Clinical trial NCT03134196
Conditions: Herpes Zoster Ophthalmicus
Keywords: Herpes Zoster Ophthalmicus Zoster Eye Disease Study Varicella Zoster Virus Zoster Shingles
Sponsor: NYU Langone Health
Start date: 2017-08-23; Completion date: 2024-07-22
Enrollment: 527 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-masked, placebo-controlled clinical trial of suppressive valacyclovir for one year in immunocompetent study participants with an episode of dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to Herpes Zoster Ophthalmicus (HZO) in the year prior to enrollment.

Detailed description:
The objective of the Zoster Eye Disease Study (ZEDS) is to determine whether prolonged suppressive oral antiviral treatment with valacyclovir reduces complications of Herpes Zoster Ophthalmicus (HZO), thereby improving clinical outcomes in this common and potentially vision- and life-threatening disease. There are 1,000,000 new cases of Herpes Zoster (HZ) per year in the USA, with 10-20% being HZO.

Specific Aims

Primary Aim: The primary aim of this double-masked, placebo controlled multicenter randomized clinical trial will test the hypothesis that suppressive antiviral treatment for 12 months with oral valacyclovir 1000 mg daily reduces the rate of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis or iritis compared to placebo, at 12 months as the primary endpoint, and at 18 months including 6 months of follow-up after treatment, as a secondary endpoint, in patients with HZO who have had an episode of one of these disease manifestations during the year prior to enrollment.

Secondary Aim: The second aim is to test the hypothesis that suppressive treatment for 12 months with oral valacyclovir 1000 mg daily reduces the severity and duration of postherpetic neuralgia (PHN), compared to placebo, at 12 months and at 18 months as secondary endpoints, in similar patients with HZO. PHN is a debilitating chronic pain syndrome that negatively impacts quality of life, especially in elderly patients.

The study will enroll immunocompetent patients age 18 years and older who have HZO diagnosed at variable times in the past, with these types of active anterior segment ocular segment disease within the past year. Eligible patients will be randomized in a 1:1 ratio to long-term suppressive treatment with oral valacyclovir 1000 mg daily or placebo for 12 months, plus usual ophthalmic care, and followed every 3 months for a total of 18 months, to determine outcomes of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis or iritis and/or severity and duration of PHN during 12 months of treatment and for 6 months following treatment discontinuation. The results with regard to PHN may be applicable to HZ in other locations. If suppressive valacyclovir treatment is determined to be effective, the potentially devastating disease burden of HZO and HZ may be reduced for patients, as well as the annual costs to society, estimated in the USA to be one billion dollars.

Arms: arm 1: Encapsulated masked placebo arm 2: Valacyclovir, 500 mg, oral pill, two 500mg pills daily
Interventions: intervention 1: Masked Placebo intervention 2: Masked Oral Valacyclovir
Intervention descriptions: intervention 1: Oral Placebo intervention 2: Oral Valacyclovir 1000 mg/day

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Zoster Eye Disease Study (ZEDS): 
A multi-center, randomized, double-masked, placebo-controlled clinical 
trial of suppressive valacyclovir for one year in immunocompetent study 
participants with an episode of dendriform epithelial keratitis, stromal 
keratitis, endothelial keratitis, and/or iritis due to Herpes Zoster 
Ophthalmicus (HZO) in the year prior to enrollment. 
NCT Number: 
NCT03134196 
Study Number: 
 
 s16-00463 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
March 25, 2020 
 
 


 
 
  Zoster Eye Disease Study (ZEDS): 
A multi-center, randomized, double-masked, placebo-
controlled clinical trial of suppressive valacyclovir for one 
year in immunocompetent study participants with an episode 
of dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis due to Herpes Zoster 
Ophthalmicus (HZO) in the year prior to enrollment.  
 
Protocol Identifying Number: 16-00463 
Principal Investigator: Elisabeth Cohen, MD 
Funded by: The National Eye Institute 
Version Number:  3.0 
 March 25, 2020 
 


 
ii 
 
Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................................................................ 7 
PROTOCOL SUMMARY ........................................................................................................................................... 8 
SCHEMATIC OF STUDY DESIGN ....................................................................................................................... 10 
1 
KEY ROLES ................................................................................................................................................. 11 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE...................... 12 
2.1 
Background Information ................................................................................................................... 12 
2.2 
Rationale ............................................................................................................................................ 16 
2.3 
Potential Risks and Benefits ............................................................................................................ 17 
2.3.1 
Known Potential Risks .................................................................................................. 17 
2.3.2 
Known Potential Benefits ............................................................................................. 20 
3 
OBJECTIVES AND PURPOSE ................................................................................................................. 20 
4 
STUDY DESIGN AND ENDPOINTS ........................................................................................................ 21 
4.1 
Description of the Study Design ..................................................................................................... 21 
4.2.1 
Primary Endpoint ........................................................................................................... 22 
4.2.2 
Secondary Endpoints .................................................................................................... 22 
4.2.3 
Exploratory Endpoints ................................................................................................... 23 
5 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................ 23 
5.1 
Participant Inclusion Criteria ............................................................................................................ 23 
5.2 
Participant Exclusion Criteria .......................................................................................................... 24 
5.3 
Strategies for Recruitment and Retention ..................................................................................... 25 
5.4 
Participant Withdrawal or termination ............................................................................................ 25 
5.4.1 
Handling of Participant Withdrawals or termination ................................................. 25 
5.5 
Premature Termination or Suspension of Study .......................................................................... 26 
6 
STUDY AGENT ........................................................................................................................................... 26 
6.1 
Study Agent(s) and Control Description ........................................................................................ 26 
6.1.1 
Acquisition ...................................................................................................................... 26 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 27 
6.1.3 
Product Storage and Stability ...................................................................................... 27 
6.1.4 
Preparation ..................................................................................................................... 27 
6.1.5 
Dosing and Administration ........................................................................................... 27 
6.1.6 
Route of Administration ................................................................................................ 27 
6.1.7 
Starting Dose and Dose Escalation Schedule .......................................................... 27 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 27 
6.1.9 
Duration of Therapy ...................................................................................................... 29 
6.1.10 
Tracking of Dose ........................................................................................................... 29 
6.1.11 
Device Specific Considerations ................................................................................... 30 
6.2 
Study agent Accountability Procedures ......................................................................................... 30 
7 
STUDY PROCEDURES AND SCHEDULE ............................................................................................. 30 
7.1 
Study Procedures/Evaluations ........................................................................................................ 30 
7.1.1 
Study specific procedures ............................................................................................ 30 
7.1.2 
Standard of care study procedures............................................................................. 30 
7.2 
Laboratory Procedures/Evaluations ............................................................................................... 31 
7.2.1 
Clinical Laboratory Evaluations ................................................................................... 31 
7.2.2 
Other Assays or Procedures........................................................................................ 31 


 
iii 
 
7.2.3 
Specimen Preparation, Handling, and Storage ........................................................ 31 
7.2.4 
Specimen Shipment ...................................................................................................... 31 
7.3 
Study Schedule ................................................................................................................................. 31 
7.3.1 
Screening/consent......................................................................................................... 31 
7.3.2 
Enrollment/RANDOMIZATION .................................................................................... 32 
7.3.3 
Follow-up STUDY VISITS ............................................................................................ 33 
7.3.4 
Final Study Visit ............................................................................................................. 34 
7.3.5 
Early Termination Visit .................................................................................................. 34 
7.3.6 
Non-STUDY VISIT (Unscheduled/SCHEDULED Visit) ........................................... 34 
7.3.7 
Schedule of Events Table ............................................................................................ 34 
7.4 
Justification for Sensitive Procedures ............................................................................................ 36 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................ 36 
7.5.1 
Precautionary Medications, Treatments, and Procedures ...................................... 36 
7.6 
Prohibited Medications, Treatments, and Procedures ................................................................ 36 
7.7 
Prophylactic Medications, Treatments, and Procedures ............................................................. 36 
7.8 
Rescue Medications, Treatments, and Procedures ..................................................................... 36 
7.9 
Participant Access to Study Agent At Study Closure .................................................................. 36 
8 
ASSESSMENT OF SAFETY ..................................................................................................................... 37 
8.1 
Specification of Safety Parameters ................................................................................................ 37 
8.1.1 
Collection of Selected Adverse Events (AE) ............................................................. 37 
8.1.2 
Definition of Serious Adverse Events (SAE) ............................................................. 37 
8.1.3 
Definition of Unanticipated (UNEXPECTED) Problems .......................................... 37 
8.2 
Classification of an Adverse Event ................................................................................................. 38 
8.2.1 
Severity of Event ........................................................................................................... 38 
8.2.2 
Relationship to Study Agent ........................................................................................ 38 
8.2.3 
Expectedness ................................................................................................................ 39 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 39 
8.4 
Reporting Procedures ...................................................................................................................... 39 
8.4.1 
Adverse Event Reporting ............................................................................................. 39 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 39 
8.4.3 
unexpected/Unanticipated Problem Reporting ......................................................... 40 
8.4.4 
Events of Special Interest ............................................................................................ 40 
8.4.5 
Reporting of Pregnancy ................................................................................................ 40 
8.5 
Study Halting Rules .......................................................................................................................... 40 
8.6 
Safety Oversight ................................................................................................................................ 40 
9 
CLINICAL MONITORING ........................................................................................................................... 41 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 42 
10.1 
Statistical Analysis Plan ................................................................................................................... 42 
10.2 
Statistical Hypotheses ...................................................................................................................... 42 
10.3 
Analysis datasets .............................................................................................................................. 44 
10.4 
Description of Statistical Methods .................................................................................................. 44 
10.4.1 
General Approach ......................................................................................................... 44 
10.4.2 
Analysis of the primary efficacy endpoint(s) .............................................................. 44 
10.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 45 
10.4.4 
Exploratory Analyses .................................................................................................... 45 
10.4.5 
Safety Analyses ............................................................................................................. 45 


