Clinical trial NCT02382588
Conditions: Herpes Zoster Keratitis
Sponsor: Northwestern University
Start date: 2013-12-10; Completion date: 2020-05-11
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficiency of topical gancyclovir 0.15% in the treatment of herpes zoster keratitis. Half the patients will receive the study drug while the other half of the patients will receive the placebo

Detailed description:
Patients with herpes zoster keratitis will be enrolled in the study. All patients will receive oral anti-viral medication as a standard-of-care therapy. The patients will be randomized into two groups and given either the study drug or the placebo at the time of enrollment. The patients will come for weekly visits during which slit lamp photograph of the dendrite will be taken. At week 2, if the dendrite has not healed the drug will by unmasked and rescue therapy will be given. the patients will be examined at week 1, 2, and 3 or until resolution occurs.

Arms: arm 1: 0.15% gancyclovir gel to be applied in the affected eye 5 times per day for a week, followed by 3 times per day for an additional 7 days or until the healing of the dendrite, whichever is earlier. arm 2: 0.3% hypromellose gel to be applied in the affected eye 5 times per day for a week, followed by 3 times per day for an additional 7 days.
Interventions: intervention 1: gancyclovir gel intervention 2: Hypromellose gel
Intervention descriptions: intervention 1: 0.15% gancyclovir gel to be applied in the affected eye 5 times per day for a week, followed by 3 times per day for an additional 7 days or until the healing of the dendrite, whichever is earlier. intervention 2: 0.3% hypromellose gel to be applied in the affected eye 5 times per day for a week, followed by 3 times per day for an additional 7 days.

Protocol documents:
Prot_SAP_000.pdf: 
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A Prospective, Double-masked, Placebo Controlled Comparison of Topical 0.15% 
Ganciclovir Gel (Zirgan®) Versus 0.3% Hypromellose Gel (Genteal Gel®; Placebo) 
for the Treatment of Herpes Zoster Keratitis While on Oral Anti-viral Treatment
Principal Investigator
Robert S. Feder, MD
Protocol Date
March 27, 2015
Statistician
Borko Jovanovic, PhD
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Table of Contents 
I.
Introduction
A. Background and Significance of Proposed Research
II.
Hypothesis
III.
Study Objectives 
IV.
Study Population
A. Inclusion Criteria 
B. Exclusion Criteria
V.
Study Procedures
A. Study Design
B. Study Drug
C. Subject Compliance
D. Randomization and Masking
E. Rescue Therapy
VI.
Risks and Benefits
A. Risks
B. Benefits
VII.
Statistical Considerations 
A. Sample Size Justification
B. Statistics 
VIII.
Ethical Considerations
A. Data Disclosure and Subject Confidentiality 
B. Human Subjects Protection
      C. Consent 
      D. Protocol Amendments
      E. Record Storage
      F. Use of Information and Publication
IX.
References
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I.
Introduction
  Herpes zoster ophthalmicus (HZO) is specific form of herpes zoster, which manifests 
as an ocular disease. This occurs as a unilateral painful skin rash in a dermatomal 
distribution of the trigeminal nerve shared by the eye and ocular adnexa. HZO occurs 
typically in older adults but can present at any age and occurs after reactivation of 
latent varicella-zoster virus (VZV) present within the sensory spinal or cerebral 
ganglia.1
It is estimated that the lifetime risk of developing a herpes zoster (HZ) viral infection 
is 10% to 20%.2 The reactivation of the VZV originates from the sensory ganglia. 
When the infection involves the first division of the trigeminal nerve (ophthalmic 
division or V1), this disorder is termed herpes zoster ophthalmicus (HZO). The first 
division of the trigeminal nerve may be involved 20 times more frequently in an HZ 
infection than the second or third division.3
HZO can result in a variety of ophthalmic sequelae, which may be chronic and 
recurrent in nature and can result in significant ocular and visual morbidity. The post 
infection complications affect all regions of the eye and adnexa, including the cornea, 
conjunctiva, and eyelids. Despite advances in therapy, HZO-related complications can 
be reduced but not eliminated and ocular damage with loss of vision frequently occurs.
