Table 3.
Clinical Trials of Loteprednol Etabonate for the Treatment of Dry Eye Disease
| Study | Patients | Study design, treatment, and duration | Key findings |
|---|---|---|---|
| LE monotherapy or with AT | |||
| Pflugfelder et al.47 | 66 patients ≥18 years of age with keratoconjunctivitis sicca of ≥6 months' duration and delayed tear clearance | Multicenter, randomized, double-masked, vehicle-controlled trial; patients received LE suspension 0.5% (n = 32) or vehicle (n = 34) QID for 4 weeks | • LE and vehicle both improved worst DED symptom and CFS compared with baseline, but differences between groups were not statistically significant |
| • LE demonstrated significant (P < 0.05) benefits over vehicle for reducing conjunctival hyperemia | |||
| • In a subset of patients with at least a moderate inflammatory component, LE significantly (P < 0.05) improved CFS staining, nasal bulbar conjunctival hyperemia, and lid margin injection versus vehicle at some visits | |||
| • No clinically significant IOP elevations noted | |||
| • No significant change in mean IOP | |||
| • ≥1 treatment-related AE: 16.7% LE versus 23.5% vehicle (treatment-related ocular AEs included increased burning, redness, blurring of vision, foreign body sensation) | |||
| • No treatment-related serious AEs | |||
| Villani et al.48 | 50 eyes/50 patients with moderate-to-severe dry eye symptoms >6 months | Prospective, open-label, masked study; all patients received LE suspension 0.5% QID for 4 weeks | • LE improved signs (fluorescein and lissamine green staining, DCD, hyperreflective keratocyte density) and symptoms (OSDI) compared with baseline (all P < 0.01) |
| • No reports of AEs | |||
| Jung et al.49 | 133 eyes/133 patients with severe dry eye associated with SS whose symptoms were refractory to AT or topical CsA | Retrospective chart review; patients received LE suspension 0.5% BID+AT 6 times per day (n = 66) or FML 0.1% BID+AT 6 times per day (n = 67) for 2 years | • LE+AT and FML+AT groups both experienced improvement in signs (Schirmer's scores, keratoepitheliopathy scores, TBUT) and symptoms over 2 years of treatment (all P < 0.05), with no significant differences between treatment groups at any time point |
| • IOP elevations >2 mmHg were more common in the FML+AT group than in the LE+AT group; among patients with IOP elevations >2 mmHg at 2 years, mean IOP at 2 years was significantly higher with FML (16.50 mmHg versus LE 15.0 mmHg; P = 0.04) | |||
| • No significant elevation in mean IOP at any follow-up visit versus baseline | |||
| • No significant differences between groups in mean IOP | |||
| • No patients required medication to treat elevated IOP | |||
| • IOP elevations >2 mmHg versus baseline occurred in LE group/FML group in 1.5%/3.0% of patients at 6 months, 1.5%/4.5% at 12 months, 4.5%/9.0% at 18 months, and 6.1%/13.4% at 24 months | |||
| • Among patients with IOP elevations >2 mmHg at 24 months, mean IOP was significantly higher at 24 months with FML (16.5 mmHg) versus LE (15.0; P = 0.04) | |||
| Barabino et al.50 | 20 patients with DED | Double-masked, randomized pilot study; patients received LE suspension 0.5% (n = 10) or saline (n = 10), each BID for 14 days, followed by QD for 15 days and then EOD for 4 weeks | • Compared with vehicle, LE significantly improved ocular surface inflammation and symptoms (OSDI questionnaire) at weeks 2 and 8 |
| • No significant differences between groups for TBUT or corneal staining, although the LE group demonstrated a consistent trend for improvement in lissamine green staining | |||
| • No significant increase in IOP in any treated eyes | |||
| • No worsening of BCVA in any treated eyes | |||