 
iv 
 
10.4.6 
Adherence and Retention Analyses ........................................................................... 45 
10.4.7  
Baseline Descriptive Statistics .................................................................................... 46 
10.4.8 
Planned Interim Analyses ............................................................................................ 46 
10.4.9 
Additional Sub-group Analyses ................................................................................... 46 
10.4.10 
Multiple Comparison/Multiplicity .................................................................................. 46 
10.4.11 
Exploratory Analyses .................................................................................................... 47 
10.5 
Sample Size ....................................................................................................................................... 47 
10.6 
Measures to Minimize Bias .............................................................................................................. 47 
10.6.1 
Enrollment/ Randomization/ Masking Procedures ................................................... 47 
10.6.2 
 Evaluation of Success of Blinding .............................................................................. 48 
10.6.3 
Breaking the Study Blind/Participant Code ............................................................... 48 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................. 48 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................................................. 48 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................................................. 48 
13.1 
Ethical Standard ................................................................................................................................ 48 
13.2 
Institutional Review Board ............................................................................................................... 49 
13.3 
Informed Consent Process .............................................................................................................. 49 
13.3.1 
Consent and Other Informational Documents Provided to Participants ................ 49 
13.3.2 
Consent Procedures and Documentation .................................................................. 49 
13.4 
Participant and data Confidentiality ................................................................................................ 50 
13.4.1 
Research Use of Stored Human Samples, SPECIMENS or Data ......................... 50 
13.5 
Future Use of Stored Specimens ................................................................................................... 50 
14 
DATA HANDLING AND RECORD KEEPING ......................................................................................... 50 
14.1 
Data Collection and Management Responsibilities ..................................................................... 50 
14.2 
study records retention ..................................................................................................................... 51 
14.3 
Protocol Deviations ........................................................................................................................... 51 
14.4 
Publication and Data Sharing Policy .............................................................................................. 51 
15 
STUDY ADMINISTRATION ....................................................................................................................... 52 
15.1 
Study Leadership .............................................................................................................................. 52 
16 
CONFLICT OF INTEREST POLICY ......................................................................................................... 52 
17  
LITERATURE REFERENCES ................................................................................................................... 52 
APPENDIX ................................................................................................................................................................ 58 
 


Zoster Eye Disease Study (ZEDS) 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
APT  
Acyclovir Prevention Trial 
CC 
Coordinating Center 
CMP 
Clinical Monitoring Plan 
CCT 
Central Corneal Thickness 
CDC 
Centers for Disease Control 
CIRB 
Central IRB 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CTSA 
Clinical Translational Science Award 
DDC    
Drug Distribution Center 
DSMC 
Data and Safety Monitoring Committee 
EDC  
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
EMR  
Electronic Medical Record 
HEDS  
Herpetic Eye Disease Study 
HSV 
Herpes Simplex Virus 
HHS 
Health and Human Services 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HUS 
Hemolytic Uremic Syndrome 
HZ  
Herpes Zoster 
HZO 
Herpes Zoster Ophthalmicus 
IC50 
Inhibitory Concentration to Reduce by 50% 
ICF 
Informed Consent Form 


Zoster Eye Disease Study (ZEDS) 
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IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IXRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Operations and Procedures 
NEI 
National Eye Institute 
NYULMC    
NYU Langone Medical Center 
NYUSoM 
NYU School of Medicine 
PCC 
Participating Clinical Center 
PCR  
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PHN  
Postherpetic Neuralgia 
PI 
Principal Investigator 
QOL 
Quality of Life 
RCT 
Randomized Controlled (Clinical) Trial 
RZV 
Recombinant Zoster Vaccine 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TMF 
Trial Master File 
TTP 
Thrombotic Thrombocytopenic Purpura  
V1 and V2 
Cranial Nerve five (Trigeminal Nerve), first and second division  
VZV  
Varicella Zoster Virus 
ZBPI 
Zoster Brief Pain Inventory 
ZVL 
Zoster Vaccine Live 
ZEDS 
Zoster Eye Disease Study 


Zoster Eye Disease Study (ZEDS) 
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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with the ICH E6 (R2) Guideline for Good Clinical Practice, the U.S. 
Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46), the Code of Federal 
Regulations applicable to clinical studies (21 CFR 312 – Investigational New Drug Application, 21 CFR 50 – 
Protection of Human Subjects and 21 CFR 54 – Financial Disclosure by Clinical Investigator, 21 CFR 56 – 
Institutional Review Boards), and the National Eye Institute Terms of Award. The Principal Investigator at the 
Participating Clinical Site (PCC) will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board (IRB), 
except where necessary to eliminate an immediate hazard(s) to the study participants. All personnel involved 
in the conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
 
 
 
 
PCC Principal Investigator (PI):  
 
 
 
 
 
 
 
 
 
 
PCC PI Signature:   
 
 
 
 
 
 
 
 
Date:   
 
 
 


Zoster Eye Disease Study (ZEDS) 
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PROTOCOL SUMMARY 
 
Title: 
Zoster Eye Disease Study (ZEDS): A multi-center, randomized, 
double-masked, placebo-controlled clinical trial of valacyclovir for 
one year in immunocompetent study participants with an episode of 
dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, 
and/or iritis due to Herpes Zoster Ophthalmicus (HZO) in the year 
prior to enrollment. 
 
Précis: 
The study is a double-masked, multi-center, randomized clinical trial 
(RCT) that will enroll immunocompetent study participants age 18 
years and older who have HZO diagnosed at variable times in the 
past, with an episode of dendriform epithelial keratitis, stromal 
keratitis, endothelial keratitis, and/or iritis due to HZO in the year 
prior to enrollment. Eligible study participants will be randomized in a 
1:1 ratio to long-term suppressive treatment with oral valacyclovir 
1000 mg daily or placebo for one year, and followed every 3 months 
for a total of 18 months, to determine outcomes of new or worsening 
dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, 
and/or iritis and severity and duration of postherpetic neuralgia 
during 12 months of treatment and for 6 months following treatment 
discontinuation. Participants will be randomized within center in four 
strata, defined by age at onset of HZO (less than 60 years or 60 
years and greater) and by recent onset or chronic HZO (recent onset 
defined as HZO diagnosed within 6 months of 
enrollment/randomization, or chronic defined as HZO diagnosed 6 
months or more prior to enrollment/randomization). 
 
Objectives: 
 
To evaluate whether or not prolonged suppressive oral antiviral 
treatment with valacyclovir reduces complications of HZO including 
new or worsening dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis and/or postherpetic neuralgia 
compared to placebo. 
 
 
Endpoint: 
The primary endpoint is the time to first occurrence of new or 
worsening episode of dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis due to HZO, during the twelve 
months of treatment, requiring pre-specified treatment changes.  The 
primary endpoint is compared for participants randomized to study 
medication or placebo 
Population: 
Immunocompetent participants age 18 years or older with a past 
diagnosis of HZO that included: 
 
Cranial nerve V1 or V2 involvement with history of typical 
rash 
 
Medically documented episode of dendriform epithelial 
keratitis, stromal keratitis, endothelial keratitis, and/or iritis 
due to HZO in the year prior to enrollment. 
 
Phase: 
NIH defined Phase 3 (FDA defined Phase 4) 
 


Zoster Eye Disease Study (ZEDS) 
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9 
Number of 
Participating Clinical 
Centers (PCC) 
 
Approximately 70-80  PCCs  
 
 
Description of Study 
Agent: 
Valacyclovir: two 500 mg pills daily 
Placebo: encapsulated matching placebo 
 
Study Duration: 
Estimated 8 years: 12 months treatment and additional follow-up 
period up to 6 months. 
 
Participant Duration: 
Up to 18 months (12 months receiving study medication) 
 
 
 


Zoster Eye Disease Study (ZEDS) 
Version 3.0 
Protocol 16-00463 
  March 25, 2020 
 
 
 
10 
SCHEMATIC OF STUDY DESIGN 
 
 


Zoster Eye Disease Study (ZEDS) 
Version 3.0 
Protocol 16-00463 
  March 25, 2020 
 
 
 
11 
1 
KEY ROLES 
 
Principal Investigator/Study Chair 
 
Elisabeth Cohen, MD 
ZEDS Coordinating Center 
NYU School of Medicine 
One Park Ave, 6th floor, 6-663 
New York, NY 10016 
929-455-2412 
Elisabeth.Cohen@nyulangone.org 
 
Study Co-Chair 
Bennie Jeng, MD 
University of Maryland School of Medicine 
419 W. Redwood Street, Suite 470 
Baltimore, MD 21201 
667-214-1232 
bjeng@som.umaryland.edu  
 
NEI Project Officer 
Sangeeta Bhargava, PhD 
Division of Extramural Science Programs 
CCR/NEI/NIH 
Suite 1300, 5635 Fishers Lane, MSC 9300 
Bethesda, MD  20892 
301-451-2020 
bhargavas@nei.nih.gov  
 
 
 


Zoster Eye Disease Study (ZEDS) 
Version 3.0 
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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
 
Herpes Zoster Ophthalmicus (HZO) is associated with unilateral acute and chronic eye disease and pain, with 
potential complications that can significantly impair functioning and reduce quality of life (QOL) among millions 
of Americans, especially older adults. Although there is considerable consensus on treatment of acute HZO in 
immunocompetent adults, there is no standard approach to treatment of HZO sequelae such as ocular disease 
and postherpetic neuralgia (PHN), a severely debilitating chronic pain syndrome. Several factors call for 
evaluating long-term suppressive antivirals to prevent HZO complications in a randomized controlled trial: 
recent discoveries about the infectious pathogenesis of complications of herpes zoster (HZ) and HZO; the 
significant benefit of suppressive antivirals in reducing recurrent herpes simplex virus (HSV) stromal keratitis; 
and evidence of comparable, marked benefit of suppressive antiviral treatment of chronic HZO and HSV in a 
retrospective study (1-4). HZO and HSV eye disease have some clinical similarities in that primary infection 
(with these different herpes viruses) is followed by latency, and recurrent infection is frequently associated with 
chronic and/or recurrent eye disease, both of which can lead to loss of vision.  HZ results from acute 
reactivation of latent varicella zoster virus (VZV). It was confirmed only recently, however, that complications of 
HZ may be associated with chronic or recurrent active infection rather than manifestations of inflammatory, 
immune, neuropathic and vascular sequelae of infection.  For example, a 1995 study showed that late 
dendriform epithelial keratitis lesions are often polymerase chain reaction (PCR) positive for VZV, and this was 
confirmed by a larger series in 2010 (2, 3).  Dendriform epithelial keratitis responds to topical and systemic 
antiviral treatment: further evidence it is caused by active VZV infection (3, 5).  There is also evidence 
associating chronic, active VZV infection with PHN, vasculopathy after HZ resulting in potentially fatal strokes, 
and giant cell (temporal) arteritis (6-9).  The concept that persistent active infection results in chronic HZO has 
generated interest and debate among experts.  A 2012 editorial in Archives of Ophthalmology suggested that, 
“…although stromal keratitis or uveitis may not represent active viral infection, clinicians may question whether 
subclinical or intermittent viral shedding may help to perpetuate destructive, inflammatory, anterior segment 
disease in HZO” (10).  Corneal changes that result in visual loss from VZV keratitis are estimated by corneal 
specialists to occur in 20-40% of cases.  In a recent report, the mean number of recurrences of HZO was 
decreased with antiviral treatment from 3.4 episodes per year to 2.1 episodes per year (p<0.05) suggesting 
that prolonged long-term antivirals at the higher dose to be used in the Zoster Eye Disease Study (ZEDS) trial 
may reduce morbidity, including visual loss, associated with chronic HZO, and could significantly reduce the 
disease burden for patients and the costs to society (1). 
 