Our study will evaluate the efficacy of ganciclovir ophthalmic gel 0.15% in the 
treatment of herpes zoster keratitis that results from HZO.
A.
Background and Significance of Proposed Research
The cornea is involved in approximately 65% of patients who develop HZO. In a study 
analyzing the corneal complications of HZO in 93 patients, Liesegang found punctate 
epithelial keratitis in 51%, early pseudodendrites in 51%, anterior stromal infiltrates in 
41%, neurotrophic keratitis in 25%, late corneal mucous plaques in 13%, exposure 
keratitis in 11% and disciform keratitis in 10%. He suggested that initial corneal 
lesions were likely due to direct damage from the viral infection, whereas the later 
sequelae were the result of vasculitis, immune reactions to the viral antigens, delayed 
hypersensitivity reactions, or damage to the nerves and tissue.4 
Piebanga and Laibson described some of the late corneal disease associated with HZO, 
including a chronic epithelial keratitis that was characterized by epithelial mucous 
plaques, which has also been termed mucous plaque keratitis (MPK). The onset was 
typically months after the initial presentation. Pavan-Langston et al performed 
polymerase chain reaction studies on an excised corneal button and observed the 
response of 4 patients to antiviral therapy. They demonstrated successful use of topical 
trifluridine, vidarabine, and oral acyclovir individually in different cases.5 The use of 
newer topical and oral antivirals may improve the general success rate of treatment.
Late-stage stromal keratitis can occur months after the initial onset of the zoster 
corneal infection.6 This condition is characterized by deep stromal inflammation, 
which presents as a typical disciform lesion or asperipheral keratitis. Corneal edema 
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may be associated with these lesions. If these lesions are not treated with 
corticosteroids, a chronic inflammation may develop that leads to neovascularization, 
scarring, and ulceration of the cornea. Later, lipid deposition may occur. 
Corticosteroids are used to treat the inflammatory component of these disorders.
Neurotrophic keratitis develops due to VZV affecting the sensory nerves and causing 
hypoesthesia, which leads to the deterioration of corneal epithelium and a punctate 
keratopathy. If the epithelial breakdown progresses, large corneal epithelial defects 
occur. Sterile corneal ulcerations occur that may also become secondarily infected. If 
untreated, the cornea may become opaque, progressively thin, and may eventually 
perforate.
For the purposes of our study, we define zoster dendrite as a stuck-on rod shaped or 
branching lesion without terminal bulbs and not a corneal melt, keratouveitis, 
sclerouveitis, or corneal erosion related to neurotrophic keratitis.
Ganciclovir ophthalmic gel 
Ganciclovir ophthalmic gel 0.15% was approved by the Food and Drug 
Administration (FDA) in September 2009 for the treatment of acute herpetic keratitis 
(dendritic ulcers). The results of three pooled phase II studies and one phase III trial 
demonstrated similar cure rates of ganciclovir ophthalmic gel 0.15% compared to 
acyclovir ophthalmic ointment 3% at day 7. Ganciclovir ophthalmic gel 0.15% 
demonstrated non-inferiority compared to acyclovir ophthalmic ointment 3%. Of note, 
acyclovir ophthalmic ointment is not commercially available in the United States and 
there are no head-to-head clinical trials of ganciclovir ophthalmic gel compared to 
trifluridine 1% ophthalmic solution for the treatment of acute herpetic keratitis. 
Ganciclovir ophthalmic gel 0.15%, has not been studied in patients with stromal 
keratitis.
Previous trials have shown that topical antivirals have been ineffective in the treatment 
of herpes zoster keratitis. However, there have been a few unpublished reports of use 
of Zirgan for herpes zoster keratitis (http://www.revoptom.com/content/c/24774/).
