Abstract
Introduction
A 3-year multicenter trial was conducted to examine safety/tolerability and potential symptom relief delays following ocular sign improvement in patients with dry eye disease (DED) and severe keratitis using once-daily ciclosporin A (CsA) 0.1% cationic emulsion (CE).
Methods
Adult patients with DED and corneal fluorescein staining (CFS) graded ≥ 3 (modified Oxford scale) received open-label CsA 0.1% CE for 12 months. Patients achieving ≥ 2-grade CFS reduction at month 12 were randomized 3:2 to CsA 0.1% CE or vehicle during months 12–36. Incidence and onset of ocular surface complications and adverse events (AEs) were reported. Spearman’s correlation coefficient (SCC) calculations examined any relationship between CFS and symptom assessment in dry eye (SANDE) changes.
Results
Overall, 336 participants received open-label CsA 0.1% CE. Mean (standard deviation) age was 59.4 (13.4) years and the majority were female (86.0%) and white (94.6%). In total, 279 (83%) demonstrated ≥ 2-grade CFS reductions and 245 were randomized at month 12. Ocular complications (infections; 3–6-line visual acuity reduction) occurred in 3.2% (n = 11; CsA 0.1% CE; open-label period), 4.7% (n = 7; CsA 0.1% CE; randomized period), and 3.1% (n = 3; vehicle). Median onset was 5.9 (open-label period), 8.2 (CsA 0.1% CE; randomized period), and 6.3 months (vehicle). SCC values comparing month 3 CFS change with SANDE reductions at months 3, 6, 9, and 12 were 0.169, 0.245, 0.274, and 0.178, respectively, and indicated a 3–6-month delay in symptom improvement. Non-serious ocular treatment-related AEs occurred in 62 open-label participants and in 5 (CsA 0.1% CE) and 4 (vehicle) randomized patients.
Conclusions
Once-daily CsA 0.1% CE was well tolerated with low ocular surface complication rates through month 36 in adults with DED. Symptom relief may be delayed by 3–6 months following CFS improvement.
Clinical Trial Number
NCT04144413; EudraCT Number: 2017-002660-41.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40123-026-01411-3.
Keywords: Ciclosporin A 0.1% cationic emulsion, Corneal fluorescein staining, CFS, CsA, Dry eye disease, SANDE
Key Summary Points
| Why carry out this study? |
| European expert consensus recommends ciclosporin A (CsA) use for at least 6–12 months in dry eye disease (DED) to ensure that patient responders obtain benefit from treatment. |
| The study aimed to report safety and tolerability outcomes over a 3-year period, including ocular complication rate, with the once-daily 0.1% CsA cationic emulsion (CE) and to examine any delay that may occur between onset of improvement in ocular surface signs and symptom relief. |
| What was learned from the study? |
| Ocular complication rate was low (< 5%) over 3 years, and no serious adverse events were associated with CsA 0.1% CE use through month 36. |
| The outcomes support expert consensus in that patients with DED demonstrated improvements in ocular surface signs through month 12 with CsA 0.1% CE, with some experiencing a potential lag in symptom-severity reduction of approximately 3–6 months. |
| Patients demonstrating improvements in DED signs and symptoms with CsA 0.1% CE use maintained these outcomes through month 36. |
Introduction
Dry eye disease (DED), or keratoconjunctivitis sicca/keratitis sicca, is complex, heterogeneous, progressive, and multifactorial [1, 2]. Overall prevalence is estimated to vary between 5.4% and 44.2% [1]. It is more common in women and risk tends to increase with age [1]. The Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS) III Definition and Classification Subcommittee characterizes DED as a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors [2]. Without treatment, a “vicious circle” of disease can occur that may significantly affect quality of life (QoL) and cause permanent ocular surface damage [2–6]. Grading of DED severity is typically based on existing studies, expert opinion, and combined presentation of signs and symptoms [2, 7–11]. Tools such as the symptom assessment in dry eye (SANDE) and dry eye-related quality-of-life score (DEQS) questionnaires have been developed to aid assessment of symptom severity and the impact of DED on QoL [12–14]. Clinicians have observed the presence and severity/intensity of patient-reported symptoms to be frequently discordant with the grading of clinical signs, and ocular surface damage can reduce corneal sensation, attenuating or masking symptomatic improvement even when signs indicate recovery of the ocular surface [1, 2, 15–19].
Immunomodulatory treatments, such as topical ciclosporin A (CsA), target underlying inflammatory mechanisms associated with DED [3, 8, 11, 20, 21]. The once-daily CsA 0.1% cationic emulsion (CE) formulation (Ikervis®, Santen Oy, Finland) is approved in Europe for the treatment of DED with severe keratitis and has demonstrated efficacy in reducing the severity of signs and symptoms in clinical practice, randomized clinical trials (RCTs), and observational/real-world studies over the past decade [3, 8, 11, 22–30]. To ensure benefit from treatment, European consensus recommends that CsA should be used for at least 6–12 months, and observations in clinical practice have suggested that a delay may occur between improvement in markers of corneal health and onset of symptom relief [3, 10, 11, 22, 24–29, 31, 32].
The current study reports outcomes from a phase 3b, prospective, interventional trial to evaluate once-daily CsA 0.1% CE treatment over a 36-month follow-up in adults with DED. The study represents the longest evaluation of CsA 0.1% CE treatment. The primary objectives were to examine occurrence of ocular surface complications in adults with DED and baseline corneal fluorescein staining (CFS) graded 3–5 on the modified Oxford scale, to evaluate the long-term efficacy of continuous CsA 0.1% CE use on corneal signs and DED symptoms, and to estimate any lag time between reduction in signs and ocular-symptom improvement.