ZEDS seeks to answer this question for HZO caused by VZV much as the Herpetic Eye Disease Study 
(HEDS) Acyclovir Prevention Trial (APT) did for HSV ocular disease, with a double-masked, placebo-
controlled, multi-center randomized controlled trial (RCT) in immunocompetent study participants age 18 and 
older with a past diagnosis of HZO and an episode of dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis diagnosed within the past year (4).  In HEDS, prolonged suppressive antiviral 
treatment was most beneficial in preventing recurrence of stromal keratitis, suggesting that active viral infection 
is an important factor contributing to stromal keratitis, although the mechanism is not understood (4). The 
ZEDS design is analogous to the HEDS design.  Study participants with HZO will be randomized in a double-
masked, placebo-controlled RCT to 1 year of suppressive antiviral treatment with oral valacyclovir or placebo, 
with follow-up every 3 months for a total of 18 months, to compare the rates of new or worsening dendriform 


Zoster Eye Disease Study (ZEDS) 
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  March 25, 2020 
 
 
 
13 
epithelial keratitis, stromal keratitis, endothelial keratitis, or iritis and severity and duration of PHN by 12 
months of treatment and 6 months after treatment. 
 
Evidence of Chronic Active VZV Infection after HZ and HZO 
The rationale for the study includes the increasing body of evidence that chronic active VZV infection occurs 
after HZ and contributes to complications, including PHN, stroke, and temporal arteritis, in addition to 
dendriform epithelial keratitis and uveitis (11-14).  VZV DNA has been found to persist in the saliva of 67% 
(21/32) of persons age 60 and older with a history of HZ up to 12 years after disease onset (15).  In HZO, 
evidence from PCR testing shows that active VZV infection contributes to late dendriform epithelial keratitis, a 
characteristic manifestation of HZO with median occurrence 5 months after HZO onset, and uveitis (2, 3, 14). 
The finding of VZV DNA in blood mononuclear cells of HZ patients with PHN, in the arteries of patients with 
zoster-related strokes, and, most recently, in temporal arteries of patients with possible and proven giant cell 
arteritis, is helping to raise awareness of the devastating consequences of chronic active VZV infection, the 
importance of accurate diagnosis, and the potential for improved antiviral treatment of these conditions. Given 
evidence that active VZV infection contributes to PHN, and the lack of effective and well tolerated treatment for 
PHN, it is important to study the efficacy of suppressive antiviral treatment for this extremely painful and 
debilitating condition that negatively impacts QOL, especially in the elderly, by prospectively collecting data 
regarding PHN severity and treatment.  The results with regard to PHN may be generalizable to HZ in other 
anatomic locations; PHN lasts more than a year in nearly half of patients older than age 70, reduces QOL in 
direct proportion to the severity and duration of pain, and more than quadruples the one year costs of the 
disease.  In 2014, HZ was reported as a risk factor for myocardial infarction in addition to cerebrovascular 
disease (16-18).  An editorial in Clinical Infectious Diseases concludes, “The growing awareness of the role of 
VZV in vascular disease promises to lead to clinical trials to assess the benefit of antiviral therapy.” (19)  
 
HEDS: Oral Antivirals to Reduce Recurrent Ocular HSV Disease 
The HEDS APT examined long-term use of oral acyclovir to prevent recurrent HSV disease, and found a 45% 
reduction (95% CI 0.41-0.75, p<0.001) in recurrent ocular disease over 1 year (4).  On the basis of this 
landmark study, recommended care for HSV eye disease changed to include prolonged suppressive antiviral 
treatment.  In HEDS, although high-dose oral antiviral therapy for 10 weeks was not effective in treating 
stromal keratitis, prolonged suppressive antiviral treatment for 1 year in the HEDS APT was most beneficial in 
preventing recurrence of this form of disease in study participants who had a history of stromal keratitis, 
reducing it from 28% to 14% (95% CI 0.29-0.80, p=0.005) (4, 20). The efficacy of suppressive antiviral 
treatment in preventing stromal keratitis and lack of efficacy of high-dose antiviral treatment for stromal keratitis 
are consistent with greater efficacy of prolonged suppressive antiviral treatment in general.  The clinical benefit 
was greater for stromal keratitis than dendritic keratitis because stromal keratitis results in more scarring and 
permanent damage than superficial epithelial (dendritic) keratitis (4). There is no direct evidence that viral 
reactivation causes HSV stromal keratitis, yet HEDS showed that suppression of HSV reduces the rate of 
recurrence of HSV stromal keratitis. There is an absence of direct evidence that viral replication contributes to 
either HZO or HSV stromal keratitis. 
Prolonged suppressive antiviral treatment has improved outcomes of ocular HSV. The HEDS trial results were 
observed in a real-world setting. A retrospective community-based cohort study investigating the impact of 
prophylactic antiviral treatment for HSV keratitis, published in 2010, concluded that patients were significantly 
less likely to have recurrent HSV epithelial keratitis and stromal keratitis on prolonged suppressive treatment 
(21).  
 


Zoster Eye Disease Study (ZEDS) 
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Protocol 16-00463 
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14 
We hypothesize that prolonged suppressive valacyclovir treatment will reduce the occurrence of stromal 
keratitis and dendriform epithelial keratitis in HZO patients.  HSV stromal keratitis is primarily immune-
mediated; while the trigger or mechanism of recurrent inflammation is uncertain, there is strong clinical 
evidence that suppressive antiviral treatment decreases its frequency (22).  HSV and VZV stromal keratitis are 
analogous diseases, and our aim is to determine whether VZV stromal keratitis can be reduced by suppressive 
antiviral treatment in a similar fashion to HSV stromal keratitis. If results of the trial are similar with regard to 
antiviral suppression reducing infectious and inflammatory chronic ocular disease in HZO, the benefits to 
patients will be significant as this therapy is adopted as standard of care. 
 
Preliminary Studies 
In preparation for this trial, study leaders conducted and published a retrospective study of over 100 HZO 
patients treated at a tertiary referral center and found that late dendriform epithelial keratitis occurred more 
often in patients who were under age 60 at time of HZO onset compared with those age 60 or older at onset 
(36% vs. 17%, p=0.03) (23).  Younger patients averaged 3.2 episodes of recurrent inflammation, and older 
patients 1.5 during follow-up (p=0.01).  In both groups, over 80% of patients remained on topical 
corticosteroids three years after referral. Complications including PHN, neurotrophic keratitis and secondary 
infected corneal ulcers were all significantly more common in older-onset patients (38% for those age 60 or 
older at onset vs. 8% for those under age 60 at onset, p=0.001, 31% v. 9% p=0.005, and 17% v. 3%, p=0.04, 
respectively) (23).  
 
Current Practice Patterns and Opinions 
A survey of 100 corneal specialists was also conducted in preparation for this study; over 85% of specialists 
reported treating cases of chronic or recurrent HZO in the preceding year.  They reported prescribing oral 
antivirals most often for 7-14 days (37%), while some used them for a year or longer (15%), and others as long 
as patients were on topical corticosteroids (15%) (24).  
 
Suppressive Antivirals Preferred by Cornea Specialists 
The choice of antiviral regimen for study was based in part on an electronic survey conducted in preparation 
for the project (25).  This survey was sent to ophthalmologists, including leaders of cornea fellowship training 
programs and/or cornea subspecialty societies, and to those with special interest in cornea, as indicated by 
participation in Kera-net, the official forum and listserv of the Cornea Society.  The 171 respondents included 
69% (46/67) of the cornea leaders surveyed.  Valacyclovir 500 mg bid was the preferred antiviral regimen 
(36%), followed by acyclovir 800 mg bid (33%), valacyclovir 1000 mg daily (28%), and finally, famciclovir 250 
mg bid (4%).  Further, over 60% of the survey respondents were definitely interested in participating in the 
study. 
 
Pilot Studies 
Several recent studies provide important lines of evidence that serve as pilot data and inform aspects of the 
trial design.   An observational study from an Ocular Immunology and Uveitis Service at an Italian referral 
center treating patients with chronic HZO, published in 2014, looked at patients who were routinely prescribed 
suppressive antiviral treatment.  The study found that in patients who were referred an average of 3 years after 
disease onset, prolonged treatment with antiviral valacyclovir 500 mg daily or acyclovir 400 mg bid reduced the 
overall number of recurrences to 2.1 per year, compared to 3.4 episodes without antiviral treatment, a 35% 
reduction (p<.05) (1).  In this study, the same suppressive antiviral treatment of HSV keratitis reduced 
recurrences to 2.3 from 3.8, a 39% reduction (p<0.05).  The percent reduction of recurrent HSV (39%) was 
comparable to the percent reduction of HSV (45%) in HEDS, and comparable to the reduction of recurrent 


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inflammation in HZO (35%) in this observational study.  This pilot data support the projected risk reduction 
(30%) postulated for the ZEDS RCT.  This observational study also provides data on the relative prevalence of 
types of recurrences: inflammation recurred in 51% of HZO patients followed for an average of 2 years (range 
1-6 years), including stromal keratitis (20%) followed by anterior uveitis (13.3%), keratouveitis (8.9%) and 
epithelial keratitis (6.7%). Inflammation recurred in 65% of HSV patients, including stromal keratitis (24.9%), 
keratouveitis (18.6%), anterior uveitis (14.8%), and epithelial keratitis (6.3%).  In both HZO and HSV, stromal 
keratitis and/or uveitis were the most common forms of recurrent disease: epithelial keratitis was least 
common.  Of note, the suppressive antiviral regimen used was weaker (valacyclovir 500 mg daily or acyclovir 
400 mg bid) than treatment planned for the current study (valacyclovir 1000 mg daily), suggesting that using a 
stronger regimen the effect may be even greater.  
 