Viral plaque reduction assays have been used to test ganciclovir’s antiviral activity in 
vitro, and ganciclovir was found to be a powerful inhibitor of viral replication for 
HSV1, HSV2, HZV, EBV, CMV, and HHV6 viruses. The GCV 0.15% strength was 
adopted on the basis of preclinical studies in experimental animal models of herpetic 
keratitis, preclinical and clinical pharmacokinetic distribution studies, and controlled 
clinical trials. The gel formulation allows for even distribution of the active drug, 
prolongs contact with the cornea better than an ointment, and provides greater efficacy 
at a concentration of 0.15%. The pH (7.45) and osmolarity (300 osmoles) of 
Ganciclovir gel 0.15% are close to normal physiological values.
In an experimental model of herpetic keratitis in rabbits ganciclovir ointment 
demonstrated antiviral activity at a concentration of 0.1% with no positive ocular viral 
samples after 5 times a day treatment at 12 days and at 14 days when applied 3 times a 
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day.7 Using this same mode, Castela et al.8 showed that ganciclovir gel at 
concentrations of 0.2%, 0.05%, and 0.0125% applied 4 times a day for 12 days, 
starting on day 3 after infection, effectively treated herpetic keratitis. Ocular isolates 
showed no positive viral samples on day 12 with GCV 0.2% and 0.05%, and on day 14 
with GCV 0.0125%.
Pharmacology/Pharmacokinetics of Ganciclovir
Ganciclovir is activated to ganciclovir triphosphate by viral and cellular thymidine 
kinases (TK).  This active metabolite then inhibits DNA replication by competitive 
inhibition and direct incorporation into viral DNA resulting in chain termination. It is 
designed to work selectively by specifically targeting infected cells. Zirgan is a 
prodrug that is phosphorylated primarily by infected cells. In contrast, the mechanism 
of action of trifluridine is nonselective and as a result, it is toxic to healthy cells.9 Also, 
trifluridine contains the preservative thimerosal, to which many patients have an 
allergic sensitivity.10 Zirgan is preserved with benzalkonium chloride (BAK) rather 
than thimerosal. While BAK has been shown to cause low-grade toxicity to ocular 
surface cells, this typically occurs only after long-term and/or frequent use of 
ophthalmic medications.
Ganciclovir has activity against Epstein-Barr virus, cytomegalovirus (CMV), 
adenovirus, herpes zoster, and herpes simplex virus (HSV) types 1 and 2.11,12 13
Ganciclovir ophthalmic gel has minimal systemic absorption, with the total daily 
topical dose approximately 0.04% and 0.1% of oral and intravenous ganciclovir doses, 
respectively.13 Rapid penetration of ganciclovir has been demonstrated within 5 
minutes with topical administration resulting in therapeutic drug levels in ocular 
tissue, which is imperative for the treatment of herpetic keratitis.14
Ganciclovir ophthalmic gel 0.15% is FDA approved for the treatment of acute herpetic 
keratitis (dendritic ulcers).13,15 This study looks at the use of ganciclovir gel for the 
treatment of zoster keratitis. Current available topical antiviral alternatives are 
trifluridine 1% ophthalmic solution and vidarabine ointment (VIRA-A Ophthalmic 
Ointment). Our study will provide data regarding the use of ganciclovir ophthalmic gel 
as an additional tool in the treatment of herpes zoster keratitis which can have 
potentially blinding sequelae.
Genteal Gel
Genteal gel is a non-prescription eye lubricant gel and is commonly used for treatment 
of dry eye, irritated eyes. There is no anti-viral agent within genteal gel. 
Oral anti-viral
Acyclovir and valacyclovir are the standard treatments used in patients with herpes 
zoster17 to prevent long-term complications, including intraocular complications.  
Acyclovir and valacyclovir have not been studied as single use treatments of herpes 
zoster dendrites.
