe) and this sub-analysis (in Germany), with only the proportion of females being slightly lower in the German cohort (69.9% versus 75.9%). Only 7 patients (2.97%) were receiving concomitant corticosteroids at baseline (six using dexamethasone and one using fluorometholone). This is fewer than in the overall study population, where 7.4% of patients initiated corticosteroids in addition to CsA 0.1% CE at the baseline visit, and 8.5% were prior corticosteroid users who were expected to continue corticosteroids in addition to CsA 0.1% CE. No patients initiated corticosteroids in the German cohort, whereas 5.9% of patients in the overall study population initiated corticosteroids after the baseline visit.

The outcomes reported are similar to those reported for the overall study population [5]. These results are also consistent with reports from RCTs showing a significant and clinically meaningful reduction in corneal surface damage and improvement in ocular signs and symptoms of patients with severe keratitis and DED following treatment with CsA 0.1% CE [11‐15]. The PERSPECTIVE study was designed to reflect real-world clinical practice, and, in contrast to conventional RCTs, no washout period was required prior to initiating treatment with CsA 0.1% CE [5]. Therefore, patients were permitted to continue concomitant treatment with corticosteroids and/or ATs when treatment with CsA 0.1% CE was initiated. As a consequence, these data reflect ophthalmology clinical practice in Germany, where patients may be prescribed multiple therapies and may also use over-the-counter medications. This approach is also consistent with the German Ophthalmology Society (DOG) and TFOS DEWS II guidelines [4, 8], as well as recent clinical consensus papers [18, 24], which have noted the anti-inflammatory and immunomodulatory effects of CsA treatment and recommended that such therapies should be used in conjunction with ATs and when AT therapy alone no longer provides adequate control [4, 8, 18, 24].

Despite potential differences in treatment approaches and/or assessment of DED (for inclusion and monitoring) across countries and healthcare settings, baseline clinical characteristics show only slight differences between this sub-analysis in Germany and the overall primary study population. To note, almost half of patients (42.9%) were using ATs at least once and up to three times a day in the overall study population, whereas this was 49.4% of patients in the German cohort. However, this may not be a confounding factor on the outcomes — while ATs may help in providing lubrication at the ocular surface, ATs do not address the underlying inflammatory pathways and subsequent ocular surface aberrations that drive the vicious cycle of DED and progressive disease [2, 4]. In addition, CFS score at baseline was typically graded at II or III, with a slightly larger proportion of patients (74.4%) in this German cohort than the overall study population (65.6%). This suggests that ophthalmologists, especially in Germany, select patients for topical CsA 0.1% CE therapy at an earlier disease stage compared with the inclusion criteria generally used in RCTs (CFS score IV or V) [11, 13, 14]. However, no formal thresholds have been defined regarding DED severity in relation to CFS score, and the patient’s perception of symptom severity might influence the grading attributed by the diagnosing physician or be conflicting with clinical signs.

Equally, it is important to note that with a real-world study design, some patients may receive topical corticosteroids during treatment with CsA 0.1% CE, and this could account for some of the anti-inflammatory effects and efficacy outcomes within the study. However, despite this potential bias, minimal corticosteroid use was reported throughout the 12-month time period in the German cohort. In the FAS, no patients initiated corticosteroids at the baseline visit in addition to CsA 0.1% CE, and only 7 patients in total were already receiving corticosteroids when they attended their baseline visit (and were expected to continue to do so). Throughout the study, four patients had corticosteroid use reported at Week 4, two at Week 12, one at Week 24, and one at Month 12. The number of patients receiving and initiating corticosteroids was fewer than that observed in the PERSPECTIVE study from the UK, but slightly more than that observed in Norway. Due to the small sample size, further sub-analyses were not carried out to account for the effect of concomitant use of corticosteroids.

The results of this sub-analysis support previous real-world study publications confirming the efficacy of CsA 0.1% CE in the treatment of severe keratitis and DED [5, 16, 21] and also provide country-level insights into real-life practice patterns and outcomes that ophthalmologists and patients may expect with this treatment in their healthcare setting in Germany.

