This study was conducted between October 2020 and March 2022. A total of 91 patients diagnosed with DED with inadequate effects from previous topical 0.05% CsA treatment and 90 patients including 11 patients with Sjogren’s syndrome underwent the study protocol (Fig. 2). A total of 56 patients (62.2%) used hyaluronic acid artificial tears, 18 patients (20%) used carboxymethyl cellulose artificial tears, 1 patient (1.1%) used 3% diquafosol, and 15 patients did not use other eyedrops. During this study, a total of 17 patients withdrew from the study early. This included 12 patients who withdrew their consent, four patients who used prohibited medications after trial registration, and one patient who was withdrawn by the investigator’s decision. This included an additional three patients who determined the exclusion by the investigator after the end of this study; 70 patients were set as per protocol set (PP) and 90 patients as FAS. The baseline clinical characteristics of the patients are summarized in Table 1. Seventy-four patients (82.22%) out of a total 90 patients had other systemic disease history including Sjogren’s syndrome (11 cases), rheumatoid arthritis (1 case), diabetic mellitus (14 cases), atopic dermatitis (1 case), hypothyroidism (7 cases), and others (Supplement 1).

Patient flow during this study. CsA = cyclosporine A, NEI = The National Eye Institute, SANDE = Symptom Assessment in Dry Eye

In both FAS set and PP populations, the corneal and conjunctival staining scores showed significant changes over 12 weeks (p < 0.0001). The corneal staining score in FAS showed 4.52 ± 2.41 at baseline, 1.64 ± 1.51 at 4 weeks, 1.25 ± 1.39 at 8 weeks, and 1.04 ± 1.76 at 12 weeks. In PP papulations, the corneal staining score showed 4.39 ± 1.96 at baseline, 1.70 ± 1.52 at 4 weeks, 1.21 ± 1.40 at 8 weeks, and 1.01 ± 1.50 at 12 weeks. Each visit had statistically significant difference with baseline (all p < 0.0001). The primary end point (corneal staining score difference between baseline and 12 weeks) had significant difference in both FAS and PP (p < 0.0001). The conjunctival staining score showed 2.09 ± 3.86 at baseline, 1.43 ± 3.13 at 4 weeks (p < 0.05), 1.14 ± 2.59 at 8 weeks (p < 0.01), and 1.02 ± 2.63 at 12 weeks (p < 0.001) with statistical significance in FAS. The conjunctival staining score in PP showed 2.03 ± 3.72 at baseline, 1.37 ± 3.10 at 4 weeks (p < 0.05), 1.09 ± 2.63 at 8 weeks (p < 0.01), and 0.96 ± 2.69 at 12 weeks (p < 0.001) with same statistical results as FAS. Conjunctival staining score difference between baseline and 12 weeks had significant difference in both FAS and PP (p < 0.0001). (Fig. 3).

Changes in the corneal and conjunctival staining score over 12 weeks after switching to 0.1% from 0.05% cyclosporine A in FAS and PP. A. Corneal staining score: All corneal staining score differences compared to baseline at each visit showed significant improvement (all p < 0.0001). The change by time showed significance (both p < 0.0001). B. Conjunctival staining score: All conjunctival staining score differences compared to baseline at each visit showed significant improvement (all p < 0.05). The change by time showed significance (both p < 0.0001). NEI = The National Eye Institute, FAS = full analysis set, PP = per protocol set. *: p < 0.0001. #: p < 0.05, ##: p < 0.01, ###: p < 0.001

