Cyclosporine Ophthalmic Emulsion for Dry Eye Disease

Two Multicenter, Randomized Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye Disease Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology. 2000 Apr;107(4):631-9. Journal Club Terry J. Alexandrou, MD Department of Ophthalmology and Visual Science University of Chicago

Inflammation in Dry Eye Disease

Evidence to suggest that dry eye disease is the result

of an underlying cytokine and receptor-mediated

inflammatory process affecting both the lacrimal

gland and ocular surface

Cyclosporin Ophthalmic Emulsion

Authors propose that topical treatment with the immunomodulatory agent Cyclosporin A (CsA) can have beneficial effects on the underlying inflammatory pathologic condition of dry eye disease, as well as to improve the signs and symptoms of the disease

Primarily affects T Lymphocytes

Objective

To compare the efficacy and safety of cyclosporin A (CsA) 0.05% and 0.10% ophthalmic emulsions in the treatment of moderate to severe dry eye disease, in patients with or without Sjogren’s Syndrome.

Study Design

Two identical multicenter, randomized, double masked, parallel group clinical trials comparing 2 concentrations of Cyclosporine (CsA) ophthalmic emulsion to its vehicle

Materials and Methods

Patient Inclusion Criteria

Shirmer Test (without anesthesia) of ≤5mm/5min in at least one eye

2) Sum of Corneal and Interpalpebral Conjunctival staining of ≥ +5 in the same eye where corneal staining was ≥ +2

3) Baseline OSDI (Ocular Surface Disease index) score of 0.1 (with no more than 3 responses of Not Applicable)

4) Subjective Facial Expression Scale of ≥ 3

Patient Inclusion Criteria

Symptoms despite conventional management

Normal lid position and closure

Best corrected EDTRS VA score of +0.7 LogMar or better in each eye

Capable of following study protocol

Patient Exclusion Criteria

Prior participation in CsA clinical trial or use of CsA in previous 90 days

Systemic or ocular disorder that could possibly interfere with interpretation of study results

Current or recent use of medications (topical of systemic) that could affect a dry eye condition

Required contact lens wear during study

Patient Exclusion Criteria

Recent (1 mo) or anticipated use of punctal plugs

Pregnant, Lactating, or planning for a baby

End stage lacrimal gland disease (Shirmer of <3mm/5min with nasal stimulation)

No longer met criteria for moderate to severe dry eye after 2 week run in phase

Study Medications

Cyclosporine 0.05%

Cyclosporine 0.1 %

Vehicle

Other medications given as necessary for patient welfare, however patients only kept in the study if they would not interfere with the response to study medications

Study Protocol

2 Week Run-In Phase

Assigned artificial tears only (as needed)

Treatment Phase

1 drop of study medication bid x 6 months (1:1:1)

Assigned artificial tears as needed up to month 4

-not within 30 minutes before or after study med

-stop 1 week before month 4 study visit

Evaluation at 1, 3, 4, and 6 months of treatment

Outcome Measures

Efficacy

Safety

Efficacy – Objective Measurements

Corneal and Interpalpebral Conjunctival Staining

Shirmer tear test (with and without anesthesia)

Tear break up time

Oxford scheme 6 point scale – each investigator used same photos Cornea – fluorescein Conj – lissamine green 5 point scale: 1 – <3 mm/5min 2 - 3-6 mm/5min 3 – 7-10 mm/5min 4 – 11-14 mm/5min 5 - >14 mm/5min Recorded only if value < 10 sec

Efficacy – Subjective Measurements

OSDI (Ocular Surface Disease Index)

Symptoms of Dry Eye

Investigator’s Evaluation of Global Response to Treatment

Treatment Success

Artificial Tears Use

Subjective Facial Expression Rating

12 questions used to eval the impact of dry eye on vision-related functioning Stinging/burning, grittiness, blurred vision, dryness, light sensitivity, and pain 7 point scale: 0 = completely cleared 5 = unchanged 6 = worsened Improvement of ≥ 90 % 1 = happiest 9=unhappiest

Other Measures

Blood samples collected

-ANA, RF, SS-A and SS-B Sjogren’s antibodies

-CsA trough concentration

Statistical Methods

Data from worse eye included in data analyses

(ANOVA) A two way analysis of variance

Cochran Mantel-Haenszel procedure

Paired t test

Wilcoxon signed rank test

Results

Participant Flow and Follow-Up

877 Patients Enrolled

- 76% (671/877) completed the study

7 % discontinued because of adverse events (61/877)

-CsA 0.05% - 19/293 (6.5%)

-CsA 0.1 % - 29/292 (9.9%)

-Vehicle - 13/292 (4.5%)

0.8% discontinued because of lack of efficacy (7/877)

Patient Demographics No differences between treatment groups Sjogrens – Ocular and oral symptoms, Schirmer ≤5mm, and 1 of following: ANA, RF, SS-A, SS-B

Efficacy – Corneal Staining Statistically significant improvement in all treatment groups (P < 0.001) At 4 months, both CsA groups demonstrated statistically significant improvement compared to vehicle (P < .044) At 6 months, CsA 0.05% group demonstrated statistically significant improvement compared to vehicle (P < .044)

Efficacy – Schirmer Tear Test Statistically significant improvement in CsA 0.05% at month 3, and in both CsA groups at month 6

Efficacy – Symptoms of Dry Eye Decrease in blurred vision statistically significant in both CsA groups at all f/u visits, but only significant in vehicle group at month 6 visit. 5 Point Scale: 0 = do not have this symptom 4 = always have this symptom

Efficacy – Concomitant use of Artificial Tears

Safety Analyses

Superficial Conjunctiva Epithelium Biopsies

Conclusions

“ Topical treatment with CsA 0.05% or 0.10% resulted in significantly greater improvements than vehicle in”:

Objective Measurements :

Corneal Staining

Categorized Schirmer values

Subjective Measurements :

Blurred Vision

Use of lubricating eye drops

Physician’s evaluation of Global response to Treatment

“ Both CsA treatments safe and well tolerated”

Study Weakness

Do any of these results have implications in clinical practice?

What is .1 of a standard photo?

Corneal Staining Oxford scheme 6 point scale – each investigator used same photos At baseline, mean value between 2.61 and 2.77 for ALL treatment groups Statistically significant improvement in all treatment groups (P < 0.001) At 4 months, both CsA groups demonstrated statistically significant improvement compared to vehicle (P < .044) At 6 months, CsA 0.05% group demonstrated statistically significant improvement compared to vehicle (P < .044)

Schirmer Values At baseline, mean values ranged between 1.94 and 2.11 At 6 months, statistically significant improvement from baseline and from vehicle in both CsA groups

Blurred Vision 5 Point Scale: 0 = do not have this symptom 4 = always have this symptom At baseline, mean value between 1.83 and 2.04 for ALL treatment groups Why not use actual visual acuities?

Use of Lubricating Drops

Subjective Facial Expressions