Remaining Gaps in Knowledge 
The morbidity associated with chronic HZO is substantial and greater than HZ in other anatomic locations due 
to eye disease, longer duration of PHN, and greater risk of stroke. Thus, determining whether long-term 
antiviral therapy reduces the disease burden for patients and costs to society will fill a critical, substantial gap. 
Another significant gap in current clinical knowledge relates to effectiveness of early vs. delayed suppressive 
treatment.  ZEDS will study patients with HZO of recent onset to determine if early suppressive antiviral 
treatment reduces chronic disease, and also patients with chronic disease to determine if delayed treatment is 
effective.  Furthermore, ZEDS will evaluate the effects of age at disease onset, since this variable affects 
disease manifestations and may affect response to treatment.  Patients with disease onset before age 60 more 
often have recurrent ocular inflammation, and patients with disease onset at age 60 and older more often have 
PHN and problems related to neurotrophic keratopathy (23).  It is unknown if antiviral suppression benefits 
both age groups and whether the risk-benefit ratio varies by age at onset of disease.  Therefore, the 
randomization to treatment group is stratified by these potentially important risk factors.  Depending on the 
findings of the study, treatment recommendations might be tailored by age at disease onset, and/or by recent 
onset or chronic disease status.   
 
Increased Incidence of HZ and HZO 
Herpes zoster is caused by reactivation of VZV in people who have had chicken pox (varicella), the primary 
infection caused by VZV.  There are about a million new cases of HZ in the US annually; up to 20% of these 
cases develop HZO, and 20-30% of these HZO patients develop chronic eye disease.  Although the rate of HZ 
increases with age, the number of cases peaks in individuals age 50-59 (26).  The incidence of HZ has been 
steadily increasing in the US among people age 40 and older for unknown reasons (27).  The incidence of HZ 
in North America, Europe, and the Asia Pacific is increasing, and this trend started in the absence of varicella 
vaccination programs against chicken pox (28).  HZ affects approximately 30% of the population, and HZO 
develops when HZ affects the first division of cranial nerve V (29).  
 
ZEDS has the potential to have a major impact in improving outcomes and changing the standard of care of a 
common, serious chronic disease.  
 
Disease Burden 
HZ in general, and HZO in particular, can be associated with serious complications that result in diminished 
QOL, chronic eye disease, reduced vision, and even death (30).  Most studies find that women are affected 
significantly more frequently than men with regard to HZ incidence, hospitalizations, and mortality (31-33).  
PHN persists for longer than 1 year in nearly half of patients older than age 70 (34-36).  The direct medical 
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year costs are more than 5 times greater than costs in HZ patients without PHN (34).  The negative impact of 
HZ and PHN on health-related QOL is closely correlated with the severity of pain and persists as long as 
clinically significant pain (37, 38). A population-based study shows that HZ is a risk factor for developing major 
depression (39). Notably, PHN has been reported to be the most common cause of suicide in chronic pain 
patients over age 70 (40). 
 
Publications that compare HZO with HZ occurring in other anatomic locations point to the risk of PHN and 
stroke being greater after HZO than HZ elsewhere (37, 41).  PHN after HZO lasts longer and is more frequent 
than PHN after HZ in general, despite recommended acute antiviral treatment (36, 37, 41).  Although 
potentially fatal strokes are an uncommon complication of HZ, HZO patients have a 4.5 times higher risk of 
stroke within a year after diagnosis compared to controls, and the adjusted hazard ratio of stroke after HZO is 
4.3 compared to 1.3 after HZ (42, 43).  In a self-controlled case-series population-based study, the risk of 
stroke for 6 months more than doubled after HZO compared to HZ in general (44).  Although the risk of stroke 
after HZ is greatest in the short term, increased risk continues after the first year and is greatest in patients 
under age 40 (45).  
   
Approximately 30% of HZO patients treated acutely with recommended oral antivirals have ocular 
complications at 6 months compared to 50% without this treatment (46, 47).  Patients with ocular complications 
of HZO often have a chronic disease with manifestations that vary by age.  Long-term topical corticosteroids 
are used to control ocular inflammation in most patients with chronic HZO disease.  Use of oral antivirals is 
highly variable, with some academic cornea specialists prescribing them frequently and many ophthalmologists 
using them infrequently or not at all (24).   
 
Support for Prolonged Antiviral Therapy in HZO-associated Ocular Disease 
As documented above, the need for this large-scale trial is supported by extensive published evidence of 
chronic active VZV infection following HZ; and the recent observational study (above) reporting 50% rate of 
recurrent inflammation in HZO and 35% reduction of recurrent disease in patients on relatively low-dose 
suppressive antiviral treatment (1).  
 
In addition, the landmark study of the long-term use of oral acyclovir for the prevention of recurrent herpes 
simplex virus (HSV) ocular disease, the Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial (APT), 
demonstrated a 45% reduction in recurrent ocular disease over one year (4). It is therefore possible that in 
view of the similarities between HSV and HZO keratitis, suppressive antiviral treatment in HZO may reduce 
stromal keratitis and other anterior segment disease manifestations thought to be predominantly immune-
mediated, as well as dendriform epithelial keratitis and iritis.  
 
Taken together, these data make a convincing case that now is the right time to conduct this trial in order to 
obtain rigorous randomized controlled evidence to determine whether suppressing VZV infection reduces 
chronic anterior segment ocular disease and/or PHN in HZO. 
 
2.2 
RATIONALE  
 
Valacyclovir is an FDA approved medication for the acute treatment of HZ, using a dose of 1000 mg three 
times a day for seven days, and for prolonged suppressive treatment of HSV genital disease in 
immunocompetent patients, using a dose of 1000 mg daily.  This study evaluates the same dose as used for 
suppression of HSV genital disease for patients with HZO, a purpose that has not been approved by the FDA. 


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This proposal has been reviewed by the FDA and approved by the IRB at the NYU School of Medicine 
(NYUSoM). 
 
This is the first prospective multicenter placebo-controlled RCT of prolonged suppressive antiviral treatment for 
chronic HZO or HZ in immunocompetent patients.  
 
Assessment of Most Frequently Preferred Suppressive Antiviral Regimens for HZO by Cornea 
Specialists  
The antiviral regimen to be studied was chosen in part on the basis of a second electronic survey conducted in 
preparation for this trial (25).  Valacyclovir 500mg bid or 1000 mg daily was preferred by 64% (108/171).  
Valacyclovir is a prodrug of acyclovir, which has better oral absorption and bioavailability than acyclovir.  The 
peak plasma concentration of acyclovir after 500 mg of oral valacyclovir is 3.28 mcg/mL and after 1000 mg of 
valacyclovir is 5.65 mcg/mL, according to the package insert.  The median inhibitory concentration of acyclovir 
to reduce VZV plaque counts by 50% (IC50) is approximately 3 mcg/mL (48).  The IC50 of acyclovir for VZV is 
higher than the IC50 of acyclovir for HSV type 1, which averages 0.45-1.47 mcg/mL (compared to the peak 
plasma concentration of 1.21 mcg/mL after 400 mg acyclovir, the dose that was effective in HEDS APT) (49).  
The VZV IC50 data supports the use of valacyclovir in this study.  In order to facilitate compliance by having 
daily dosing rather than bid dosing, 1000 mg of valacyclovir will be used, the same dose approved for 
suppressive treatment of genital HSV disease in immunocompetent patients.  Study participants will be 
randomized to take two 500 mg tablets of valacyclovir once daily or two tablets of placebo, because the 1000 
mg valacyclovir tablet is too large to be encapsulated, as required for this masked placebo controlled study.  
 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 
KNOWN POTENTIAL RISKS  
 
Risks to Study Participants Relative to Benefit to Study Participants and Others 
The risk of suppressive antiviral treatment is low, and in view of the protocol measures to minimize them, the 
risk to study participants is low relative to the clinically important potential benefits in patients with HZO and HZ 
in general.  If suppressive valacyclovir is effective, outcomes in HZO and PHN will be improved, benefiting 
afflicted study participants and society.  
 
The blood test(s) is (are) associated with the risks and discomfort of any blood test requiring one tube, 
equivalent to two teaspoons of blood. 
 
Risk of Study Drug Valacyclovir   
The risk related to participation in this study relates to the risk of oral antiviral treatment with valacyclovir. 
Valacyclovir is approved and recommended for acute treatment of HZ, but not for chronic treatment of HZ.  
Previous studies of long-term suppressive treatment have been done in patients with HSV disease, using a 
similar dose of valacyclovir 1000 mg daily in immunocompetent patients (package insert).  The most common 
side effects of suppressive treatment of recurrent genital HSV infections in immunocompetent adults with 
valacyclovir 1000 mg daily include headache (35%, compared to 34% with placebo), nausea (11%, compared 
to 8% with placebo), and abdominal pain (11%, compared to 6% with placebo), according to the package 
insert.  Less common side effects include dysmenorrhea (8%, placebo 4%), depression (7%, placebo 5%), 
arthralgia (6%, placebo 4%), vomiting (3%, placebo 2%) and dizziness (4%, placebo1%).  Rates of drug 
discontinuation in prior studies are not listed. 


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According to the package insert regarding laboratory results, hematologic abnormalities occurred in 0-0.7% in 
adults treated with valacyclovir 1 gram daily compared to 0.8-1.5% of adults treated with placebo.  In addition, 
AST (SGOT) liver function test abnormalities occurred in 4.1% of adults on valacyclovir 1000 mg daily, 
compared to 3.0% on placebo.  With regard to geriatric use, elderly patients age 65 and over are more likely to 
have renal or CNS adverse events and hematological and liver function problems are not mentioned.  With 
regard to adults with liver impairment including cirrhosis, dosage modification is not recommended. Despite 
widespread use, there is little evidence that oral acyclovir (valacyclovir is prodrug of acyclovir) causes 
significant liver injury, or changes in serum liver enzyme levels (http:livertox.nih.gov/acyclovir.htm).  
Suppressive valacyclovir for HSV genital disease in immunocompetent patients at the same dose of 1000 mg 
daily and duration of one year, or longer, as used in our study has a long established safety profile with 
adverse events similar to placebo in numerous studies, both before and after its approval in 1995 (50).  Long-
term suppressive valacyclovir was not associated with laboratory abnormalities, including creatinine levels.  
Headache, nausea, and diarrhea were the most common adverse events attributed to the drug.  Thrombotic 
microangiopathy that has been reported at high doses (8000 mg/d) for prolonged periods for prophylaxis of 
cytomegalovirus (CMV) infection, especially in severely immunosuppressed patients, has not been reported in 
3050 participants in 4 trials of valacyclovir suppression of recurrent genital HSV. 
 