| Rolando et al.51 | 36 patients with keratoconjunctivitis sicca | Prospective randomized study; patients assigned to LE suspension BID for 10 days (n = 12) or LE suspension 0.5% BID for 7 days followed by LE QD for 15 days and then EOD for 3 weeks, followed by 2 × /week; all patients received continuous use of AT TID | • Although signs and symptoms of DED improved significantly compared with baseline, the group receiving tapered doses of LE over a prolonged period performed better than the group receiving LE BID for 10 days (P < 0.001) |
| • No significant increase in IOP in any treated eyes | |||
| Aragona et al.52 | 15 female healthy controls, 30 female patients with SS, and 30 female patients with MGD | Investigator-masked, randomized, case–control study; patients with SS or MGD received LE suspension 0.5% QID+saline as needed at least QID (n = 15) or saline as needed at least QID alone for 15 days (n = 15) | • Compared with healthy control subjects, patients with SS or MGD had elevated levels of both MMP-9 and TG-2 expression (P < 0.0001 for all comparisons) |
| • In patients with SS or MGD, LE significantly (P < 0.05) improved signs (corneal and conjunctival staining, Schirmer test scores in patients with SS only, TBUT in patients with MGD only) and symptoms of DED, whereas saline alone did not | |||
| • In both patient subgroups, LE reduced MMP-9 and TG-2 levels versus baseline and versus saline alone (P ≤ 0.006 all comparisons) | |||
| • IOP findings not reported | |||
| • Additional safety results not reported | |||
| LE in combination with and/or compared to CsA | |||
| Wan et al.53 | 68 eyes/34 patients aged 18–60 with grade 2 or 3 (based on the DEWS standard) xerophthalmia | Prospective, randomized study; patients received LE suspension 0.5% BID (n = 38 eyes) or CsA 1% BID (n = 30 eyes) in addition to carbomer eye gel (4–6 times/day) | • Signs (CFS, goblet cell density, TBUT) and symptoms of DED improved versus baseline in both groups (all P < 0.05) |
| • LE significantly (P < 0.05) improved symptoms (sum of scores for dryness, foreign body sensation, burning, photophobia, and blurred vision, each rated on a severity scale of 0–9) versus CsA at 2, 4, and 6 weeks, but not 8 weeks | |||
| • Mean IOP did not differ significantly from baseline or between treatment groups | |||
| • No AEs were reported | |||
| Boynton et al.54 | 150 eyes/75 patients with DED after HSCT | Single-center randomized prospective trial; patients received LE suspension 0.5% BID (n = 76 eyes/38 patients) or CsA 0.05% BID (n = 74 eyes/37 patients) from 1 month before HSCT to 12 months after HSCT | • No significant differences between LE and CsA groups in DED incidence or progression |
| • Among eyes with no DED at enrollment, the rate of development of DED at 12 months after HSCT was 79% in LE-treated eyes and 90% in CsA-treated eyes | |||
| • At 12 months, no significant differences between treatment groups in signs (tear osmolarity, corneal and conjunctival staining, Schirmer test score) or symptoms (OSDI scores) of DED | |||
| • Mean change in BCVA did not differ between treatment groups at 12 months | |||
| • No patient from either group had an IOP elevation ≥10 mmHg at any time point or discontinued treatment due to IOP elevation | |||
| • No difference between treatments in mean change in IOP from baseline over 12 months | |||
| Evans et al.55 | 102 patients with mild or moderate DED | Phase 2, multicenter, randomized, exploratory study; patients received LE gel 0.5% BID for 12 weeks (n = 36), LE gel 0.5% BID for weeks 1–4+CsA 0.05% BID for weeks 3–12 (LE induction therapy; n = 33), or CsA 0.05% BID for 12 weeks (n = 33) | • LE BID for 12 weeks, LE BID for weeks 1–4+CsA BID for weeks 3–12 (induction therapy), and CsA BID for 12 weeks all significantly (based on 95% CIs) reduced fluorescein staining and symptoms (OSDI, Comfort Index) of DED over 12 weeks and LE and CsA also significantly reduced lissamine green staining |