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II.
Hypothesis
We hypothesize that ganciclovir ophthalmic gel 0.15% will be an effective treatment 
of herpes zoster dendritic keratitis as measured by reduction of the dendritic ulcer by 
90% within 2 weeks in at least 50% of subjects receiving ganciclovir while on oral 
anti-viral therapy compared with 0% of subjects receiving placebo while on oral anti-
viral therapy.
III.
Study Objectives
The purpose of this study is to evaluate the efficacy (defined as the reduction in ulcer 
size by 90%) of topical ganciclovir 0.15% in treatment of herpes zoster dendritic 
keratitis. 
The investigators will enroll 33 patients with a diagnosis of HZO with corneal 
involvement. Their medical records will be reviewed, including their demographic 
data as well as ophthalmic and medical histories. Subjects will be recruited from the 
Department of Ophthalmology at Northwestern University (NU), as well as from the 
qualified practices of physician members of the Chicago Cornea Association and 
selected cornea practices nationwide. 
IV.
Study Population
A. Inclusion Criteria
1. Males and Females, age 18 and above who have been diagnosed with a corneal 
infection caused by the  herpes zoster virus
2. Have not been on ganciclovir gel or any other form of topical antiviral therapy for 
the past month 
3. Able and willing to attend subsequent follow-up visits
 
B.
Exclusion Criteria 
1. Associated retinitis
2. Patients with a known allergy to hypromellose gel, ganciclovir, acyclovir, or 
valacyclovir
3. Patients who will require systemic or intra-vitreal ganciclovir therapy
4. Patients who are pregnant or breastfeeding
V.
Study Procedures
A.
Study Design
This is a prospective, randomized, parallel group study with two arms: subjects 
receiving oral anti-virals as standard of care therapy while receiving either ganciclovir 
ophthalmic gel 0.15% (Zirgan) or a placebo ointment (genteal gel). Subjects with 
corneal dendritic involvement from herpes zoster will be randomized (1:1) to receive 
ganciclovir ophthalmic gel 0.15% gel or placebo, which will be applied to the affected 
eye 5 times a day for 7 days, followed by 3 times a day for an additional 7 days. At 
two weeks, if the zoster dendrite has not healed, rescue therapy can be performed at 
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the discretion of the treating physician (Zirgan, the study drug, will not be used as a 
rescue therapy).
Clinical examinations including a dilated fundus examination will be performed at the 
Screening/Baseline Visit. Subsequent clinical examinations will be performed at study 
visits 1, 2, and the End of Study/Early Termination Visit, however, fundus 
examinations are not completed at subsequent examinations. Two sets of slit lamp 
photographs will be obtained at each visit. 
Slit-lamp photographs can be obtained with fluorescein or Rose Bengal staining; 
however the same staining method should be used throughout the study. Photos will 
first be taken without fluorescein or Rose Bengal and then taken with fluorescein or 
Rose Bengal. Time to reduction ulcer size will be recorded as the primary end point 
and compared among the two groups from the slit lamp photographs. Slit lamp 
photographs will be reviewed by a qualified physician, who will be masked to the 
patient information and the study drug received. Intraocular pressure (IOP) 
measurement will be performed at each study visit and subjects will receive numbing 
eye drops prior to the IOP.
Both groups will receive the standard 7-day oral therapy of acyclovir (800 mg po five 
times daily), valacyclovir (800 mg po five times daily), or valacyclovir (1000 mg po 
three times daily). This oral anti-viral treatment is being given as standard treatment 
for herpes zoster to prevent long-term complications, including intraocular 
complications. If the treating physician feels strongly about an altered dosing regimen, 
this is allowed as long as it is reported. A topical steroid will not be administered 
unless there is associated inflammation.