Methods
A phase 3b, 36-month, prospective, interventional, multicenter study was conducted at 36 sites in 7 countries (Spain, Italy, Poland, Czech Republic, France, Russia, and Turkey) between 31 May 2019 and 14 July 2023 (EudraCT no. 2017-002660-41; NCT04144413). The study protocol was reviewed and approved by the relevant independent ethics committee for each site, and participating patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) guidelines.
Study Population
Demographic information was recorded in the case report form (CRF) for each patient participant enrolled in the trial. The study included adult (aged ≥ 18 years) tear-substitute users (≥ 4 weeks) with DED and severe keratitis, defined as having baseline CFS grade of 3–5 (modified Oxford scale: 0–5; at least one eye), Schirmer test (without anesthesia) scored at < 10 mm/5 min (same eye) and ≥ 2 moderate to very severe (based on a 5-point Likert scale: 0–4 for mild–severe) symptoms of dry eye (burning/stinging, foreign body sensation, eye dryness, eye pain, and blurred/poor vision) [7, 33]. Best-corrected distance visual acuity (BCDVA) score was > 20/200 Snellen (both eyes). Key exclusion criteria were topical CsA use (within the past 3 months), any change in systemic immunosuppressant drugs (within 30 days), ocular disease, trauma or infection (during the past 90 days), concurrent ocular allergy or chronic conjunctivitis, and pregnancy or breastfeeding. Full inclusion/exclusion criteria can be viewed in the Supplementary Materials, alongside additional details of the methodology, assessments, and statistical analysis used during the study.
Study Design and Treatments
The trial comprised a 12-month open-label period (baseline [day 1] through month 12) followed by a 24-month randomized, double-masked period (months 12–36; Supplementary Materials Figure S1). During the open-label period, patients used once-daily CsA 0.1% CE (one drop) for 12-months to obtain sufficient data to support correlation analysis regarding signs and symptoms. Participants demonstrating marked improvement in CFS grade (≥ 2-grade reduction for individuals with baseline CFS 3–4 grades or ≥ 3-grades for those with CFS 5) at month 12 were randomized 3:2 to continue CsA 0.1% CE or receive vehicle (the same cationic emulsion containing no CsA) for 24 months (months 12– 36). The threshold of ≥ 2-grade improvement in CFS was based on demonstration of efficacy in CsA 0.1% CE pivotal trials [22, 23]. A vehicle arm was included in the 24-month randomized period with the aim of allowing any ocular complications due to long-term CsA 0.1% CE treatment to be differentiated from those associated with DED. All participants used the same unpreserved artificial tears (Larmabak® saline solution) up to six times daily throughout the 36-month study period.
Open-label period participants attended visits at months 3, 6, 9, and 12. Visits were conducted every 3 months during the randomized period (months 12–36). The schedule of key assessments at each visit is presented in Supplementary Materials Table S1.
Study Endpoints
Primary endpoints were incident rate of ocular surface complications, comprising corneal ulceration, corneal perforation, decrease in visual acuity (3–6-line reduction since last assessment), and ocular infection, as well as time to onset of ocular surface complications. The correlation between the change from baseline in CFS grade and SANDE score was also a primary endpoint [12, 13].
Safety endpoints included adverse event (AE) and treatment-related AE reporting throughout the study period and the change from baseline in intraocular pressure (IOP; mmHg) and BCDVA (LogMAR). Other endpoints were occurrence and time to onset of marked CFS improvement (open-label period only), and incidence and time to relapse (≥ 2-grade CFS increase; randomized period only),
Secondary efficacy endpoints evaluated during the 36-month study period were CFS grade, SANDE score, conjunctival fluorescein staining, DED symptom severity, tear break-up time (TBUT; s), Schirmer's test (mm/5 min), use of artificial tears (over the past week), and the change in DEQS (symptom frequency and symptom degree) from baseline [14].
Statistical Analysis
Statistical analyses were performed using SAS Software Version 9.4. Spearman’s correlation coefficient (SCC) and 95% confidence interval (CI) were used to calculate the correlation between the change from baseline in CFS grade at a given visit/time (t) and the SANDE score at the same visit (t + 0) or a subsequent visit (t + i; further details of SCC analysis are available in the Supplementary Materials) [34]. Log-rank testing was used to calculate the nominal p value for differences in time to relapse, with values ≤ 0.05 considered statistically significant. The safety population comprised all patients who received ≥ 1 dose of the study medication with follow-up data available. The full analysis set (FAS) population was used for endpoints relating to changes in signs/symptoms and included all enrolled patients who received ≥ 1 dose of the study medication and had ≥ 1 post-baseline (open-label period) or post-month 12 (randomized period) sign/symptom assessment. Owing to the exploratory nature of the study, which was designed to explore long-term effects of the CsA 0.1% CE formulation on ocular surface complications, signs, and symptoms, no multiplicity controls were planned or conducted. A mixed model for repeated measures (MMRM) was applied to estimate the response of change from month 12 for CFS, SANDE symptoms score, conjunctival fluorescein staining, TBUT, Schirmer test, and use of artificial tears over the last week.