There were significant changes over 12 weeks in TF-BUT, mean SANDE, ODS, and tear volume (all p < 0.0001). TF-BUT was 4.28 ± 1.22 at baseline, 5.21 ± 1.35 at 4 weeks (p < 0.0001), 5.35 ± 1.43 at 8 weeks (p < 0.0001), and 5.55 ± 1.53 at 12 weeks (p < 0.0001) in FAS, and 4.29 ± 1.21 at baseline, 5.20 ± 1.30 at 4 weeks (p < 0.0001), 5.37 ± 1.43 at 8 weeks (p < 0.0001), and 5.54 ± 1.44 at 12 weeks (p < 0.0001) in PP. Mean SANDE was 67.69 ± 16.50 at baseline, 57.26 ± 19.50 at 4 weeks (p < 0.0001), 48.55 ± 22.41 at 8 weeks (p < 0.0001), and 42.40 ± 23.25 at 12 weeks (p < 0.0001) in FAS, and 68.10 ± 16.40 at baseline, 57.19 ± 20.36 at 4 weeks (p < 0.0001), 49.69 ± 22.52 at 8 weeks (p < 0.0001), and 43.71 ± 24.24 at 12 weeks (p < 0.0001) in FAS in PP. ODS was 17.30 ± 7.24 at baseline, 14.33 ± 6.53 at 4 weeks (p < 0.0001), 11.95 ± 6.48 at 8 weeks (p < 0.0001), and 10.43 ± 7.16 at 12 weeks (p < 0.0001) in FAS, and 17.27 ± 7.29 at baseline, 14.13 ± 6.88 at 4 weeks (p < 0.0001), 12.19 ± 6.37 at 8 weeks (p < 0.0001), and 10.49 ± 6.80 at 12 weeks (p < 0.0001) in PP. Tear volume was 2.81 ± 1.64 at baseline, 3.53 ± 2.46 at 4 weeks (p < 0.05), 3.81 ± 2.86 at 8 weeks (p < 0.01), and 3.71 ± 2.21 at 12 weeks (p < 0.01) in FAS, and 2.69 ± 1.41 at baseline, 3.41 ± 2.41 at 4 weeks (p < 0.05), 3.73 ± 2.53 at 8 weeks (p < 0.01), and 3.71 ± 2.34 at 12 weeks (p < 0.001) in PP (Fig. 4).

Changes in the tear film break-up time, SANDE, ODS, and tear volume over 12 weeks after switching to 0.1% from 0.05% cyclosporine A in FAS and PP. A. Tear Film Break-up time (TF-BUT): All TF-BUT differences compared to baseline at each visit showed significant improvement (all p < 0.0001). The change by time showed significance (both p < 0.0001). B. SANDE (symptom assessment in dry eye): All SANDE differences compared to baseline at each visit showed significant improvement (all p < 0.0001). The change by time showed significance (both p < 0.0001). C. ODS (ocular discomfort scale): All ODS differences compared to baseline at each visit showed significant improvement (all p < 0.0001). The change by time showed significance (both p < 0.0001). D. Tear volume: All tear volume differences compared to baseline at each visit showed significant improvement (all p < 0.05). The change by time showed significance (both p < 0.0001). FAS: full analysis set, PP: per protocol set. *: p < 0.0001. #: p < 0.05, ##: p < 0.01

The improvement rate of SANDE represented 44 (48.89%) at 4 weeks, 69 (76.67%) at 8 weeks, and 73 (81.11%) at 12 weeks in FAS, and 36 (51.43%) at 4 weeks, 52 (74.29%) at 8 weeks, and 56 (80.00%) at 12 weeks in PP. There was a significant increase in both FAS and PP (p < 0.0001) (Fig. 5). PRO of 75 patients who had finished this clinical trial showed 4 much improvement (5.33%), 46 improvement (61.33%), 24 no change (32.00), 1 aggravation (1.33%), and no one much aggravation (0%). Discomforts in the use of 0.1% CsA were blurring (26, 34.67%), pain (16, 21.33%), foreign body sensation (14, 18.67%), irritation (10, 13.33%), and others (9, 12%). The mean medication compliance of 0.1% CsA was 95.57 ± 10.34 and there were two cases which showed compliance under 70%.

The improvement rate of SANDE between each visit with baseline in FAS and PP. A. Improvement rate of SANDE in FAS: The change by time showed significance (p < 0.0001). B. Improvement rate of SANDE in PP: The change by time showed significance (p < 0.0001). SANDE = symptom assessment in dry eye. FAS: full analysis set, PP: per protocol set

