A Placebo Controlled Comparison of Topical Zirgan Versus Genteal Gel for the Treatment of Adenovirus Conjunctivitis

Study Objectives To evaluate the safety and efficacy of 0.15% ganciclovir gel (Zirgan®) in patients with adenoviral keratoconjunctivitis in comparison with 0.3% hypromellose gel (Genteal gel®) as placebo.

Background Adenoviruses are the most common cause of ocular viral infection worldwide. Conjunctivitis and keratoconjunctivitis caused by adenoviruses are highly contagious. Adenovirus is a non-enveloped, double-stranded DNA virus comprised of 53 serotypes. Unlike many enveloped viruses which can be more easily inactivated, adenoviruses are resilient to disinfection and are long lasting on fomites. The ocular infection generally begins unilaterally and, in many cases, spreads to both eyes. It may cause epidemics and endemics, being most commonly spread in the summer or winter. Epidemics are common in day care centers, schools and the military and have been spread in the offices of eye care professionals. Patients may have painful conjunctival membranes and palpable preauricular adenopathy. Subsequent subepithelial corneal infiltrates can cause light sensitivity, reduced vision and lead to irregular astigmatism. The differential diagnosis includes herpes simplex, Chlamydia and enteroviral infection.

There are 3 major presentations of ocular adenovirus infection: Follicular conjunctivitis (predominantly serotypes 3, 4,7a); epidemic keratoconjunctivitis (EKC; predominantly serotypes 8, 19, 37, 53); and pharyngealconjunctival fever (mostly serotypes 3, 4, 7a, 11).

There is supporting laboratory and clinical data to warrant a clinical trial of topical ganciclovir for the treatment of adenoviral keratoconjunctivitis. Several studies has shown that ganciclovir (GCV) is active in vitro against adenovirus.

Primary Outcome The primary outcome of the study is to determine whether topical 0.15% ganciclovir (Zirgan®) gel alone will reduce the duration of viral shedding from the ocular surface, as determined by quantitative viral isolation in A549 cell tissue culture, compared to placebo 0.3% hypromellose gel (Genteal gel®).

Secondary Outcomes The secondary outcomes of the study are whether topical 0.15% ganciclovir will (1) reduce the incidence and severity of second eye involvement, (2) reduce the incidence and severity of subepithelial infiltrates, (3) reduce the secondary spread to family members, friends, classmates or co-workers (The virus is very stable at room temperature and can last for days on fomites, like towels, doorknobs, etc), (4) reduce the degree of bulbar conjunctival injection (redness of the eye, as determined by the Efron scale in the Appendix 2), (5) reduce ocular discomfort, and (6) be considered an effective treatment by the patient.

Sample Size The sample size for this study is based on the objective to demonstrate a statistically significant difference in the primary outcome measure (i.e., time to viral eradication). Approximately 350 subjects will be screened with Rapid Pathogens Screening (RPS) Adeno Detector Plus Immunoassay for adenovirus (applied to the conjunctiva of the most involved eye) to allow recruitment of approximately 80 RPS positive subjects in this study, with approximately 40 subjects per treatment group (randomization ratio of 1:1), in anticipation of approximately 40 culture positive subjects per treatment group (assuming a 100% culture positivity rate) and 38 of these culture positive subjects per treatment group completing the study (assuming a 5% dropout rate).

Thirty eight viral positive culture subjects per treatment group yields 90% power to detect a statistically significant difference in time of viral eradication between ganciclovir gel 0.15% and placebo (hypromellose gel) assuming: (1) a mean time to viral eradication of 7.0 days in the placebo group and 5.5 days in the ganciclovir group, (2) an estimated standard deviation of 2.0 days for both groups, and (3) using a two-sided α = 0.05 (two sample comparison of means).

The estimate of approximately 320 to 350 screenings to find approximately 80 RPS positive subjects was based on previous studies documenting approximately 25% prevalence of adenoviral conjunctivitis among patients with acute conjunctivitis. The estimated mean time to viral eradication of 7.0 days for the placebo was based on a placebo arm of a previous study evaluating the safety and efficacy of cidofovir in the treatment of viral epidemic keratoconjunctivitis and the estimated mean time to viral eradication of 5.5 days was based on assumed clinically significant decrease of 1.5 days compared to the placebo arm.

Virological Studies At the first study visit, the lower palpebral conjunctiva of each eye will be rubbed six to eight times using the Rapid Pathogen Screening (RPS) Adeno Detector Plus Immunoassay device. A positive result in the most involved eye is required to meet entry criteria. For patients entered and randomized into the treatment or placebo arms, further virologic studies for quantitative culture, PCR confirmation and viral serotyping using DNA sequencing will be performed,