Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group.
OBJECTIVE
To investigate the efficacy, safety, formulation tolerability, and optimal dosing of a novel cyclosporin A oil-in-water emulsion formulation for the treatment of moderate-to-severe dry eye disease.


METHODS
Randomized, multicenter, double-masked, parallel-group, dose-response controlled trial.


METHODS
Total enrollment: 162 patients; cyclosporin A groups: 129 patients; vehicle group: 33 patients.


METHODS
Patients instilled study medication (cyclosporin A ophthalmic emulsion 0.05%, 0.1%, 0.2%, or 0.4%, or vehicle) twice daily into both eyes for 12 weeks, followed by a 4-week posttreatment observation period.


METHODS



RESULTS
rose bengal staining, superficial punctate keratitis, Schirmer tear test, symptoms of ocular discomfort, and the Ocular Surface Disease Index (OSDI; a measure of symptom frequency and impact on vision-related functioning).


RESULTS
biomicroscopy, cyclosporin A blood levels, conjunctival microbiology, intraocular pressure, visual acuity, and monitoring of adverse events.


RESULTS
In a subset of 90 patients with moderate-to-severe keratoconjunctivitis sicca, the most significant improvements with cyclosporin A treatment were in rose bengal staining, superficial punctate keratitis, sandy or gritty feeling, dryness, and itching, with improvements persisting into the posttreatment period in some treatment groups. There was also a decrease in OSDI scores, indicating a decrease in the effect of ocular symptoms on patients' daily lives. There was no clear dose-response relationship, but cyclosporin A 0.1% produced the most consistent improvement in objective and subjective end points and cyclosporin A 0.05% gave the most consistent improvement in patient symptoms. The vehicle also performed well, perhaps because of its long residence time on the ocular surface. There were no significant adverse effects, no microbial overgrowth, and no increased risk of ocular infection in any treatment group. The highest cyclosporin A blood concentration detected was 0.16 ng/ml. All treatments were well tolerated by patients.


CONCLUSIONS
Cyclosporin A ophthalmic emulsions, 0.05%, 0.1%, 0.2%, and 0.4%, were safe and well tolerated, significantly improved the ocular signs and symptoms of moderate-to-severe dry eye disease, and decreased the effect of the disease on vision-related functioning. Cyclosporin A 0.05% and 0.1% were deemed the most appropriate formulations for future clinical studies because no additional benefits were observed with the higher concentrations.
Stevenson
D
D
Mercy Hospital, New Orleans, Louisiana, USA.
Tauber
J
J
Reis
B L
BL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004655:Emulsions; D005260:Female; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000009:adverse effects; D012449:Safety; D013666:Tears / Q000378:metabolism; D014792:Visual Acuity
D004655:Emulsions; D009883:Ophthalmic Solutions; D016572:Cyclosporine