Screening/
Baseline 
Visit 
(Week 0)
Study 
Visit 1
(Week 1)
Study 
Visit 2 
(Week 2)
End of Study 
Visit/Early 
Termination 
Visit (Week 3)
Informed 
consent
X
Medical 
history
X
X
X
X
Dilated 
fundus 
examination
X
Eye exam
X
X
X
X
IOP
X
X
X
X
Slit lamp 
photos
X
X
X
X
Oral anti-
viral 
dispensed
X
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Study drug 
dispensed
X
Diary 
reviewed
X
X
The study drug will be sent to the study doctor in a sealed container that should be 
opened by the patient at home. Patients will be required to fill out a dosing diary. The 
dosing diary and the remaining drug must be returned to the NU study site from all 
participating sites. 
A Coded Identifier List (CIL) will contain the subject’s name, subject’s medical record 
number, subject’s date of birth, and the Study ID Number assigned by the study staff. 
The CIL will be stored on a secure server, be password protected, and will be 
maintained by authorized study personnel. Once a subject has been given a Study ID 
Number, all data collected will be identified through this Study ID Number. Each site 
will maintain their own Coded Identifier List and Northwestern University will not 
have access to each site’s CIL.
B. Study Drug
Ganciclovir ophthalmic gel 0.15%: Sufficient quantity for 15 eyes. The subjects will 
put the study drug into affected eye(s) 5 times a day while awake for 7 days, followed 
by 3 times a day while awake for 7 days, or until healing of corneal ulcer. Clinical 
examinations will be performed at the Screening/Baseline Visit and study visits 1, 2, 
and the End of Study/Early Termination Visit. 
The drug and placebo will be randomized and distributed to the participating centers 
that will not have access to the drug by Northwestern University study staff. The study 
drug will be stored and maintained by the Department of Ophthalmology at 
Northwestern Memorial Hospital located at 259 E. Erie St., Suite 15-20; Chicago, IL 
60611.
C. Subject Compliance
In order to obtain reliable safety and efficacy data, it is critical that each subject 
complies with the dosing schedule specified in this protocol. Each subject will be given 
a dosing diary to fill out every time they apply the study drug or placebo.
Subjects must also continue with the intake of their systemic medications prescribed.
D. Randomization and Masking
We anticipate enrollment of 33 patients. The study groups will be assigned in a 1:1 
ratio, with expected non-completion rate of 10% this will give us 15 patients per 
treatment group. Neither the patient nor the study doctor or study staff will be able to 
pick which study group the patient is in or know which study group the patient is in. If 
subjects have an infection in both eyes, only on eye will be randomized to receive 
either Zirgan or placebo. The other eye will be given standard of care treatment.
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Subjects will be randomized to receive ganciclovir gel (Zirgan®) versus hypromellose 
gel (Genteal Gel®; Placebo) to be applied topically. A computer algorithm for random 
number generation will be used to generate the treatment assignments. The study is 
double-masked and all site investigators, study staff, and subjects will be masked to the 
group to which subjects are randomized. Masked study doctors at Northwestern 
University will be reading all slit lamp photos, including those from the other 
participating sites. The study staff that will be dispensing the study drug and placebo 
will also be masked.
E.  Rescue Therapy
Rescue therapy is defined as any treatment that would have a therapeutic effect on the 
herpes zoster keratitis. Rescue therapy will be offered if progressive corneal thinning, 
corneal inflammation, or worsening of the dendritic keratitis occurs. All uses of rescue 
therapy will be deemed medically necessary by the site investigator.
If rescue therapy is needed after a subject has treatment failure, the site investigator 
must report the treatment failure and the type of rescue therapy used to the lead site. 
The lead site study staff can be reached by calling 312-695-0252.
VI.
Risks and Benefits 
A.
Risks 
Ganciclovir ophthalmic gel 0.15%
Most common adverse reactions reported in patients were blurred vision (60%), eye 
irritation (20%), punctate keratitis (5%), and conjunctival hyperemia (5%).16
Dilated fundus examination
The dilation medicine will cause some minor stinging after being placed in the eye. 