Results
The open-label period enrolled 350 patients, of which 344 (98.3%) were included in the open-label safety population and 336 (96.0%) were in the FAS. In total, 62 (17.7% of enrolled patients) discontinued before month 12 and 288 completed the open-label study (Fig. 1). Discontinuations during the open-label period were most commonly due to an AE (27 patients), subject withdrawal (15 patients), or lack of efficacy (11 patients). Marked improvement in CFS (reduction in CFS grade of ≥ 2 for those with baseline scores of 3–4 and a decrease of ≥ 3 for patients with CFS 5 at baseline) at month 12 was demonstrated by 279 completers (83.0% of the open-label FAS) and 245 chose to participate in the randomized, double-masked period. All 245 patients were included in the randomized, double-masked period safety population and FAS. Overall, 148 were randomized to CsA 0.1% CE and 97 to vehicle from month 12 through 36. The total number of patients completing the study at month 36 was 223 (91.0% of the randomized period FAS). Eleven subjects (4.5% of the safety population and FAS) in each treatment arm discontinued prematurely from the randomized period. Reasons for leaving the CsA 0.1% CE arm were withdrawal by subject (six patients), noncompliance with study drug (three patients), and an adverse event. Vehicle users most commonly left the study owing to lack of efficacy (four patients), withdrawal by subject (three patients), or an AE (two patients).
Fig. 1.
Patient disposition. During the open-label period, patients were treated with CsA 0.1% CE (one drop daily) and unpreserved saline solution artificial tears (≤ 6 times daily) from baseline through month 12. Patients demonstrating marked improvement in CFS grade at month 12 (defined as a ≥ 2-grade reduction where baseline CFS was graded as 3-4 or ≥ 3-grade reduction for those with baseline CFS grade of 5 on the modified Oxford scale) were randomized to continue CsA 0.1% CE or to receive vehicle (the same cationic emulsion containing no CsA) during the randomized, double-masked period (months 12–36). Overall, 350 patients were enrolled in the open-label period; 62 discontinued before month 12 and 288 completed the open-label study. The open-label safety population included 344 patients and the full analysis set (FAS) included 336 patients. Of the 288 FAS participants completing the open-label period, 279 showed marked improvement in CFS at month 12 and 245 went on to be randomized to receive CsA 0.1% CE (n = 148) or vehicle (n = 97) during months 12–36. All 245 patients were in the randomized period safety population and FAS, and 223 patients completed the study at month 36. The definitions of study populations are as follows: full analysis set—all randomized subjects who received at least one dose of the study medication and had at least one post-baseline sign or symptom assessment of the study eye (used for efficacy analyses); safety population—all subjects who received at least one dose of study medication and for whom any follow-up information was available (used for safety analyses). CE cationic emulsion, CFS corneal fluorescein staining, CsA ciclosporin A
Baseline demographics and characteristics for the open-label FAS (baseline through month 12) and those responders who went on to be randomized are presented in Table 1.
Table 1.
Patient demographics and characteristics at baseline (day 1) for participants included in the open-label period and those responders who were included in the randomized, double-masked period (full analysis set)
| Patient demographics/characteristics at baseline (day 1) | Patients included in the open-label perioda | Responders included in the randomized, double-masked perioda | |
|---|---|---|---|
| CsA 0.1% CE | CsA 0.1% CE | Vehicle | |
| (N = 336) | (N = 148) | (N = 97) | |
| Age (years) | |||
| Mean (SD) | 59.4 (13.4) | 59.3 (13.4) | 57.6 (13.5) |
| Minimum, maximum | 24, 88 | 24, 88 | 27, 85 |
| Aged < 65 years, n (%) | 202 (60.1) | 92 (62.2) | 63 (64.9) |
| Sex, n (%) | |||
| Male | 47 (14.0) | 19 (12.8) | 20 (20.6) |
| Female | 289 (86.0) | 129 (87.2) | 77 (79.4) |
| Race, n (%) | |||
| American Indian or Alaska Native | 3 (0.9) | 2 (1.4) | 0 |
| Asian | 4 (1.2) | 3 (2.0) | 0 |
| Black or African American | 1 (0.3) | 0 | 1 (1.0) |
| Native Hawaiian or Other Pacific Islander | 10 (3.0) | 5 (3.4) | 1 (1.0) |
| White | 318 (94.6) | 138 (93.2) | 95 (97.9) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 47 (14.0) | 19 (12.8) | 10 (10.3) |
| Not Hispanic or Latino | 288 (85.7) | 128 (86.5) | 87 (89.7) |
| Unknown | 1 (0.3) | 1 (0.7) | 0 |
| Tobacco smoking status | |||