If participants in this study develop side effects, such as gastrointestinal symptoms or headache, they will be 
instructed to take one tablet twice daily, as the study medication may be better tolerated in divided doses. 
Study participants with side effects that require discontinuation of the study medicine will continue to be 
followed, and be included in the study on an intention-to-treat basis.  The study ophthalmologist will be allowed 
to restart the study medication after mild or moderate side effects resolve, if the study participant agrees.  If 
side effects recur, the dose can be reduced to one pill daily, as this lower dose has been reported in a 
retrospective study to be effective in reducing recurrences in HZO (1).  
 
Valacyclovir and Renal Insufficiency 
Oral antiviral medications are generally very safe and can be used in patients with impaired renal function, but 
their dosage needs to be adjusted.  For valacyclovir, a suppressive regimen of 1000 mg daily is reduced to 500 
mg daily, in study participants with creatinine clearance < 30.  Study participants on dialysis or with a baseline 
eGFR < 45 within one month prior to enrollment will be excluded from the study.  On the basis of 
recommendations of a geriatrician, infectious disease specialist, and nephrologist, study participants with 
eGFRs 45 -59 will be eligible, based on assessment of potential risk/benefit ratio.  Elderly patients are at 
increased risk for and most negatively impacted by HZO and often have reduced eGFR.  Approximately 25% 
of people age 70 years and older can be estimated to have eGFRs between 45 and 59 (51).  Study 
participants with a baseline eGFR of 45-59 will have repeat eGFRs prior to the three, six, nine, 12-month study 
visits.  If the eGFR decreases to less than 45, the eGFR will be repeated.  If on repeat testing the eGFR is less 
than 45 the study medication will be discontinued.  Study participants will be told to see their primary care 
doctor and have eGFR repeated monthly until it is 45 or more. The study participant will continue to be 
followed, but the study medication will not be restarted. 
 
The package insert contains a warning that acute renal failure can occur in the elderly, with or without reduced 
renal function.  Nephrotoxicity is more frequent after intravenous than oral acyclovir.  Serum creatinine >1.5 of 
the upper limit of normal occurred in 0.2% of HZ patients on 1000 mg oral valacyclovir tid and 0% of genital 
HSV patients on oral valacyclovir suppression with 1000 mg daily.  Dehydration contributes to nephrotoxicity. 


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Study participants will be provided with a participant instruction sheet, which will include directions to maintain 
adequate hydration to decrease the likelihood of nephrotoxicity.   
 
In a report of a population based study conducted in Canada with over 160,000 patients age 66 years or older, 
patients treated with the oral dose of acyclovir and valacyclovir used for acute HZ were compared to patients 
treated with famciclovir, with regard to the outcome of hospitalization within 30 days for acute kidney injury, 
and the risk was no higher with acyclovir and valacyclovir than famciclovir, a drug not known to be associated 
with renal toxicity (52).  In this study, acute kidney injury occurred in less than 1% of patients (0.27% of 
acyclovir or valacyclovir treated patients and 0.28% of famciclovir treated patients). Risk factors for acute 
kidney injury included higher age (patients age 85 years or older: 0.62% in acyclovir/valacyclovir group and 
0.71% in famciclovir group) and chronic kidney disease (1.46% in acyclovir/valacyclovir group and 1.86% in 
famciclovir group).  Acute kidney injury related to acyclovir/valacyclovir is associated with birefringent needle 
crystals on urinalysis.  
 
Although renal toxicity is an expected complication of valacyclovir, the frequency and severity of new or 
worsening renal disease will be monitored to determine if it is more common than expected.  Study participants 
with follow-up eGFRs less than 45, or who develop urinary symptoms, will be referred to their primary care 
doctors for evaluation, including urinalysis to detect crystals, and management. 
 
Valacyclovir and Pregnancy  
Antivirals including valacyclovir (Category B) are used during pregnancy only if the potential benefit outweighs 
potential risk to the fetus.  Women of reproductive age will need to agree to use a recommended form of 
contraception during the one year of study treatment, and pregnant women will be excluded by pregnancy 
blood testing within one month after a menstrual cycle prior to enrollment/randomization visit. Nursing women 
will be excluded.  Study participants who become pregnant during the study will be withdrawn from the study 
medication and continue to be followed.  
 
Valacyclovir and Central Nervous System (CNS) Reactions   
The package insert contains a warning that agitation, hallucinations, confusion, encephalopathy, delirium and 
seizures can occur in patients taking valacyclovir, and that elderly patients are more likely to have these 
problems.  HZO can also be complicated infrequently by central nervous system (CNS) vasculopathy (stroke).   
Study participants who have CNS adverse events will have their study medicine discontinued, at least 
temporarily, and be referred for neurological evaluation and treatment.  If the treating physician thinks the 
safety of the study participant is an issue, the 24/7 help line is available, and, if necessary, to differentiate 
between drug and disease related CNS disease, the medical monitor can initiate the process to unmask study 
medication (see Manual of Procedures, MOP).  CNS complications of HZ are thought to be rare, but may be 
under-diagnosed, and additional information regarding their frequency may be obtained in the placebo 
treatment arm of the study.  
 
Valacyclovir and Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)  
The package insert has a warning that TTP/HUS has occurred in patients with advanced HIV disease and 
bone marrow or renal transplant recipients on 8 grams per day of valacyclovir, a dose used for 
cytomegalovirus, not herpes zoster or simplex.  Since immunocompromise is an exclusion criterion and the 
dose of valacyclovir is much lower, 1 gram per day, TTP/HUS will be considered an unanticipated and serious 
adverse event in this study.   
 


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Protections Against Risk 
The investigational plan is specifically designed to manage and minimize risks through careful selection of 
study participants and suppressive antiviral treatment regimen, thorough training of study investigators and 
coordinators, adherence to the pre-determined time points to assess study participant clinical status, and 
regular clinical monitoring by study Coordinating Center (CC) personnel and the Data and Safety Monitoring 
Committee (DSMC). Suppressive treatment with valacyclovir 1000 mg daily of immunocompetent individuals 
age 18 years and older is FDA approved and recommended for herpes simplex virus (HSV) genital disease.  
This study evaluates the efficacy and safety of valacyclovir, at the same dose used for HSV suppression, for 
study participants with a different diagnosis, HZO, for which valacyclovir is approved at a higher dose, for a 
short duration.  HZO patients are generally older than HSV patients, with approximately mean age of onset of 
HZO of 52 years compared to ocular HSV with a mean age onset of 37 years (2, 4, 53).  
  
In order to minimize risks of valacyclovir in an older population of study participants, a baseline eGFR will be 
obtained prior to enrollment. If the eGFR is 60 or more, i.e. normal, it will not be repeated for study purposes. 
In order not to unfairly exclude many elderly study participants by requiring an eGFR of 60 or more, a baseline 
eGFR of 45 or more is an eligibility criterion. Study participants with eGFRs between 45-59 will have repeat 
eGFR testing every 3 months during treatment with the study drug. If the eGFR decreases to less than 45, the 
eGFR will be repeated. If repeat eGFR is 45 or more, the study medication will be continued, and the eGFR 
will be repeated prior to the next study visit.  If on repeat testing the eGFR is less than 45 the study medication 
will be discontinued.  Study participants will be told to see their primary care doctor and have eGFR test 
repeated monthly until it is 45 or more. The study medication will not be restarted, and the participant will 
continue to be followed for safety assessments.  
 
There are no known study-related risks in addition to the use of the study medication, oral valacyclovir and 
blood testing. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
 
It is unknown whether prolonged suppressive antiviral treatment with valacyclovir reduces complications of 
HZO, including ocular disease and PHN, although oral antiviral medication is prescribed by approximately 30% 
of corneal specialists according to one study, and reported effective in significantly reducing episodes of 
recurrent HZO disease in another recent observational study (1, 24).  If this study determines that valacyclovir 
is effective and safe in reducing complications of HZO, study participants randomized to receive valacyclovir 
may directly benefit, as well as future HZO patients treated using this evidence.  If the study treatment is 
effective and safe in decreasing the severity, duration and frequency of PHN after HZO, this may be 
generalizable to HZ in other locations, and benefit many patients with PHN.  If suppressive antiviral treatment 
is ineffective or study participants receive placebo treatment, participants will not directly benefit from 
participation in this research.  If treatment is ineffective, its current ad hoc usage in the absence of evidence 
will be reduced.  
 
3 
OBJECTIVES AND PURPOSE 
 
The objective of this double-masked, multicenter placebo controlled RCT is to evaluate whether or not 
prolonged suppressive oral antiviral treatment with valacyclovir 1000 mg/daily reduces complications of HZO, 
in immunocompetent study participants, compared to treatment with placebo and standard care without 
prolonged systemic antiviral treatment, thereby improving the outcomes in this common and potentially vision 


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and life-threatening disease. Valacyclovir, a prodrug of acyclovir, has been chosen as the antiviral agent to be 
used in the trial due to its superior bioavailability. 
 
Central Hypothesis:  
Prolonged suppressive oral antiviral treatment with valacyclovir 1000 mg daily, compared to placebo, will be 
effective in reducing complications and in improving clinical outcomes in HZO.  
 
Primary Objective:  
The primary objective is to test the hypothesis that long-term suppressive antiviral therapy can reduce 
complications of HZO by conducting a double-masked, placebo-controlled RCT of oral valacyclovir 1000 mg 
daily.  Specifically, we will evaluate whether or not long term suppressive antiviral therapy compared with 
placebo therapy delays the time to the first occurrence of new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis (accompanied by prespecified changes in treatment; see 
MOP) by 12 months (primary endpoint) in immunocompetent study participants with HZO who have a history of 
one of these disease manifestations within the year prior to enrollment. The primary endpoint is measured by 
the time to first occurrence of any one of these specified complications associated with pre-specified treatment 
– see MOP. 
 