The dilation will cause light sensitivity and blurry vision for 4-6 hours.
Slit lamp photography
Bright flashes may cause discomfort to the subject.  
Intraocular pressure (IOP) measurement
Numbing eye drops (proparicaine 0.5% ophthalmic solution) will be used prior to 
taking subject’s intraocular pressure. These eye drops may cause redness and 
stinging. During the measurement, the study doctor will use a machine that touches 
the surface of the eyes. In rare circumstances, this machine could scratch the subjects’ 
cornea. Such scratches are usually self-heal in less than 24 hours.
The potential harm to the subjects is loss of privacy and confidentiality.  Indirect 
identifiers will be used to link data obtained from different methods. The key will be 
stored separately from the data and will be destroyed after data collection has been 
completed.
B.     Benefits
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Subjects’ herpes zoster keratitis may get better as a result of the use of ganciclovir gel. 
The knowledge gained from this study may benefit future patients with this condition.
VII.
Statistical Considerations
A.
Sample Size Justification
We will recruit 33 patients in order to account for drop-out or non-completion rate of 
10%, providing approximately 15 patients per treatment group. 
With 15 patients per group we have sufficient power to test H:p1=p2 vs H1: p1>p2 
with type 1 error of 5%, when true values of p1=55% and p2=5%. See below. 
Two Independent Proportions (Null Case) Power Analysis
Numeric Results of Tests Based on the Difference: P1 - P2
H0: P1-P2<=0. H1: P1-P2=D1>0. Test Statistic: Fisher's Exact test 
Sample Sample
Prop|H1
Prop
Size
Size
Grp 1 or
Grp 2 or
Diff
Diff
Grp 1
Grp 2
Trtmnt
Control
if H0
if H1
Target
Actual
Power
N1
N2
P1
P2
D0
D1
Alpha
Alpha
Beta
0.9978
30
30
0.5500
0.0500
0.0000
0.5000
0.0500
0.0022
B.  Statistics
We will use descriptive statistics to present the data in a convenient fashion, including 
graphics. Success rates in two treatment groups will be compared using Fisher’s 
Exact test. 95% Confidence intervals for rates in each of the treatment groups will 
also be provided.
VIII.
Ethical Considerations
A.
Data Disclosure and Subject Confidentiality 
Subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than the principal investigator and 
the co-investigators is prohibited. Medical information resulting from a subject’s 
participation in this study may be given to the subject’s primary physician or to the 
appropriate medical personnel responsible for the subject’s welfare. Data generated as 
a result of this study are to be available for inspection on request by the Faro other 
government regulatory agency auditors, the Northwestern University Institutional 
Review Board (IRB), and the IRB of Ann & Robert H. Lurie Children’s Hospital of 
Chicago.
The existence of this clinical study is confidential, and it should not be discussed with 
persons outside of the study. Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, but 
all such persons must be instructed not to further disseminate this information to 
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others. These restrictions of disclosure will apply equally to all future information 
supplied that is indicated as confidential.
The data generated by this clinical study are the property of Northwestern University 
Department of Ophthalmology (the lead site) and Bausch and Lomb (Sponsor) and 
should not be disclosed without the prior written permission of NU. 
B.
Human Subjects Protection 
A periodic review will be submitted to the IRB at least once per year. The IRB will be 
notified of completion of the study. After study completion or termination, a final report will 
be provided to the IRB to close the study. The investigator will maintain an accurate and 
complete record of all submissions made to the IRB, including a list of all reports and 
documents submitted. Adverse events that are reported to the FDA as IND Safety Reports 
will be submitted promptly to the IRB per IRB guidelines.
At least once per year, the IRB will review and give written approval in order to continue the 
study. This trial will be conducted in accordance with Good Clinical Practices and the 
Declaration of Helsinki.
C.
