Clinical Trials in Cornea

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Article initiated by:

Francesc March de Ribot, MD, PhD

All contributors:

Apoorva Chowdhary, Vatinee Y. Bunya, MD, MSCE, Francesc March de Ribot, MD, PhD, Shu Feng, MD

Assigned editor:

Neha Shaik, MD

Review:

Assigned status Update Pending

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Contributing Editors:	add

Herpetic Eye Disease Study - 1 (HEDS - 1)

Ophthalmology 1994;1871-1882| Ophthalmology 1994;1883-1896| Arch Ophthalmol 1996;1065-1072.

Objectives

The goal was to determine the role of 1) topical steroids in stromal keratitis associated with HSV; and 2) oral acyclovir in HSV stromal keratitis and HSV iridocyclitis (receiving treatment with topical trifluridine -antiviral- and topical steroids treatment).

Design

3 separate controlled clinical trials, randomized, double-masked, placebo-controlled to evaluate HSV 1) Stromal keratitis with steroids, 2) without steroids, and 3) Iridocyclitis. Groups:

1. SKN – Stromal keratitis, not on steroids: 106 patients who had not used a topical steroid in the preceding ten days were randomised to receive topical prednisolone or placebo. The drops over a ten-week period, commencing with 1% prednisolone phosphate 8 times a day, tapering to ⅛ once a day.
2. SKS – Stromal keratitis, on steroids: 104 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten weeks, or placebo. Topical steroid therapy was standardised for both groups as per the SKN trial.
3. IRT – Iridocyclitis, receiving topical steroids: 50 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten-weeks or placebo. Topical steroid and antiviral therapy were standardised for both groups.

Patients were evaluated weekly for ten weeks, fortnightly for six more weeks, and at six months.

Main outcome measures

VA, resolution of active disease, treatment failure.

Results

1. SKN – Stromal keratitis, not on steroids: 106 patients who had not used topical steroid in the preceding ten days were randomised to receive topical prednisolone or placebo. Corticosteroid therapy had a longer time to treatment failure, reduced the risk of persistent or progressive stromal keratouveitis by 68%, and had a shorter resolution time. At 6 months, there were no differences in VA or herpetic recurrence between the groups.
2. SKS – Stromal keratitis, on steroids: 104 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten weeks, or placebo. The median time to treatment failure was longer in the acyclovir group 84 days, vs. to placebo 62 days. There were no differences in treatment failure (75% in acyclovir and 74% in placebo) or worsening (18% in acyclovir and 19% in placebo). However, VA improved over 6 months in more patients in the acyclovir group.
3. IRT – Iridocyclitis, receiving topical steroids: 50 patients using topical steroids were randomised to receive acyclovir or placebo. Oral acyclovir added to topical trifluridine and prednisolone appeared to improve the recovery in HSV iridocyclitis, after the first 3 weeks of follow-up. Treatment failure in the first ten weeks was 68% in the placebo compared to 50% in the oral acyclovir group. Relapse rates were similar between the two groups. Overall, the numbers of patients in this trial were too small to have conclusions.

Limitations

Many patients got lost in the follow-up. Modern treatment involves topical acyclovir or ganciclovir.

Conclusions

Topical corticosteroid reduced persistence or progression of stromal inflammation and HSV stromal keratitis. Postponing steroids delayed resolution of stromal keratitis but had no detrimental effect in VA at 6 months. Oral acyclovir was not useful for HSV stromal keratitis already receiving topical trifluridine and topical steroids, and it was not clear the benefits in HSV iridocyclitis.

Pearls for clinical practice

Topical steroids may speed the resolution of HSV stromal keratitis.

Omega-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease, by the Dry Eye Assessment and Management (DREAM) Study Research Group

Objective

Dry eye disease (DED) is a widespread condition, affecting approximately 14% of adults in the United States. Previous clinical trials had demonstrated the efficacy of supplementation with poly-unsaturated fats, particularly omega-3 fatty acids, in mitigating inflammation. The DREAM trial sought to determine the effects of omega-3 fatty acid supplementation on dry eye disease.

Design

Multi-center, double-blind randomized clinical trial. Enrolled 535 patients with DED across 27 sites in the US. Subjects randomized to 2:1 ratio to receive active or placebo supplements for 12 months. 349 patients received active supplements, and 186 received placebo.

• Active Supplement Regimen: Active capsules contained 400 mg of eicosapentaenoic acid (EPA) and 200 mg docosahexaenoic acid (DHA), for a total daily dose of 2000 mg EPA and 1000 mg of DHA.
• Placebo Supplement Regimen: Placebo capsules contained 1000 mg of olive oil (68% oleic acid, 13% palmitic acid, 11% linoleic acid).

The regimen was reduced or suspended when patients reported gastrointestinal symptoms or when a contraindication to treatment with the full dose of active supplements developed. If these symptoms resolved, the patient could restart or increase the regimen.

• Visits were conducted at 3, 6, and 12 months after initiation of study. Participants were also contacted via telephone at 9 months to report adverse events.

Main outcome measure

1. Mean change from baseline in the Ocular Surface Disease Index (OSDI) score

Results

• OSDI scores decreased between baseline and 12 months in the active supplement group and in the placebo group (P<0.001), most of the decrease occurring in the first 3 months.
• The mean change in scores was -13.9+15.6 points in active supplement group and -12.5+18.2 points in placebo group, resulting in mean difference in change of -1.9 that was not statistically significant (95% CI, -5.0 to 1.1, p=0.21)

Limitations

According to the study design, participants were able to continue with or change their dry eye therapies during the study. Additionally, some have questioned the use of olive oil as a placebo, due to its potential anti-inflammatory properties.

Clinical Pearls

In patients with moderate-to-severe dry eye disease despite the use of other treatments, 12 months of supplementation with 3000 mg of omega-3 fatty acids did not contribute to a significant difference in improvement of dry eye disease symptoms and signs when compared to placebo.