Secondary Objectives: 
The secondary objectives are: 
 
to evaluate  the effect of treatment on the primary endpoint at 18 months (6 months after the 
completion of study drug treatment)  
o by comparing  the rates of new or worsening dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis in study participants randomized to valacyclovir versus placebo 
o by comparing time to development of the primary endpoint over the 18-month period from 
randomization and  
o by comparing the occurrence of the primary endpoint during the 6-month post treatment period.  
 
to test the hypothesis that suppressive treatment for 12 months with oral valacyclovir 1000 mg daily 
reduces the incidence, severity and duration of post herpetic neuralgia (PHN) compared to placebo 
at 12 and 18 months in study participants with HZO. 
 
to test the hypotheses that vaccination against herpes zoster with the Recombinant Zoster Vaccine 
(RZV) may impact the natural history of HZO, and that suppressive antiviral treatment with 
valacyclovir 1000 mg daily compared to placebo may alter the impact of this vaccination on HZO 
activity during 12 months of study treatment.   
 
See sections 4.2.2 for details regarding additional objectives. 
 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
 
The study is a double-masked, multi-center RCT that will enroll immunocompetent study participants age 18 
years and older who have HZO diagnosed at variable times in the past, with an episode of dendriform epithelial 
keratitis, stromal keratitis, endothelial keratitis, and/or iritis within one year of enrollment.  Eligible study 
participants will be randomized in a 1:1 ratio to long-term suppressive treatment with oral valacyclovir 1000 mg 


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daily or placebo for one year, and followed every 3 months for a total of 18 months, to determine outcomes of 
new or worsening anterior segment ocular disease (e.g. dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis) and/or severity and duration of postherpetic neuralgia during 12 months of 
treatment and for 6 months following treatment discontinuation. Within each center, participants will be 
randomized within four strata, defined by age at onset of HZO (less than 60 years or 60 years and greater) and 
by recent onset or chronic HZO (recent onset defined as HZO diagnosed within 6 months of enrollment/ 
randomization, or chronic defined as HZO diagnosed 6 months or more prior to enrollment/randomization). 
 
4.2.1 
PRIMARY ENDPOINT 
 
The primary endpoint is the time to first occurrence of new or worsening episode of dendriform epithelial 
keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to HZO, requiring pre-specified changes in 
treatment (see MOP) during the twelve months of treatment.  The primary endpoint is compared for 
participants randomized to study medication or placebo. 
 
To assess the primary objectives, study participants will be monitored at each visit for new or worsening of any 
of the following conditions  
1. Dendriform epithelial keratitis 
2. Stromal keratitis 
a. Without ulceration  
b. With ulceration  
3. Endothelial keratitis  
4. Iritis 
The endpoint of first occurrence of new or worsening dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis will be determined by clinical examination requiring pre-specified changes  in 
treatment for the same disease manifestation (see MOP for definition), as there are no validated confirmatory 
biomarkers or other tests.  Primary endpoints will be reviewed by Clinical Event Review Committee (CERC).  
See MOP.    
 
4.2.2 
SECONDARY ENDPOINTS 
 
To assess the secondary objectives, the study participants will be monitored at each visit for the following 
events: 
1. Time to development and number of episodes of new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis due to HZO, requiring pre-specified changes in 
treatment (see MOP), during the 18 months following randomization, that includes the 6 months 
following cessation of treatment; and during the 6 months following the end of the 12 month 
treatment period.  
2. The incidence, severity, and duration of PHN at one year of treatment, and after the 6-month post-
treatment follow up.   
3. Impact of Recombinant Zoster Vaccine (RZV) vaccination on primary endpoints during 12 months 
of study treatment.   
 


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4. Development of specific manifestations of HZO, classified as dendriform epithelial keratitis, stromal 
keratitis (all types), endothelial keratitis, iritis requiring pre-specified changes in treatment (see 
MOP), neurotrophic keratopathy with or without melting and/or microbial superinfection, episcleritis, 
and/or scleritis during the twelve months of treatment.  
5. Secondary glaucoma determined by IOP and treatment required. 
 
4.2.3 EXPLORATORY ENDPOINTS 
 
1. Changes in strength and/or frequency of prescribed topical corticosteroids at 12 and 18 months. 
2. Occurrence of stroke 
3. Occurrence of temporal arteritis/giant cell arteritis 
4. Occurrence of myocardial infarction 
5. Occurrence of new or worsening malignancy 
a. Solid tumor (other than non-melanoma skin cancer) 
b. Hematologic malignancy 
c. Lymphoma 
6. Time to development and number of episodes of new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis due to HZO, with a recent substantial reduction in 
treatment during 12 months of treatment. 
7. Impact of suppressive antiviral treatment prior to enrollment on study outcomes.  
 
Rates of these events will be estimated among study participants randomized to valacyclovir and placebo.   
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible for study participation, an individual must meet all of the following criteria:   
1. Ability to understand, and willingness and ability to read and sign, the informed consent form. 
2. Ability to understand and follow instructions and study procedures. 
3. Willingness to comply with all study procedures and be available for the duration of the study. 
4. Ability to take oral medication, and are willing to adhere to study medication regimen. 
5. Age 18 years or older.  
6. Diagnosed with HZO in one eye based on both of these criteria: 
a. History of characteristic unilateral, usually vesicular, HZO rash in the dermatomal distribution of 
cranial nerve V1 or V2.  
b. Medical record documentation of an episode of active dendriform epithelial keratitis, stromal 
keratitis, endothelial keratitis, and/or iritis due to HZO within the preceding year.  This episode of 
active anterior segment ocular disease may be due to HZO of recent onset (within the preceding 
6 months); or chronic HZO (with onset six or more months ago); may be new, worsening, or 
recurrent disease after a period of inactivity; and may occur after medication was reduced.  
i. 
Study participants with chronic HZO must be on a stable treatment regimen and off antivirals 
for at least 30 days before enrollment.  Study participants with chronic HZO who do not 
meet this criterion may be rescreened, if they are able to meet this criterion within 3 months 
after the study visit.   


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This is not a requirement for study participants with recent onset HZO, who may be 
enrolled at any time, preferably after completing recommended acute antiviral 
treatment, if prescribed, is completed.  They can be on variable dose of steroids, and 
only need to be off oral and topical antivirals by the enrollment visit.  
7. For females with reproductive potential, willingness to use highly effective contraception (e.g., 
hormonal contraception, barrier contraception, intrauterine device, or abstinence). 
 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. History of immunocompromised status as defined by current CDC contraindications for the vaccine 
against zoster (44). 
a. Study participants who are diagnosed with leukemia, lymphomas or other malignant neoplasms 
affecting bone marrow or lymphatic system, unless leukemia in remission and off chemotherapy 
for at least 3 months. 
b. Study participants who are diagnosed with Acquired Immune Deficiency Syndrome (AIDS) or 
presents with other clinical manifestations of Human Immunodeficiency virus (HIV) including 
CD4 count of ≤ 200 cells/ml. 
c. Study participants on immunosuppressive therapy including: 
i. 
High-dose corticosteroids (greater than equivalent of prednisone 20 mg/day within 1 month) 
ii. 
Chemotherapy, other than low dose used for treatment of immune-mediated diseases 
within 3 months 
iii. 
Study participants receiving recombinant human immune mediators and immune 
modulators, especially antitumor necrosis agents, within 1 month prior to enrollment 
d. Study participants with unspecified cellular immunodeficiency. 
e. Study participants with history of hematopoietic stem cell transplantation. 
2. Medical history of a systemic disease and thought likely to meet one of the exclusion criteria listed 
in exclusion criterion #1 during the 18-month study period.  
3. Renal insufficiency: 
a. Requires dialysis or has history of renal transplant or 
b. eGFR less than 45, determined within 3 months preceding enrollment. 
4. Allergy or adverse reaction to valacyclovir or acyclovir. 
5. History of vaccination against zoster within one month prior to enrollment.  Study participants who 
meet this exclusion criterion may be screened and enrollment delayed until eligible within 3 months.  
If the study participant receives the Herpes Zoster Subunit vaccine (Recombinant Zoster Vaccine 
(RZV), Shingrix), rescreening should take place one month after the second required dose of the 
vaccine. 
6. Keratorefractive surgery, other than limbal relaxing incisions or astigmatic keratotomies at the time 
of cataract surgery, within 5 years of enrollment, or keratoplasty of the involved eye with zoster.  
7. On systemic antivirals with activity against herpes within the past 30 days, including acyclovir, 
valacyclovir, or famciclovir, for any reason except for treatment of recent onset HZO, including 
investigational drug trial. 
8. History of another condition that may require treatment with one of these three antivirals listed 
above in exclusion criterion #7, during the course of the study; study participants who require 
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9. Sexually active women who are pregnant, nursing, or in their reproductive years who do not agree 
to use contraception during the 1-year treatment period.  
10. Incarceration 
11. Any condition or circumstance that in the opinion of the study investigator, would place the study 
participant in increased risk or affect his/her full compliance or completion of the study. 
12. Participation in a clinical study testing a drug, biologic, device or other intervention within the last 30 
days from enrollment visit. Study participants who meet this criterion may be rescreened. 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The study protocol, informed consent form, recruitment materials and all participant materials will be submitted 
to the responsible Institutional Review Board (IRB) registered with the US Office for Human Research 
Protections (OHRP) under a Federal Wide Assurance (FWA) for review and approval.  
 
Eligible study participants will be identified by study investigators and coordinators at Participating Clinical 
Centers (PCC) by retrospective (e.g. computerized search of HZO diagnostic codes) and prospective methods 
(e.g. advertising, referrals from other doctors).   All recruitment methods, advertising and materials will be 
submitted to responsible IRBs prior to release.  Potential study participants may be contacted through IRB 
approved communication methods. Pre-screening interview questionnaires and screening logs to assess 
patient eligibility and interest, together with materials to be used for collection of patient information prior to the 
consenting process will be submitted to responsible IRBs for review and approval. (See MOP for recruitment 
and retention strategies.)  
 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
Study participants may voluntarily withdraw from study participation at any time upon request.  
 