| Tobacco smoker | 21 (6.3) | 13 (8.8) | 3 (3.1) |
| Ex-tobacco smoker | 51 (15.2) | 18 (13.2) | 16 (16.5) |
| Exposed to passive tobacco smoke | 25 (7.4) | 16 (10.9) | 5 (5.2) |
| Sjögren patient population, n (%) | 70 (20.0) | 29 (19.6) | 18 (18.6) |
| CFS score (modified Oxford scale), n (%) | |||
| < 3 | 0 | 0 | 0 |
| 3 | 163 (48.5) | 68 (45.9) | 47 (48.5) |
| 4 | 138 (41.1) | 65 (43.9) | 44 (45.4) |
| 5 | 35 (10.4) | 15 (10.1) | 6 (6.2) |
| Mean (SD) CFS score (modified Oxford scale) | 3.6 (0.7) | 3.6 (0.7) | 3.6 (0.6) |
| Schirmer test without anesthesia (category), n (%) | |||
| < 10 mm/5 min | 330 (98.2) | 147 (99.3) | 96 (99.0) |
| ≥ 10 mm/5 min | 6 (1.8) | 1 (0.7) | 1 (1.0) |
| Number of moderate-to-very severe DED symptoms (severity score ≥ 2), n (%) | |||
| 1 | 2 (0.6) | 1 (0.7) | 0 |
| 2 | 38 (11.3) | 19 (12.8) | 11 (11.3) |
| 3 | 54 (16.1) | 27 (18.2) | 18 (18.6) |
| 4 | 81 (24.1) | 33 (22.3) | 26 (26.8) |
| 5 | 161 (47.9) | 68 (45.9) | 42 (43.3) |
| DED, n (%) | |||
| Both eyes | 329 (97.9) | 145 (98.0) | 95 (97.9) |
| Duration of DED in study eye (years) | |||
| Mean (SD) | 7.0 (6.3) | 6.8 (5.9) | 6.2 (5.7) |
The full analysis set included all enrolled patients who received ≥ 1 dose of the study medication and had at least one post-baseline (open-label period) or post-month 12 (randomized, double-masked period) sign or symptom assessment for the study eye
CFS corneal fluorescein staining, CE cationic emulsion, CsA ciclosporin A, DED dry eye disease, SD standard deviation
aDuring the open-label period, patients were treated with once-daily CsA 0.1% CE (one drop daily) and unpreserved saline solution artificial tears (≤ 6 times daily) from baseline through month 12. Patients demonstrating marked improvement in CFS score at month 12 (defined as a ≥ 2-grade reduction or ≥ 3-grade reduction for those with baseline CFS grade of 5 on the modified Oxford scale) were randomized to continue CsA 0.1% CE or to receive vehicle (the same cationic emulsion containing no CsA) during the randomized, double-masked period (months 12–36)
Primary Study Endpoints
Incidence rates for ocular surface complications were 3.2% with open-label CsA 0.1% CE (baseline through month 12) and 4.7% (CsA 0.1% CE arm) and 3.1% (vehicle arm) during the randomized period (months 12–36; Table 2). Ocular complications arising during the full 36-month study period comprised 3–6-line reduction in visual acuity and ocular infection. Median time to onset of ocular complications was 5.9 (open-label period), 8.2 (CsA 0.1% CE), and 6.3 months (vehicle) during the randomized period.
Table 2.
Incidence of ocular complications during the open-label (baseline through month 12) and randomized, double-masked (months 12 through 36) periods (safety population)
| Open-label period | Randomized, double-masked period | ||
|---|---|---|---|
| CsA 0.1% CE | CsA 0.1% CE | Vehicle | |
| (N = 344) | (N = 148) | (N = 97) | |
| Ocular surface complications, n (%) | 11 (3.2) | 7 (4.7) | 3 (3.1) |
| Corneal perforation | 0 | 0 | 0 |
| Corneal ulceration | 0 | 0 | 0 |
| Decrease in visual acuity | 4 (1.2) | 3 (2.0) | 2 (2.1) |
| Ocular infection | 7 (2.0) | 4 (2.7) | 1 (1.0) |
Patients received open-label CsA 0.1% CE (one drop daily) from baseline through month 12 (open-label period) and CsA 0.1% CE or vehicle during months 12–36 (randomized, double-masked period)
The safety population included all patients enrolled in the study who received ≥ 1 dose of the study medication and had follow-up data available
CE cationic emulsion, CsA ciclosporin A
Mean (standard deviation [SD]) CFS grade was reduced from 3.6 (0.7) at baseline to 2.2 (1.1), 1.7 (1.1), 1.4 (1.1), and 1.1 (1.0) at months 3, 6, 9, and 12, respectively, representing mean (SD) changes of −1.4 (1.0), −1.9 (1.1), −2.2 (1.1), and −2.5 (1.0) (Fig. 2). Likewise, mean (SD) SANDE symptom score was reduced from 76.56 (18.56) at baseline to 53.92 (26.25), 46.80 (24.87), 43.93 (24.01), and 41.15 (24.31) at months 3, 6, 9, and 12, respectively, representing mean (SD) changes of −22.48 (26.14), −29.51 (27.40), −32.03 (26.99), and −35.06 (27.69). SCC analysis indicated that improvement in SANDE score lagged CFS grade reduction by approximately 3–6 months. SCC values for comparisons examining the change from baseline in CFS grade at month 3 with reductions in SANDE score at months 3, 6, 9, and 12 were 0.169, 0.245, 0.274, and 0.178, respectively. The increase (from 0.169 to 0.274) in correlation suggested a probable lag of 3–6 months. The same analysis comparing CFS outcomes at month 6 with SANDE improvements at months 9 and 12 showed similar results.
Fig. 2.