Consent
Prior to study entry, all subjects will be required to sign an informed consent form to 
participate. All subjects will be informed of new information as it comes available during the 
study.
D.
Protocol Amendments 
All changes will be submitted to the IRB. Protocol modifications that impact subject safety 
or the validity of the study will be approved by the IRB before initiation.
E.
Record Storage 
FDA and Good Clinical Practice guidelines require that an investigator retain subject 
identification codes, subject files, and source data for the maximum period of time permitted 
by the hospital, institution, or private practice, but not less than 15 years after the completion 
or discontinuation of the trial. This will be followed for the study.
F.
Use of Information and Publication
The Principal Investigator, sub-investigators may publish the results of this study in 
conjunction with appropriate scientific and medical personnel.
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IX.
References
1.
Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical 
presentation, and morbidity. Ophthalmology. Feb 2008;115(2 Suppl):S3-12.
2.
Liesegang TJ. Herpes zoster virus infection. Curr Opin Ophthalmol. Dec 
2004;15(6):531-536.
3.
Ostler HB, Thygeson P. The ocular manifestations of herpes zoster, varicella, 
infectious mononucleosis, and cytomegalovirus disease. Surv Ophthalmol. Sep-
Oct 1976;21(2):148-159.
4.
Liesegang TJ. Corneal complications from herpes zoster ophthalmicus. 
Ophthalmology. Mar 1985;92(3):316-324.
5.
Pavan-Langston D. Herpes zoster ophthalmicus. Neurology. Dec 1995;45(12 
Suppl 8):S50-51.
6.
Kaufman SC. Anterior segment complications of herpes zoster ophthalmicus. 
Ophthalmology. Feb 2008;115(2 Suppl):S24-32.
7.
Trousdale MD, Nesburn AB, Willey DE, Taaid H. Efficacy of BW759 (9-[[2-
hydroxy-1(hydroxymethyl)ethoxy]methyl]guanine) against herpes simplex virus 
type 1 keratitis in rabbits. Curr Eye Res. Aug 1984;3(8):1007-1015.
8.
Castela N, Vermerie N, Chast F, et al. Ganciclovir ophthalmic gel in herpes 
simplex virus rabbit keratitis: intraocular penetration and efficacy. J Ocul 
Pharmacol. Summer 1994;10(2):439-451.
9.
Villarreal. Current and potential therapies for the treatment of herpes virus 
infections. Prog Drug Res. 2003;60:263-307.
10.
Hong J, Bielory L. Allergy to ophthalmic preservatives. Curr Opin Allergy Clin 
Immunol. Oct 2009;9(5):447-453.
11.
Colin J. Ganciclovir ophthalmic gel, 0.15%: a valuable tool for treating ocular 
herpes. Clinical ophthalmology. Dec 2007;1(4):441-453.
12.
Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan; 0.15%) in 
the treatment of herpes simplex keratitis. Cornea. Jul 1997;16(4):393-399.
13.
Insert P. Ganciclovir ophthalmic gel (Zirgan™) 0.15% package insert. Sirion 
Therapeutics, Inc.,. 2009;September(Tampa, FL).
14.
Lowe ER, Jiang S, Proksch JW. Rapid Ocular Penetration of Ganciclovir with 
Topical Administration of Zirgan(R) to Rabbits. Invest. Ophthalmol. Vis. Sci. 
April 22, 2011 2011;52(6):3258-.
15.
FDA.gov. FDA Documents. Center for Drug Evaluation and Research. NDA 
Application 22-211.  . 2012; 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022211_zirgan_toc.cfm
%3E.
16.
Zirgan. Package Insert. In: Lomb B, ed. Bausch & Lomb Incorporated. Tampa, 
FL: Bausch + Lomb; 2010.
17.       Hoang_Xuan T, Buchi ER et al. Oral Acyclovir for Herpes Zoster. 
Ophthalmology. 1992 Jul; 99(7): 1062-70, discussion 1070-1
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