Study participants will be followed for a minimum of 12 months and through the final visit, approximately 18 
months after enrollment, whether or not they have reached the primary endpoint of time to the development of 
the first occurrence of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, 
and/or iritis, or discontinue the study medication.  Every effort will be made to collect this follow up information. 
Study participants who withdraw without an event will be considered censored in the analyses. 
 
A study participant may be withdrawn, if, the study investigator determines that an event or medical condition 
has occurred that would make continued study participation not in the best interest of the study participant.   
 
Efforts will be made to refer study participants to another PCC if they move or are away at the time of study 
visits.  All efforts should be made to locate or communicate with study participants who have missed study 
visits. (e.g. contact by telephone, written communication, text, email, through participant’s family, friends or 
healthcare proxy which were provided by study participants to PCC, to determine if outcome events have 
occurred.)  
 
 


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5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the study chair, funding agency, the IND sponsor and the FDA.  If the study 
is prematurely terminated or suspended, the study chair will promptly inform the IRB and the PCC principal 
investigators, and will provide the reason(s) for the termination or suspension. Circumstances that may warrant 
termination or suspension include, but are not limited to:   
 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the sponsor, IRB and/or FDA. 
 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 
ACQUISITION 
 
The CC at NYULMC will purchase 500 mg pills of lactose-free generic valacyclovir and have them sent to a 
drug manufacturer for over encapsulation. An over encapsulated matching pill will be backfilled with similar 
excipients contained in the active agent to create the matching placebo pill.  Both active and placebo pills will 
be sent to a Drug Distribution Center (DDC). The DDC will receive, store, and dispense study medication to 
PCCs.  Upon receipt of the of the study treatment supplies in individually labeled bottles at the PCC, drug 
handling and accountability procedures must be followed (see MOP).   At the time of randomization, the 
appropriate drug supply will be dispensed to study participants.  The study medication is dispensed only after 
eligibility is confirmed and study participant age at onset of HZO and duration of HZO at time of enrollment/ 
randomization is provided to the Electronic Data Capture web-based interactive computer system.  At the 3, 6, 
9, and 12-month follow-up visit, unused pills will be counted by the coordinator at the PCC.  Unused drug will 
be returned to the ZEDS CC for disposal; PCCs can dispose of the unused drug on site if they have a policy 
compliant with applicable regulations. 
There will be reconciliation of drug shipped, drug consumed, and drug remaining at each PCC as specified in 
the MOP.  
 
 
 


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6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Valacyclovir was approved for the treatment of HSV and HZ in 1995, and has been available as a generic drug 
since 2009. (See MOP and MOP appendix: FDA package label for drug information).  Generic study drug will 
be purchased from a manufacturer. 
 
The drug manufacturer will deliver the study drugs to a DDC. The DDC will label and distribute the study 
medication to the PCCs as directed by the CC at NYUSoM. The DDC will repackage the masked study 
medication (active or placebo) into bottles with child-resistant caps and tamper-foil seals. 
 
Study participants will be given a sufficient supply of encapsulated study medication in labeled bottles at the 
enrollment, 3, 6, and 9-month follow-up visits.  Each bottle of study medication will be labeled to ensure 
masking and provision of study medication in accordance with randomization assignment. The study label will 
also state the expiration date. (See MOP) 
 
6.1.3 
PRODUCT STORAGE AND STABILITY 
 
The study medication is to be stored at room temperature 15 to 25°C (59 to 77°F) in a secure location (e.g. 
locked cabinet, restricted access pharmacy) accessible only to designated staff at the PCC (see MOP for drug 
storage, drug stability, expiration time, or instructions for when bottle seal is broken). 
 
6.1.4 
PREPARATION 
 
No further preparation of the study medication is required by study staff or study participant. 
 
6.1.5 
DOSING AND ADMINISTRATION 
 
Eligible study participants will be randomized in a 1:1 ratio to suppressive treatment with oral valacyclovir 1000 
mg daily or placebo for one year.  Study participants will be followed every 3 months for a total of 18 months, 6 
months following completion of the 12-month treatment period.  Study participants will be instructed to take 2 
pills once daily.   
 
6.1.6 
ROUTE OF ADMINISTRATION 
 
Study medication will be taken by study participants orally. 
 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE 
 
The starting dose of valacyclovir is 1000mg daily. There is no dose escalation. 
 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
Study investigators will be trained and study participants will be instructed regarding dose adjustments of study 
medication.  


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Use of Divided Dose of Study Medication for Intolerance  
If the study participant has mild to moderate side effects to the study medication, the medication may be 
temporarily discontinued.  The study participant may take one pill twice daily, instead of two pills once daily, as 
it may be better tolerated. 
 
Use of Reduced Dose of Study Medication for Intolerance 
If the study participant has mild to moderate side effects to the study medicine when taken in divided doses, 
the medication may be temporarily discontinued.  The study participant may take a reduced dose of one 
capsule daily.  
 
Discontinuation of Study Medication due to Intolerance 
If intolerance to the study medication is moderate or worse after restarting the study medication in divided 
doses and reducing the dose, the study medication will be permanently discontinued. The study participant will 
be treated at the discretion of ophthalmologists involved in their care, and continue to be followed.  Open label 
use of other antivirals after study medication is discontinued will be collected and monitored. 
 
Discontinuation of Study Medication  
If the study participant develops a contraindication to valacyclovir during the course of the study (See 5.2.).The 
study medication will be permanently discontinued and the study participant will continue to be followed.   
 
Discontinuation due to Pregnancy 
 
If a study participant becomes pregnant, the study medication will be discontinued and the study participant will 
continue to be followed. If a study participant thinks she may be pregnant, a pregnancy test will be performed.  
 
Discontinuation due to Worsening Chronic Kidney Disease  
 
If a study participant develops worsening chronic kidney disease with confirmed eGFR less than 45, the study 
medication will be discontinued and the study participant will continue to be followed.  
 
Discontinuation due to Acute Kidney Failure  
 
If a study participant develops acute kidney failure, and requires temporary or permanent dialysis, the study 
medication will be discontinued and the study participant will continue to be followed.  
 
Temporary Discontinuation due to Vaccination Against Zoster 
 
If the study participant decides to get the Zoster Vaccine Live (ZVL),Zostavax, manufactured by Merck) against 
zoster, the study medication will be discontinued one day before and resumed one month after vaccination.  If 
the study participant gets the Recombinant Zoster Vaccine (RZV), also referred to as the herpes zoster subunit 
vaccine  (Shingrix manufactured by Glaxo Smith Kline), the study medication is to be  continued. As of 
January, 2018 the CDC recommends the RZV as preferred over ZVL.  
 
Temporary or Permanent Discontinuation due to Use of Open Label Oral Valacyclovir, Acyclovir or 
Famciclovir Treatment for Other Conditions  


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 
If the study participant develops ocular, orofacial, or genital HSV disease and requires a short term 
(maximum two weeks) course of oral antiviral treatment, the study medication will be temporarily 
discontinued during this treatment, and resumed afterwards. If the study participant requires long-
term antiviral treatment for HSV, the study medication will be permanently discontinued, the 
participant will continue to be followed in the study, and the study medication will not be unmasked.  
 
If study participant develops HZ in another anatomical location, study medication will be 
discontinued, the participant will be given recommended acute antiviral treatment for 7 days, and 
then the study medication will be resumed. 
 
If study participant is diagnosed with central nervous system disease (including stroke) due to 
zoster, study medication will be discontinued while participant receives intravenous antiviral 
treatment, sometimes followed by a course of oral antiviral treatment, and resumed afterwards, if 
the treating neurologist agrees. The study participant will continue to be followed in the study. 
 
If study participant develops any other medical condition that necessitates treatment with 
valacyclovir, acyclovir, or famciclovir, the study medication will be discontinued while on open label 
treatment and resumed afterwards,. The open label treatment period should not usually exceed two 
weeks.  
 
Temporary Discontinuation due to Short-term (maximum two weeks) Open Label Use of Valacyclovir, 
Acyclovir or Famciclovir for HZO 
If the study participant develops a possible primary endpoint - new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis - and the study investigator thinks the study participant may 
benefit from a one to two-week course of open label oral antiviral treatment, the study medication will be 
temporarily discontinued, and resumed when the course of open label treatment is completed.  (After a study 
participant develops a possible primary endpoint, if topical antiviral treatment is prescribed, the study 
medication is continued.) 
 
Permanent Discontinuation due to Prolonged Open Label Use of Valacyclovir, Acyclovir or Famciclovir 
for HZO 
If the study participant develops a possible primary endpoint - new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis - and the study investigator thinks the participant may benefit 
from prolonged open label antiviral treatment, the study medication will be discontinued, and the participant will 
continue to be followed.  Any open label use of antivirals will be collected and centrally monitored. 
 
6.1.9 
DURATION OF THERAPY 
 
The duration of therapy is one year (12 months) from study enrollment/randomization.  All study participants 
randomized will be included in the analyses of the primary efficacy endpoint in this intent to treat trial.     
 
6.1.10 
TRACKING OF DOSE 
 
At the 3, 6, 9, and 12-month follow-up study visits, study participants will return the study medication bottles 
with all unused study medicine and completed diary cards.  Unused pills will be counted by PCC study staff to 
determine compliance.  Diary cards will be provided to study participants to enhance compliance (see MOP).  
The importance of compliance will be included on the participant instruction sheet and will be discussed at 
each study visit during the one year of treatment by the study investigator and coordinator (see MOP).  
 


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6.1.11 
DEVICE SPECIFIC CONSIDERATIONS 
 
Not applicable. 
 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
 
Study medication will be sent to the PCCs by the DCC in masked labeled bottles.  Designated study staff at the 
PCCs will distribute the medication to participants at Visits 2, 3, 4, and 5, and will be required to complete 
relevant drug accountability documents (see MOP).  Study participants will be asked to return the medication 
bottles and any unused medication at study visits 3, 4, 5 and 6. 
 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 
STUDY SPECIFIC PROCEDURES  
  
The following procedures will be performed for study-specific purposes: 
 
Review of inclusion/exclusion criteria for eligibility 
 
Informed consent 
 
Collection of demographic information 
 
eGFR and Pregnancy Tests 
 
Collection of HZO treatment information 
 
Randomization: Eligible participants will be randomized to receive either valacyclovir or matching 
placebo. 
 