| • No significant differences for LE gel or LE gel+CsA versus CsA alone at 12 weeks, however improvement with LE gel or LE gel+CsA versus CsA was observed for some outcomes at earlier time points • 2 instances of elevated IOP (>21 mmHg), both at week 12: 1 in the LE gel group and 1 during CsA treatment in the LE gel+CsA group | |||
| • Few instances of burning, stinging, or discomfort upon instillation | |||
| • Few AEs (all ocular) | |||
| • No serious AEs | |||
| Sheppard et al.56 | 72 patients with mild-to-moderate chronic DED | Retrospective analysis; first cohort of consecutive patients (LE induction group) received LE suspension 0.5% BID for 2–16 months, followed by concomitant topical CsA 0.05% emulsion for 3–6 months and CsA alone thereafter (n = 36); second cohort of consecutive patients received CsA alone for at least 6 months (n = 36) | • Compared with CsA alone, significantly fewer patients in the LE induction group developed severe stinging (5.5% versus 22%, P < 0.02) or discontinued treatment due to severe stinging (2.8% versus 8.3%, P < 0.04) |
| • LE induction therapy resulted in significant improvement in objective signs of DED at 3 months (based on a composite score that included fluorescein staining, conjunctival redness, and tear meniscus height; relative risk [95% CI], 1.1 [0.8–1.6]; odds ratio [95% CI], 1.2 [0.5–2.8]) | |||
| • No significant differences between treatment groups in rates of improvement in patient-reported eye comfort | |||
| • No clinically significant IOP elevations (increase from baseline of ≥6 mmHg at 2 consecutive visits) were reported | |||
| Sheppard et al.22 | 118 patients with DED | Multicenter, randomized, double-masked study; patients received LE QID for 2 weeks followed by CsA 0.05% BID+LE suspension 0.5% BID for 6 weeks (n = 61) or AT QID for 2 weeks, followed by CsA BID+AT BID for 6 weeks (n = 57) | • Pretreatment with LE resulted in an earlier onset of efficacy for reducing DED symptoms (OSDI scores) |
| • Schirmer test scores improved significantly (P < 0.05) only in the LE+CsA group | |||
| • Only the LE+CsA group showed significant bilateral improvements in central and cumulative staining, and lissamine green staining decreased to a greater extent in the LE+CsA group (P < 0.05) | |||
| • Pretreatment with LE significantly reduced stinging upon initial instillation of CsA at 1 month (P < 0.05), but not at 2 months | |||
| • No changes were observed in IOP within either treatment group during the study | |||
| • No patients discontinued due to IOP changes | |||
| • Most frequent ocular AEs in either group were eye pain, conjunctival hyperemia, IOP increase, reduced visual acuity, and abnormal sensation in the eye | |||
| Singla et al.57 | 140 patients with moderate DED | Prospective, randomized, comparative, interventional study; patients (n = 70 per group) received CsA 0.05% BID or LE 0.5% QID for 2 weeks, tapering to BID over the following 6 weeks plus CsA 0.05% BID. All patients also received AT. | • The LE+CsA group had significantly greater improvement in OSDI score, TBUT, fluorescein staining, and lissamine green staining at 3 and 6 months (P ≤ 0.03 for all). |
| • Schirmer scores were significantly greater with LE+CsA group versus CsA alone from 2 weeks onward (P ≤ 0.008 for all) | |||
| • No significant IOP elevations were observed in the patients receiving LE | |||
| LE for the treatment of MGD | |||
| Lee et al.58 | 70 eyes/70 patients with moderate or severe MGD | Randomized, controlled, single-masked trial; patients received 2 months of treatment with LE suspension 0.5% QID plus eyelid scrubs/warm compresses (n = 34 eyes/34 patients) or eyelid scrubs/warm compresses alone (control group; n = 36 eyes/36 patients) | • At 2 months, there were significant decreases in tear levels of IL-6, IL-8, and IL-1β in the LE group and IL-6 and IL-8 in the control group (P < 0.05) |