In a real-world clinical practice setting, patients in Germany who were diagnosed with severe keratitis and DED benefited from CsA 0.1% CE treatment [5]. At Month 12, most patients (81.6%) experienced reductions in CFS score compared with baseline. Significant reductions in mean CFS score were observed from Week 4 and maintained throughout the 12-month study period (P < 0.0001), suggesting that the majority of patients treated with CsA 0.1% CE in clinical practice experience and maintain ocular surface improvements over a prolonged period. This change in CFS was observably different in the German cohort than the overall study population (both FAS) at Week 24 and Month 12, where the mean CFS score was 0.96 and 0.85, respectively, compared with 1.24 and 1.10. In a previous study, patients treated with CsA 0.1% CE for 12 months who experienced improvements in CFS scores sustained these improvements following treatment discontinuation [15]. Given the study design and typical bridging approaches with topical CsA in Germany, this is probably indicative of routine clinical practice in Germany and suggests that the majority of patients treated with CsA 0.1% CE may maintain ocular surface improvements over a prolonged period.

Consistent with the results reported in the primary analysis, patients treated with CsA 0.1% CE in Germany showed significant (P ≥ 0.01) improvements in the severity of clinical signs and ocular symptoms from Week 4, which were sustained through to Month 12 [5]. Physicians rated treatment effectiveness and clinical signs as better with CsA 0.1% CE compared with prior treatments, and both physicians and patients regarded tolerability with CsA 0.1% CE treatment to be "very good", "good", or "satisfactory". All of these results show commonality with the primary analysis. However, in contrast to the findings reported for the overall study population, changes in VA were not significant in the cohort of patients with DED who were treated with CsA 0.1% CE in Germany [5]. In addition, changes in the Schirmer’s test were neither significant in the overall population nor in the German cohort [5].

It is well established that a proportion of patients with DED seen by ophthalmologists in clinical practice will exhibit conflicting signs and symptoms, and this seems congruent with the population observed in the PERSPECTIVE study [5]. This may be of particular note in patients with CFS score of II (“mild”) or III (“moderate”). Additional sub-analyses to examine the change in ocular signs and symptoms by baseline CFS scores would be of value to provide further data regarding the key signs/symptoms that may have prompted decisions to initiate CsA 0.1% CE therapy and the treatment outcomes achieved in each of these subgroups.

Safety and tolerability data were consistent with the known safety profile of CsA 0.1% CE [5, 11‐14]. There were no noticeable discoveries in the AEs reported in this German sub-analysis. Despite reports of some patients experiencing tolerability issues with CsA 0.1% CE, only 11 patients discontinued CsA 0.1% CE in the German cohort due to poor local tolerance (4.7% of the FAS – two by Week 4, three by Week 12, two by Week 24, and four by Month 12), which was higher than reported for the overall study population (6.6% of the FAS) but similar to the rate of discontinuation due to ocular treatment-related AEs reported in other studies of CsA 0.1% CE in the treatment of severe keratitis and DED (9.3–10.4%) [11, 14, 25]. It could be hypothesized that the lower proportion of patients with tolerability issues in the German cohort could be due to the difference in AT and/or corticosteroid use prior to and with CsA 0.1% CE treatment. Overall, the safety profile and treatment benefit reported in real-world clinical studies suggest a favorable benefit–risk ratio for CsA 0.1% CE in the treatment of severe keratitis and DED [5, 16, 21].

This sub-analysis includes one cohort from the overall study population that was enrolled in the PERSPECTIVE study, and therefore, the number of patients is smaller than those included in the primary analysis, which may impact the results. Although the study was prospective, it was also observational, which is associated with limitations, such as a lack of a control or placebo arm for comparison. The study population is heterogenous as it was based on clinical practice, and clinical judgement was used to determine which patients were suitable for treatment with CsA 0.1% CE, according to the approved European label [20]. Although the population is heterogeneous, as a country-level analysis, the population is assumed to be more homogenous than the overall study population. It also reflects the range of signs, symptoms, and effects that patients with severe keratitis and DED might experience on a day-to-day basis rather than a defined population with specific characteristics as seen in RCTs, and therefore, it is consistent with routine clinical practice in Germany.

A country-level sub-analysis of the PERSPECTIVE study data from ophthalmology clinics in Germany shows similar outcomes to those reported for the overall study population and is indicative of the treatment results that ophthalmologists may expect to see with CsA 0.1% CE treatment in real-life clinical practice. CsA 0.1% CE provided significant reductions in the severity of keratitis and DED signs and symptoms, which were demonstrated from Week 4 and maintained through to Month 12. Treatment with CsA 0.1% CE was generally well tolerated.