Change in signs and symptoms of dry eye disease and severe keratitis with open-label ciclosporin A 0.1% cationic emulsion treatment (full analysis set). A Mean corneal fluorescein staining grade (modified Oxford scale). B Mean symptom assessment in dry eye score. Median time to marked improvement in CFS grade (≥ 2 grades on the modified Oxford scale) with open-label CsA 0.1% CE was 6 months. CE cationic emulsion, CFS corneal fluorescein staining, CsA ciclosporin A, SANDE symptom assessment in dry eye, SD standard deviation. The full analysis set included all enrolled patients who received ≥ 1 dose of the study medication and had at least one post-baseline sign or symptom assessment for the study eye
Safety Endpoints
In the open-label safety population, 146 patients (42.4%) reported AEs and 24 (7.0%) discontinued treatment owing to AEs. Treatment-related AEs with open-label CsA 0.1% CE occurred in 62 (18.0%) participants. All treatment-related AEs reported between baseline and month 12 were ocular events, except for rhinitis (one patient, 0.3%) and pharyngeal edema (one patient, 0.3%). The main ocular treatment-related AEs were eye irritation (7.0%), dry eye (2.6%), eye pain (2.6%), eye pruritus (2.3%), and ocular hyperemia (2.3%; Table 3). All treatment-related AEs were recovered/recovering by the end of the study period apart from one case each of dry eye (moderate) and product intolerance (mild). In the randomized safety population, 61 (41.2%) CsA 0.1% CE recipients and 45 (46.4%) vehicle users reported AEs, and 2 discontinued in each arm owing to AEs between months 12 and 36. Treatment-related AEs (all ocular) occurred in five (3.4%) CsA 0.1% CE recipients and four (4.1%) vehicle users, with the most frequent being ocular hyperemia (1.4%; CsA 0.1% CE arm) and dry eye (3.1%; vehicle arm). Treatment-related AEs were mainly mild or moderate in intensity throughout the 36-month study period and none were serious. One death occurred during the open-label period and another during the randomized period (vehicle arm); neither were related to treatment. Mean (SD) IOP and BCDVA (LogMAR) remained stable through month 36 (Supplementary Materials Tables S2 and S3). During the open-label period, the mean (SD) change in IOP from baseline at month 12 was 0.20 (2.25) mmHg and the change in BCDVA was −0.04 (0.15). During the randomized period, mean (SD) IOP change was 0.37 (2.18), 0.06 (2.53), and 0.10 (2.43) mmHg with CsA 0.1% CE at months 12, 24, and 36. Respective IOP changes in the vehicle group for the same time points were −0.08 (1.93), −0.09 (2.05), and −0.04 (2.56) mmHg. Mean (SD) changes from baseline in BCDVA at months 12, 24, and 36 were −0.04 (0.15), −0.03 (0.15), and −0.02 (0.17) with CsA 0.1% CE and −0.04 (0.11), −0.01 (0.13), and −0.01 (0.10) with vehicle. No cases of treatment-related malignancy were reported.
Table 3.
Treatment-related ocular adverse events during the open-label (baseline through month 12) and randomized, double-masked (months 12–36) periods (safety population)
| Open-label period, n (%) | Randomized period, n (%) | ||
|---|---|---|---|
| CsA 0.1% CE (N = 344) | CsA 0.1% CE (N = 148) | Vehicle (N = 97) | |
| All ocular treatment-related AEs | 62 (18.0) | 5 (3.4) | 4 (4.1) |
| Eye disorders | 57 (16.6) | 3 (2.0) | 4 (4.1) |
| Eye irritation | 24 (7.0) | 1 (0.7) | 0 |
| Dry eye | 9 (2.6) | 0 | 3 (3.1) |
| Eye pain | 9 (2.6) | 0 | 1 (1.0) |
| Eye pruritus | 8 (2.3) | 1 (0.7) | 1 (1.0) |
| Ocular hyperemia | 8 (2.3) | 2 (1.4) | 0 |
| Conjunctival hyperemia | 3 (0.9) | 0 | 1 (1.0) |
| Lacrimation increased | 3 (0.9) | 0 | 0 |
| Ocular discomfort | 3 (0.9) | 0 | 0 |
| Vision blurred | 3 (0.9) | 0 | 1 (1.0) |
| Corneal edema | 2 (0.6) | 0 | 0 |
| Eyelid pruritus | 2 (0.6) | 0 | 0 |
| Foreign body sensation | 2 (0.6) | 0 | 0 |
| Conjunctival edema | 1 (0.3) | 0 | 0 |
| Eyelid erythema | 1 (0.3) | 0 | 0 |
| Eyelid edema | 1 (0.3) | 0 | 1 (1.0) |
| Photophobia | 1 (0.3) | 0 | 0 |
| General disorders and administration site conditions | 5 (1.5) | 0 | 0 |
| Instillation-site pain | 3 (0.9) | 0 | 0 |
| Instillation-site paresthesia | 1 (0.3) | 0 | 0 |
| Product intolerance | 1 (0.3) | 0 | 0 |
| Injury, poisoning, and precrural complications | 2 (0.6) | 0 | 1 (1.0) |
| Foreign body in eye | 2 (0.6) | 0 | 1 (1.0) |
| Infections and infestations | 1 (0.3) | 2 (1.4) | 0 |
| Conjunctivitis | 1 (0.3) | 0 | 0 |
| Herpes ophthalmic | 0 | 1 (0.7) | 0 |
| Ophthalmic herpes zoster | 0 | 1 (0.7) | 0 |
AEs adverse events, CE cationic emulsion, CsA ciclosporin A
Secondary Efficacy Endpoints
Median time to marked improvement in CFS grade (reduction in CFS grade of ≥ 2 for those with baseline scores of 3–4 and a decrease of ≥ 3 for patients with CFS 5 at baseline) with open-label CsA 0.1% CE was 6 months. Mean CFS grade remained stable in both arms during months 12–36. At month 12, 19.8% achieved corneal clearing (CFS 0) with open-label CsA 0.1% CE (Supplementary Materials Figure S2). At month 36, 37.2% (both arms) had CFS 0 grades. During months 12–36, 17.6% (CsA 0.1% CE) and 25.8% (vehicle) experienced relapse (≥ 2 grade CFS increase). Median time to relapse was 10.0 (CsA 0.1% CE) and 12.1 months (vehicle; nominal p = 0.1191). Mean SANDE symptom score remained stable during months 12–36.