| • The LE group showed significantly lower tear levels of IL-8 than the control of IL-8 at 1 month (P = 0.034) and IL-7 at 2 months (P = 0.03) | |||
| • The LE group showed greater improvement in signs (TBUT, corneal and conjunctival staining at 1 month, lid margin abnormality at 2 months, and meibum quality at 1 and 2 months; all P < 0.05) | |||
| • Symptoms (OSDI scores) improved over time in both treatment groups (P < 0.001), with no significant differences between groups at 2 months | |||
| • No clinically significant IOP elevations | |||
| • A small but statistically significant increase in mean IOP occurred in the LE group (P = 0.005), although there was no significant difference between treatment groups in mean IOP at any time point | |||
| • Additional safety data not reported | |||
| Ko et al.59 | 30 patients with a unilateral ocular prosthesis for >1 year and obstructive MGD in the blind eye | Interventional, prospective case series; all patients (N = 30) performed eyelid scrubs/warm compresses BID and instilled LE suspension 0.5% QID into the prosthetic eye for 2 months | • LE+eyelid scrubs/warm compresses was associated with significant decreases over 2 months in tear levels of IL-6, interferon-γ, monocyte chemotactic protein-1, IL-8, tumor necrosis factor-α, and IL-1β (P < 0.001 for each cytokine) |
| • At 2 months, there were significant improvements in prosthetic eye wearers in ocular symptoms (P < 0.001), lid margin abnormalities (P < 0.001), meibomian gland expressibility (P < 0.001), and overall meibography findings (P = 0.037) | |||
| • Tear levels of IL-6, interferon-γ, monocyte chemotactic protein-1, IL-8, tumor necrosis factor-α, and IL-1β decreased significantly after 2 months (P < 0.001 for each cytokine) | |||
| • No change in meibography scores of the upper eyelid | |||
| • IOP findings not reported | |||
| • No AEs reported | |||
| Kheirkhah et al.60 | 60 patients with MGD-related DED and 27 age-matched controls | Double-masked, randomized trial; patients with DED received 4 weeks of BID treatment with LE suspension 0.5% (n = 20), LE suspension 0.5%/tobramycin 0.3% (n = 20), or AT (n = 20) | • At 4 weeks, LE-treated patients with low baseline SNFL showed no improvement in signs or symptoms of DED, while those with near-normal SNFL had significant improvements in SANDE severity (P = 0.04) and corneal fluorescein (P = 0.01) scores |
| • Patients administered with AT with near-normal SNFL demonstrated improvement in OSDI, SANDE frequency and severity scores, and CFS (all P ≤ 0.04) at 4 weeks | |||
| • SNFL may help explain variations in response to therapy | |||
| • IOP findings and other safety findings not reported | |||
| Opitz et al.61 | 30 patients with MGD-related DED | Prospective, multicenter, open-label study; all patients received LE gel 0.5% BID for 30 days | • LE treatment was associated with improvement at day 30 in signs (TBUT, corneal staining, conjunctival staining, MGD signs; all P ≤ 0.006) and symptoms (OSDI and SPEED scores; both P < 0.004) of DED |
| • No significant changes in Schirmer II or tear osmolarity | |||
| • IOP findings and other safety findings not reported | |||
AE, adverse event; AT, artificial tears; BCVA, best-corrected visual acuity; BID, twice daily; CFS, corneal fluorescein staining; CI, confidence interval; CsA, cyclosporine A; DCD, dendritic cell density; EOD, every other day; FML, fluorometholone; HSCT, hematopoietic stem cell transplantation; IL, interleukin; IOP, intraocular pressure; MMP-9, matrix metalloproteinase-9; OSDI, Ocular Surface Disease Index; QD, once daily; QID, 4 times per day; SANDE, Symptom Assessment in Dry Eye; SNFL, subbasal nerve fiber length; SPEED, Standard Patient Evaluation of Eye Dryness; SS, Sjögren's syndrome; TG-2, transglutaminase-2; TID, 3 times a day; TBUT, tear film breakup time.