In the FAS, eleven of ninety patients had Sjögren’s syndrome, and in the PP analysis, nine of seventy patients were diagnosed with Sjögren’s syndrome. In the FAS, both groups showed significant decreases over 12 weeks in corneal and conjunctival staining scores (p < 0.0001, p < 0.001 respectively), but no significant differences were observed between the groups (p = 0.60, p = 0.29). The conjunctival staining score was significantly lower in the non-Sjögren’s syndrome group (p < 0.0001). TF-BUT, mean SANDE, ODS, and tear volume all showed significant decreases over 12 weeks in both groups (all p < 0.0001), with no significant differences between two groups (all p > 0.05). However, the non-Sjögren’s syndrome group exhibited significantly longer TF-BUT and lower SANDE scores compared to the Sjögren’s syndrome group (Fig. 6). In the PP analysis, the corneal staining score significantly decreased over 12 weeks in both groups (p < 0.0001), with no significant differences between two groups (p = 0.24). There were also no significant differences between two groups (p = 0.52). The conjunctival staining score was significantly lower in the non-Sjögren’s syndrome group than in the Sjögren’s syndrome group (p < 0.0001), but there was no significant change over 12 weeks (p = 0.06). Furthermore, no significant differences were found between two groups (p = 0.18). TF-BUT, mean SANDE, and ODS all showed significant decreases over 12 weeks in both groups (all p < 0.0001), with no significant differences between two groups (all p > 0.05). The non-Sjögren’s syndrome group had significantly longer TF-BUT, lower SANDE, and lower ODS scores than the Sjögren’s syndrome group (all p < 0.05). However, tear volume showed no significant differences between two groups (all p > 0.05) (Fig. 7).

Subgroup analysis between Sjogren’s syndrome and non-Sjogren’s syndrome in FAS. A. Corneal staining score: Change pattern by time was no significant difference between two group (p = 0.60). Change by time was significant (p < 0.0001). B. Conjunctival staining score: Change pattern by time was no significant difference between two group (p = 0.60). Change by time was significant (p < 0.0001). There were significant differences between two groups at baseline, 4, 8, 12 weeks. C. Tear Film Break-up time (TF-BUT): Change pattern by time was no significant difference between two group (p = 0.08). Change by time was significant (p < 0.0001). There were significant differences between two groups at baseline, 4, 8, 12 weeks. D. SANDE (symptom assessment in dry eye): Change pattern by time was no significant difference between two group (p = 0.08). Change by time was significant (p < 0.0001). There were significant differences between two groups at 8, 12 weeks. E. ODS (ocular discomfort scale): Change pattern by time was no significant difference between two group (p = 0.91). Change by time was significant (p < 0.0001). F. Tear volume: Change pattern by time was no significant difference between two group (p = 0.91). Change by time was significant (p < 0.0001). There were significant differences between two groups at 12 weeks. FAS: full analysis set. *: p < 0.05, #: p < 0.01, §: p < 0.001

Subgroup analysis between Sjogren’s syndrome and non-Sjogren’s syndrome in PP. A. Corneal staining score: Change pattern by time was no significant difference between two group (p = 0.52). Change by time was significant (p < 0.0001). B. Conjunctival staining score: Change pattern by time was no significant difference between two group (p = 0.18). Change by time had no significance (p = 0.06). There were significant differences between two groups at baseline, 4, 8, 12 weeks. C. Tear Film Break-up time (TF-BUT): Change pattern by time was no significant difference between two group (p = 0.06). Change by time was significant (p < 0.0001). There were significant differences between two groups at baseline, 4, 8, 12 weeks. D. SANDE (symptom assessment in dry eye): Change pattern by time was no significant difference between two group (p = 0.14). Change by time was significant (p < 0.0001). There were significant differences between two groups at 8, 12 weeks. E. ODS (ocular discomfort scale): Change pattern by time was no significant difference between two group (p = 0.80). Change by time was significant (p < 0.0001). There were significant differences between two groups at 12 weeks. F. Tear volume: Change pattern by time was no significant difference between two group (p = 0.52). Change by time had no significance (p = 0.27). PP: per protocol set. *: p < 0.05, #: p < 0.01, §: p < 0.001

There was no significant difference of change in the corneal staining score (p = 0.60), conjunctival staining score (p = 0.29), TF-BUT (p = 0.09), SANDE (p = 0.38) ODS (p = 0.9), tear volume (p = 0.66) between non-Sjogren’s syndrome patients (79 cases) and Sjogren’s syndrome patients (11 cases) through the study. Moreover, there was no significant difference at each visit compared to baseline in all parameters (all p > 0.05).

Adverse effects were observed in 16 patients (23 cases) out of 90 patients. There were 7 cases of ocular symptoms associated with adverse events (AEs), of which pain after instillation had a clear association. The remaining 22 cases were not relevant with the clinical trial. Most of the AEs were grade I (18 cases, 78.26% of all AEs) and grade II AE was seen in four patients (17.39%). A Grade III AE of mechanical ileus was reported in one patient. It was not associated with the clinical trial, and the patient has recovered. The information regarding AEs is provided in Supplement 2.