Conjunctival fluorescein staining grade (modified Oxford scale) and individual ocular symptoms showed similar patterns of improvement from baseline through month 12 followed by stabilization during months 12–36. Mean (SD) TBUT rose from 3.95 (3.23) s at baseline to 6.47 (4.42) s at month 12 and was then maintained in both arms through month 36 (Supplementary Materials Tables S4 and S5). Mean (SD) Schirmer test value increased from 4.1 (3.4) mm/5 min at baseline to 8.2 (6.4) mm/5 min at month 12 and was sustained in both arms during months 12–36. Mean artificial tear use was 5.4 times/day at baseline, 4.2 times/day at month 12 (open-label CsA 0.1% CE), and 3.9 times/day (CsA 0.1% CE) and 4.2 times/day (vehicle) at month 36. MMRM analysis for changes in CFS, conjunctival fluorescein staining, TBUT, Schirmer’s test, and artificial tear use are presented in Supplementary Materials Table S6. Only artificial tear use at month 36 reached statistical significance for between-arm comparisons (nominal p = 0.0362). Mean (SD) reduction (improvement) from baseline in DEQS symptom frequency score was 26.2 (20.6) at month 12 with open-label CsA 0.1% CE and 28.6 (22.5; CsA 0.1% CE) and 32.8 (22.7; vehicle) at month 36 in the randomized FAS. Mean (SD) reduction in DEQS symptom degree score was 27.2 (21.6) at month 12 (open-label CsA 0.1% CE) and 30.3 (24.2; CsA 0.1% CE) and 36.8 (25.2; vehicle) at month 36 in the randomized FAS.
Discussion
Discordance between improvement in ocular signs and symptoms of DED represents an ongoing challenge for clinicians in the management of this common and complex condition [1, 2, 15–19]. CsA 0.1% CE is among the treatments most widely used by patients with DED and the current study represents the longest investigation of its use in this group [8, 10, 20–26]. Once-daily CsA 0.1% CE was well tolerated and associated with a low incident rate of ocular complications and typically mild/moderate treatment-related AEs throughout the entire 3-year study period. In addition, the study was the first to attempt to quantify any potential delay between reduction in clinical signs (CFS) and improvement in patient-reported symptoms (SANDE score). The knowledge that symptomatic relief may be delayed for some individuals, even when parameters pertaining to corneal health have improved, may help clinicians in managing patient expectations and providing reassurance during the early stages of CsA 0.1% CE treatment. In line with previous data, CsA 0.1% CE treatment was associated with clinically relevant reductions in the severity of DED signs and symptoms from month 3 through month 12 as well as QoL indicators, and our analysis estimated that (for those patients who experience any delay in symptom relief) CFS reductions may precede SANDE score reduction by 3–6 months [8, 10, 26, 28, 31, 32].
Prevalence of ocular surface complications was low (< 5%) throughout the entire study period and comprised moderate decreases in visual acuity and ocular infection in both arms. Rates of reduced visual acuity were comparable across the CsA 0.1% CE and vehicle arms during the randomized period and could have been influenced by patient factors, such as ageing and worsening of cataracts. Slightly more patients had infections in the CsA 0.1% CE arm, which was expected given the immunosuppressive mechanism of CsA [29]. There were no reports of corneal perforation or ulceration. Safety outcomes reflected those of previous RCTs and real-world studies with no new signals identified [8, 22–26]. No serious AEs or cases of malignancy were related to CsA 0.1% CE, and treatment-related AEs were generally mild/moderate and occurred at the site of administration. Most patients completed the open-label (85.7%) and randomized (91.0%) periods and discontinuations due to AEs were low. IOP and BCDVA remained similar to baseline values through month 36, indicating that long-term CsA 0.1% CE use was not directly associated with increased risk of ocular hypertension or sight loss.
As shown in previous RCTs and observational studies, CsA 0.1% CE treatment provided CFS reductions that were evident from month 3 and incrementally lowered to give a clinically relevant mean reduction from baseline of 2.5 grades at month 12 [8, 10, 26, 28, 31, 32]. Likewise, symptom severity was progressively reduced from month 3 through month 12. While SCC analysis revealed only a weak correlation, the estimated delay of 3–6 months was broadly consistent with observations from clinical practice and literature, and the observed variation highlights the need for individualized approaches to management, as not all patients experience a delay in symptom improvement [1, 2, 8, 10, 15–19, 31, 32, 35]. Corneal nerve damage resulting from severe ocular surface disease can lead to neurosensory abnormalities and changes in the individual’s experience of ocular symptoms, so that perceived severity may not necessarily correlate with DED signs [9, 36]. As highlighted in the 2025 update to the DEWS III Management and Therapy report, a range of CsA formulations have emerged for the treatment of DED in recent months [21]. However, these formulations were not available at the start of the current study and they only became obtainable in a limited number of countries very recently (November 2025 to January 2026; UK, Germany, and Spain). As yet, no European data are available for these newer treatments, and no head-to-head trials have been conducted across the various formulations. Differences in study design prevent direct comparisons concerning treatment outcomes from existing studies [21]. Comparisons may be appropriate and of clinical interest in the future, if studies examining newer formulations are able to demonstrate similar long-term safety and efficacy outcomes to those achieved with CsA 0.1% CE in the current study.
