From Preserved, to Preservative-free Cyclosporine 0.1% Enhanced Triple Glaucoma Therapy

Study Overview
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Brief Summary
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There is a lack of evidence on the impact of switching from a combined preserved anti-glaucoma regimen to a preservative-free (PF) one, while employing sufficiently robust OSD metrics. The investigators have therefore carried out a single center, prospective, crossover investigation to compare the 6-month effect of switching well controlled open-angle glaucoma patients with at least moderate glaucoma therapy-related ocular surface disease from preserved to triple preservative-free therapy with and without cyclosporine 0.1% dosed in the evening.

Detailed Description
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Halting and reversing glaucoma therapy-related ocular surface disease (GTR-OSD) will improve the success of long-term medical therapy, impacting millions of patients worldwide. Chronic medical therapy for glaucoma may be immensely benefitted by limiting disabling GTR-OSD, which would aid in the prevention of blindness. In 2015 a novel cationic formulation of cyclosporine A 0.1% was approved with once in the evening dosing in Europe. It is an effective, targeted immunomodulatory compound reducing inflammatory mediators and providing healing of the ocular epithelium. There remains however a paucity of published controlled evidence for GTR-OSD patients treated with this formulation. In addition, there is a lack of evidence on the impact of switching from a combined preserved anti-glaucoma regimen, to a preservative-free one, while employing sufficiently robust OSD metrics. The investigators have therefore carried out a single center prospective, crossover investigation to compare the 6-month effect of switching well controlled open-angle glaucoma patients with at least moderate GTR-OSD, from preserved to triple PF therapy with and without PF cyclosporine 0.1% dosed in the evening.

Official Title
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Changing From Preserved, to Preservative-free Cyclosporine 0.1% Enhanced Triple Glaucoma Therapy: Impact on the Rate and Severity of Ocular Surface Disease

Conditions
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Glaucoma, Ocular Surface Disease

Intervention / Treatment
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* Diagnostic Test: Assessment of ocular surface staining (Oxford score 0-15 scale)
* Drug: mean diurnal intraocular pressure-lowering


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Adult patients with well controlled open-angle glaucoma Patients chronically treated for more than 6 months with preserved, branded, or generic, triple antiglaucoma therapy comprising latanoprost and dorzolamide/timolol fixed combination Subjects should have experienced at least 1 symptom of dry eye (soreness, scratchiness, dryness, grittiness, and burning) Additionally, patients should demonstrate at least one of the objective signs for OSD at baseline: positive conjunctival staining with lissamine green and/or evidence of positive corneal staining with fluorescein (assessed with the 15-point Oxford scale), Patients must show a BUT<8 seconds On screening patients should show a Schirmer test without anesthesia (Schirmer-I test) ≥3 and ≤10 mm in 5 minutes. When both eyes qualify the worse eye will be included in the study. Exclusion criteria Best corrected visual acuity <1/10 Patients with severe dry eye disease or Sjogren's disease Presence of eyelid abnormality, corneal disorder or abnormality, ocular surface metaplasia, filamentous keratitis, or corneal neovascularization Patients who have undergone ocular surgery (of any type, including laser surgery), or ocular trauma within 4 months prior to screening Subjects who had punctal occlusion, or diathermy within 3 months prior to screening or abnormality of the nasolacrimal drainage apparatus. Known allergy, or sensitivity to any of the study medications Uncontrolled systemic disease, or history or active signs of ocular trauma, infection, inflammation, allergic disease, or herpes; corneal ulcers; recurrent erosions; or uveitis Female patients will be excluded if they are pregnant, breastfeeding, planning a pregnancy, or are unwilling to use a reliable form of contraception.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Masked, prospective, placebo-controlled, crossover trial of glaucoma patients with moderate to severe GTR-OSD on preserved latanoprost and dorzolamide/timolol fixed combination therapy for well-controlled open-angle glaucoma was conducted. Patients were randomized to receive preservative-free tafluprost and dorzolamide/timolol fixed combination with either topical placebo or cyclosporine 0.1% for 6 months and will then be crossed over to the opposite therapy. Oxford score of staining will be the primary outcome; osmolarity, matrix-metalloproteinase-9 testing (MMP-9), meibomian gland dysfunction (MGD), adverse events and diurnal intraocular pressure (IOP) comprise the secondary outcomes.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Triple preservative-free therapy with placebo in the evening<br>In this arm subjects will be randomized to topical therapy comprising preservative-free tafluprost drops dosed in the evening (20:30) and dorzolamide/timolol fixed combination drops administered twice daily (8:00 and 20:00). Patients will use placebo (artificial tears) in the evening (21:00) for 6 months. At the end of this period patients will be crossed over to the other therapy (cyclosporine 0.1% in the evening) | Diagnostic Test: Assessment of ocular surface staining (Oxford score 0-15 scale)<br>* Corneal and conjunctiva staining will be recorded according to the Oxford grading scheme for ocular staining (0-15 score).<br>Drug: mean diurnal intraocular pressure-lowering<br>* At the end of each 6-month period patients will undergo diurnal intraocular pressure assessment with both therapies.<br>|
| Active Comparator: Triple preservative-free therapy with cyclosporine 0.1% in the evening<br>In this arm subjects will be randomized to topical therapy comprising preservative-free tafluprost drops dosed in the evening (20:30) and dorzolamide/timolol fixed combination drops administered twice daily (8:00 and 20:00). Patients will use cyclosporine 0.1% drops in the evening (21:00) for 6 months. At the end of this period all patients will be crossed over to the other therapy (placebo in the evening) | Diagnostic Test: Assessment of ocular surface staining (Oxford score 0-15 scale)<br>* Corneal and conjunctiva staining will be recorded according to the Oxford grading scheme for ocular staining (0-15 score).<br>Drug: mean diurnal intraocular pressure-lowering<br>* At the end of each 6-month period patients will undergo diurnal intraocular pressure assessment with both therapies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in ocular staining (Oxford score) | The primary efficacy endpoint for this crossover study will be the mean change from baseline in the total ocular staining score as determined by the 15-point Oxford scale of staining on the study eye. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean diurnal IOP | Mean diurnal intraocular pressure with the two preservative-free therapies versus preserved baseline will be evaluated as secondary endpoint. | 6 months | 
| Osmolarity | Mean tear osmolarity with the two PF therapies versus preserved baseline will be evaluated as secondary endpoint. | 6-months | 
| Matrix-metalloproteinase-9 (MMP-9) over-expression | Mean MMP-9 over-expression with the two PF therapies versus preserved baseline will be evaluated as secondary endpoint. | 6 months |