Inclusion of statistical analysis regarding changes in CFS and SANDE score from baseline with open-label CsA 0.1% CE could have strengthened the study design. However, the trial was not designed or powered to demonstrate CsA 0.1% CE efficacy, which has already been proven in the SANSIKA and SICCANOVE studies [22–25, 30]. Selection bias could have been introduced by including in the randomized period only those patients achieving marked improvement with open-label CsA 0.1% CE use. However, it would not have been ethical to include those patients who had not shown benefit with treatment by month 12 in a 2-year extension study examining treatment-related corneal complications. It was therefore important that patients enrolled in the randomized period had already demonstrated improvement during the open-label period, so that any complications due to long-term treatment could be assessed and differentiated from complications of DED itself through the use of a vehicle group comparator. This approach also supported examination of relapse rates during extended follow-up. Statistical comparison of ocular complication rate and relapse rate against vehicle might also have been useful for clinicians, although this would have required much larger treatment arms to obtain sufficient statistical power. While a total of 62 patients (17.7% of enrolled participants) discontinued from the study during the open-label period and 11 patients (4.5% of the randomized Safety Population) in each group left through the randomized period, this level of withdrawal was to be expected during a long-term follow-up of 36 months [22, 24]. Similar dropout rates were seen in the SANSIKA trial, in which 16.2% of CsA 0.1% CE users and 12.2% of vehicle recipients discontinued during the initial 6-month randomized study, and a further 12.2% of the original FAS had left at the end of the open-label extension (month 12). In the current study, withdrawals due to AEs were typically seen during the open-label period, indicating that those who were able to tolerate CsA 0.1% CE during the first 12 months of treatment were generally able to continue for a further 24 months without experiencing tolerability issues that would cause them to cease treatment. Other limitations may include the choice of vehicle during the randomized period, as the formulation chosen (the same cationic emulsion without CsA) could have helped in maintaining lower levels of inflammation, making it difficult to distinguish between complications of DED and those associated with treatment [37, 38]. No subanalysis according to sex or race/ethnicity was planned or conducted. Participants were largely female (86.0%), reflecting the fact that women tend to have greater risk for DED compared with men [1]. The study population was also typically white, potentially owing to the countries in which the trial was conducted. This represents a limitation of the study design, which would have benefited from a greater ethnic diversity and could have enabled subanalysis according to race/ethnicity. Future study protocols should also include the requirement for routine collection of slit-lamp images to demonstrate changes in corneal staining during treatment, as these were not requested or collected for the current trial.
TBUT, Schirmer’s test, and conjunctival staining were improved during the open-label period and then stabilized during month 12–36 in both treatment arms, reflecting the pattern of change seen in CFS and SANDE assessments. Future studies would benefit from inclusion of tear volume assessments, as improvements in markers of inflammation (e.g., CFS) can be accompanied by increases in tear production/volume that may support improved homeostasis at the ocular surface [2, 3, 11].
The stabilization of signs and symptoms seen during months 12–36 was reflective of SANSIKA extension data, which observed that individuals achieving CFS grades ≤ 2 did not relapse during a 24-month follow-up (after CsA 0.1% CE discontinuation at 6 or 12 months) [30]. Relapse was also less likely to occur in individuals receiving CsA 0.1% CE for 12 months [30]. In our study, mean CFS grade was 1.1 at month 12 (indicating moderate disease), and patients entering the randomized period had already shown ≥ 2-grade CFS improvement, making them broadly aligned with those in the SANSIKA extension study [30]. Although more patients in the vehicle arm (25.8%) relapsed compared with the CsA 0.1% CE arm (17.6%), the majority did not relapse in either treatment arm. The current study also showed that the percentage achieving corneal clearing (CFS 0) continued to increase from 19.8% at month 12 to 37.2% at month 36 (both arms), indicating a potential legacy effect with CsA 0.1% CE. Further studies would be required to examine this theory. The current study supports European consensus that patients with DED should benefit from CsA 0.1% CE treatment when continued for at least 6–12 months, and our results indicate that prolonged treatment should not pose additional safety concerns [10, 11].
Conclusions
Once-daily CsA 0.1% CE was well tolerated with low rates of ocular surface complications over a 3-year study period in patients with DED with baseline CFS graded above 3 on the modified Oxford scale. CsA 0.1% CE provided clinically relevant reductions in DED signs that preceded symptom severity improvements by approximately 3–6 months and were maintained for a further 24 months.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the patient participants and Study Group Investigators for their valuable contribution. Study Group Investigators: Czech Republic: Ivana Liehneova (Masarykova nemocnice v Usti nad Labem), Vladimir Korda (Ocni klinika Oftex, Pardubice), Jana Nekolova (Fakultni nemocnice Hradec Kralove, Hradec Kralove), Petr Masek (Fakultni nemocnice Ostrava), Ales Cech (Nemocnice Teplice), Daniela Rybarova (Medoko s.r.o, Praha), Tatana Laboha (Axon clinical, Praha). Italy: Paolo Fogagnolo (ASST Santi Paolo e Carlo—Presidio Ospedale San Paolo, Milano), Stefano Barabino (Polo Universita degli Studi di Milano—Ospedale Luigi Sacco), Andrea Leonardi (Azienda Ospedaliera di Padova), Pasquale Aragona (Depertment of Biomedical Sciences, Ophthalmology Unit, University of Messina, Messina), Francesco Viola (Fondazione IRCCS CA’GRANDA—Ospedale Maggiore Policlinico, Milano), Edoardo Villani (Multimedica SpA—Presidio Ospedale Maggiore San Giuseppe, Milano). Poland: Malgorzata Siewierska (Szpital Sw. Rozy, Kraków), Tomasz Zarnowski (Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie, Lublin), Ewa Mrukwa-Kominek (Uniwersyteckie Centrum Kliniczne im. Prof. K. Gibinskiego Slaskiego Uniwersytetu Medycznego w Katowicach), Piotr Fryczkowski (Retina Okulistyka, Warszawa), Edward Wylegala (Śląski Uniwersytet Medyczny w Katowicach), Marta Misiuk-Hojlo (Uniwersytecki Szpital Kliniczny im. Jana Mikulicza -Radeckiego we Wrocławiu). Russia: Sergey Astakhov (Omska State University), Natalya Gavrilova (State Budget Educational Institution of High Professional Education Moscow State Medical Stomatology University named after A.I. Evdokimov of MoH of RF), Ekaterina Gornostaeva (Saratov Railway Clinic, Saratov), Aleksei Seleznev (Ivanovo Regional Clinical Hospital), Nadezhda Pozdeeva (Federal State Institution Intersectoral Research and Technology Complex Eye microsurgery n.a. academician S.N. Fyodorov – Cheboksary). Spain: Arturo Ruiz Vargas (Institut Catala de Retina, Barcelona), Cristina Peris-Martinez (Fundacion de Oftalomologia Medica de la Comunitat Valenciana, València), Javier Mendicute (Hospital Universitario de Donostia, Donostia-San Sebastian), Jesus Montero (Cartuja Vision, Sevilla), Maite Sainz de la Maza (Hospital Clinic of Barcelona), Isabel Pinilla Lozano (Hospital Clínico Universitario Lozano Blesa, Zaragoza), Jose Lamarca Mateu (Centro de Oftalmologia Barraquer, Barcelona). Turkey: Banu Bozkurt Alptekin (Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi Hastanesi, Meram/Konya), Omur Gunduz (Ankara Üniversitesi Tıp Fakültesi Vehbi Koç Göz Hastanesi, Meram/Konya), Melis Palamar (Ege Üniversitesi Tıp Fakültesi, Bornova/İzmir). France: Christophe Baudouin (Centre Hospitalier National d’Ophtalmologie, Paris).
Medical Writing, Editorial, and Other Assistance
Claire Lea and Aygul Yalaletdinova provided input and guidance on the reporting of scientific data on behalf of Santen SA. Clinical study development and management was led and overseen by Auli Ropo and Edith van Dijkman, with data analysis by the Data Science team at Santen. Medical writing services were provided on behalf of the authors by Rebecca Down, PhD, at Copperfox Communications Limited, with funding provided by Santen SA, Switzerland.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors critically appraised the data and associated analyses discussed in this paper, and each conducted in-depth review of the manuscript content ahead of submission for publication.
Author Contributions
Andrea Leonardi: Methodology, investigation, writing—review and editing. Pasquale Aragona: Investigation, writing—review and editing. Maite Sainz de la Maza: Investigation, writing—review and editing. Aleksei Seleznev: Investigation, writing—review and editing. Edward Wylegala: Investigation, writing—review and editing. Edoardo Villani: Investigation, writing—review and editing. Christophe Baudouin: Methodology, Investigation, writing—review and editing.
Funding
This Phase 3b post-approval study was mandated by the European Medicines Agency. The study was funded by Santen SAS, France. The organization participated in the design and conduct of the study, including data collection, management, analysis, and interpretation. The funding organization also reviewed the final manuscript for accuracy ahead of journal submission. The journal’s rapid service fee was funded by Santen. All statistical analyses were conducted according to the prespecified statistical analysis plan, and all analyses underwent independent statistical quality control.
Data Availability
The study was registered on the European Union Clinical Trials Register (EudraCT no. 2017-002660-41). Key data from the study are available via the EU Clinical Trials Register website or are available from the corresponding author upon reasonable request.
Declarations
Conflict of Interest
Andrea Leonardi is a consultant for or has received speaker fees from AstraZeneca, Bausch & Lomb, Dompè, FAES Farma, FIDIA, Novartis, Santen Pharmaceutical Co. Ltd., Laboratoires Théa, and SIFI. Pasquale Aragona received honoraria from Abbvie, Alcon, Bausch & Lomb, FB Vision, Fidia, Medivis, Santen, Sifi, Sun Pharma, Tarsus, Thea, and TRB Chemedica for participating in advisory boards, educational events, focus groups and/or expert panels, and scientific research support given to his department. Maite Sainz de la Maza received honoraria from Santen, Thea, Bausch & Lomb, NTC, Sanofi, and Novartis for participating in advisory boards, educational events, focus groups,and/or expert panels, and scientific research support. Aleksei Seleznev received honoraria from Sentiss Rus, Santen, Thea, NTC, Novartis, AbbVie, and Viatris for participating in advisory boards, educational events, focus groups and/or expert panels, and scientific research support. Edward Wylegala is a consultant for Bausch & Lomb, Santen, Fidia, and Théa. Edoardo Villani has received honoraria from AbbVie, Alcon, Bausch & Lomb, Diadema, Essilor Luxottica, FB Vision, Fidia, Santen, Sifi, Thea, Unifarco, and Visufarma for contributing to advisory boards, educational events, and focus groups and/or expert panels. Christophe Baudouin is a consultant for Bausch & Lomb, Horus Pharma, Oculis, Santen, Glaukos, and Théa.
Ethical Approval
The study was performed after independent ethics committee (IEC) approval. The protocol and amendments were reviewed and approved by the relevant IECs for each study site. Participating patients were required to give written informed consent. The study was conducted in accordance with the Declaration of Helsinki and its most recent update and the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) guideline.
Footnotes
Prior Presentation: Data from this study were presented in the form of abstracts and posters at the European Dry Eye Society Congress (EuDEC), Madrid, Spain (20–22 June 2024), the Tear Film & Ocular Surface, Venice, Italy (30 October–2 November 2024) and EuDEC, Kraków, Poland (19–21 June 2025).
Study Group Investigators are listed in acknowledgements section.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The study was registered on the European Union Clinical Trials Register (EudraCT no. 2017-002660-41). Key data from the study are available via the EU Clinical Trials Register website or are available from the corresponding author upon reasonable request.