Study specific history: assessment of post herpetic neuralgia using question #3 of Zoster Brief Pain 
Inventory (ZBPI) 
 
Study specific ophthalmic exam of the eye with HZO 
 
Completion of medical event form 
 
Collection of information regarding any serious adverse events (SAEs) 
 
Assessment of study adherence:  counts of returned unused pills and study participants diary card 
records. 
 
Monthly contact between study visits, eg. telephone, email, text, or letter is encouraged.  (See 
MOP) 
 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
 
The following procedures will be performed as standard of care: 
 
 
History and exam of zoster eye unrelated to zoster  
 
History and exam of the non-zoster eye 
 
History and exam at visits other than required study visits  
 


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7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS  
 
The following laboratory procedures/evaluations will be performed at the study participant’s closest study 
designated diagnostics laboratory, or local laboratory when necessary: 
 
 
Blood test for eGFR prior to enrollment: All study participants will be asked to obtain a serum 
creatinine blood test for eGFR determination. Measurement of creatinine to calculate eGFR will not 
be required if it has been completed in the past 30 days and the results are available for 
investigator review. Subjects with an eGFR of 45-59 will be enrolled in the study, but asked to have 
repeat testing at intervals throughout the study, as described in section 7.3. This is a study-specific 
procedure and is not standard of care. 
 
Blood test for pregnancy prior to enrollment:  Women of childbearing potential will be asked to take 
a pregnancy test. During the study, women who are able to become pregnant must agree to use a 
medically accepted method of birth control, including hormonal methods, barrier method, 
intrauterine device, or abstinence, while on the study drug. This is a study-specific procedure and is 
not standard of care. 
 
Urinalysis: For study participants with acute kidney disease to look for crystals associated with 
valacyclovir. 
 
A urine dipstick test for pregnancy will be conducted by PCC study staff if a study participant 
suspects pregnancy at the time of a study visit. 
 
7.2.2 OTHER ASSAYS OR PROCEDURES 
 
Not applicable. 
 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
 
Not applicable. 
 
7.2.4 
SPECIMEN SHIPMENT 
 
Not applicable. 
 
7.3 
STUDY SCHEDULE 
 
7.3.1 
SCREENING/CONSENT  
 
HZO patients who are thought likely to be eligible for the study on the basis of an eligibility checklist and review 
of their medical records by the study investigator and/or coordinator will have a screening visit. The following 
will be performed/obtained:  
 
 
The consent form will be reviewed and signed.  


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 
Study specific review of medical records.  
 
Study specific review of demographics. 
 
Review of study inclusion/exclusion criteria. 
 
Blood test for eGFR ordered. 
 
Blood test for pregnancy order for women of child bearing potential  
Measurement of creatinine to calculate eGFR will be ordered within 30 days of enrollment, unless it has 
already been obtained within this time period. If the eGFR is 45 or more, the study participant is eligible for 
enrollment. If the eGFR is 45-59, it will be repeated within 30 days of the 3, 6, 9, and 12 month study visits.  
 
If a woman of child-bearing potential who has provided written informed consent is found to be eligible and is 
interested in participating in the study, a pregnancy test will be ordered   A negative pregnancy test is required 
within 30 days, preferably within 2-3 days of enrollment and after a menstrual cycle.   
 
The eGFR and pregnancy tests are study-related procedures and not part of routine care. During the study, 
women who are able to become pregnant must agree to use a medically accepted method of birth control, 
including hormonal methods, barrier method, intrauterine device, or abstinence, while on the study drug. 
 
7.3.2 
ENROLLMENT/RANDOMIZATION  
 
At the enrollment/randomization visit, the following will be performed/obtained: 
 
 
Study specific history of HZO treatment.  
 
Study specific ophthalmic exam, including: routine visual acuity and manifest refraction, (not 
standardized or by certified technician) anterior segment ophthalmic exam, measurement of corneal 
thickness, dilated fundus exam and pachymetry of study eye. 
 
Study specific review of inclusion/exclusion criteria. 
 
Study specific post herpetic neuralgia score and review of medication history for PHN. 
 
Randomization: Study participants who have provided written consent and meet study entry criteria 
will be randomized within center to one of the four strata depending on their age at the onset of 
HZO (age less than 60 years compared to 60 or older) and duration of HZO at the time of 
enrollment and randomization (less than 6 months compared to greater than or equal to 6 months). 
 
Study participants will be dispensed an adequate supply of study medication consistent with 
randomization assignment and will receive instructions to take 2 pills once daily, in addition to any 
other medication(s) (See MOP). 
 
Study participants will receive instructions to maintain adequate hydration to decrease the likelihood 
of nephrotoxicity (See MOP). 
 
Study participants will a diary to record when study medication is taken. 
 
If the baseline eGFR was 45-59, the study participant will be given a prescription for repeat testing 
prior to their next visit.  
 
An appointment to return during a specified window of days for their three-month follow-up visit will 
be scheduled.  
 
The importance of compliance with the study medication and visits will be emphasized. Study participant’s 
contact information will also be confirmed at each study visit (see MOP).  
 


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7.3.3 
FOLLOW-UP STUDY VISITS  
 
Study visit number at 3, 4, 5 occurring at months 3, 6, and 9 after enrollment:  
At the follow-up visits, the following activities will occur/be performed: 
 
 
Study specific history of HZO treatment. 
 
Study specific anterior segment ophthalmic exam. 
 
Assessment of post herpetic neuralgia score and review of medications taken for PHN. 
 
Returned study medication pills will be counted to assess medication compliance.  Diaries will be 
returned. 
 
Assessment for possible medical events of interest 
 
Assessment for possible primary endpoints. 
 
Assessment for possible SAEs. 
 
Study participants will be dispensed an adequate supply of study medication and will receive 
instructions to take 2 pills once daily. in addition to any other medication(s).  At the discretion of the 
investigator, dosage may be adjusted to one pill twice daily or once daily and appropriate study 
participant instruction sheet will be provided (see MOP). 
 
Study participants will receive a diary to record when study medication is taken. 
 
If the study participant had a baseline eGFR of 45-59 repeat eGFRs will be completed prior to the 3, 
6, 9 month study visits.  
o If eGFR is 45 or above, study medication will be continued.  
o If eGFR is less than 45, the study medication will be discontinued, and the eGFR will be 
repeated within one week. If on repeat testing the eGFR: 
 
is 45 or more, the study medication will be resumed, and eGFR will be repeated within 30 
days of the next study visit.  
 
is less than 45, study participant will be given a prescription to visit their local study 
designated laboratory for monthly eGFR testing until it is 45 or more. In addition, study 
participants will be told to see their primary care doctor for management of their kidney 
disease. The study medication will not be resumed, and the study participant will continue to 
be followed in the study.  
 
An appointment to return during a specified window of days for their three-month follow-up visit will 
be scheduled.  
 
The study participant will be instructed to continue their non-study treatment.   
 
The importance of compliance with the study medication and visits, will be emphasized at each study visit. 
Study participant’s contact information will also be confirmed at each study visit (see MOP).  
 
Visit 6 (12 month follow-up visit): 
 
At this visit, study medication will be discontinued. The visit will be the same as the 3, 6, and 9- month follow-
up visits, with the addition of: 
 
 
Study specific ophthalmic exam including direct fundus exam. If visual acuity is 2 or more lines 
lower than enrollment visual acuity, then a routine refraction will be done in the study eye. If visual 
acuity is not improved by a routine refraction, then a dilated fundus will be performed. 


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 
In study participants with enrollment eGFR 45-59, an eGFR test will be done prior to this visit: 
 
if 45 or above, will not be repeated (this is not part of routine care). 
 
If less than 45, eGFR will be repeated within one week. If on repeat testing the eGFR: 
o is 45 or more, it will not be repeated.  
o is less than 45, study participants will be given a prescription to visit their local study designated 
laboratory for monthly eGFR testing until it is 45 or more. In addition study participants will be 
told to see their primary care doctor for management of their kidney disease, and the study 
participant will continue to be followed.   
 
The study participant will be instructed to continue their non-study treatment.   
 
Visit 7 (15 month follow-up visit):  
 
The visit will be the same as the 3, 6, and 9- month follow-up visits (please note there is no study medication 
involved and eGFR testing is not repeated (see MOP).  
 
7.3.4 
FINAL STUDY VISIT 
 
Visit 8 (18 month final study visit) 
 
The visit is the same as the 15 month follow-up visit (Visit 7). This visit is the last study visit for the participant 
and the study completion form will be filled out (see MOP).  
 
7.3.5 
EARLY TERMINATION VISIT 
 
This visit is similar to the 18-month visit (See MOP). 
 
7.3.6 
NON-STUDY VISIT (UNSCHEDULED/SCHEDULED VISIT) 
 
At non-study visits, a standard office medical exam will be completed (routine care) (See MOP).  A CRF for 
non-study visit will be completed by the study staff.  Additional CRFs may be required if a primary endpoint 
may have occurred at the time of the non-study visit.  
 
7.3.7 
SCHEDULE OF EVENTS TABLE 
 
Source documents include medical records, images and all other information necessary to reconstruct and 
evaluate the clinical trial.  Study monitors will compare data entered in electronic CRF’s to information in 
source documents to verify the accuracy of trial data.   
 
Please see Table 1 for Schedule of Events. 
 
 
 
 
 
 


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Table 1:  Schedule of Events.   
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
 
Not applicable. 
 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
The FDA-approved label for the use of valacyclovir does not list contra-indications to the use of other 
medications concomitantly with valacyclovir. 
 
While it is recommended that study participants with HZO receive acute high dose antiviral treatment within 72 
hours of the onset of the rash for seven days, and study participants will be asked their history regarding this, it 
will not be required for entry into the study, as it would make many participants ineligible. Optimal medical 
treatment aside from acute antiviral treatment has not been determined for HZO. The study medication will be 
given to study participants in addition to standard treatment.  It is the purpose of this study to evaluate the 
efficacy of prolonged suppressive antiviral treatment, to determine whether it should become optimal medical 
therapy in the future.  Aside from the antiviral medications valacyclovir, acyclovir, and famciclovir, all other 
concomitant systemic medications are allowed during the study. Study participants who require topical steroids 
will be strongly recommended to be treated with prednisolone acetate 1% or loteprednol 0.5% at the discretion 
of their study investigator. Study participants who develop dendriform epithelial keratitis will be recommended 
to be treated with topical ganciclovir (0.15%) five times daily until healed and then two times daily for two 
weeks.  These topical steroids and antiviral medications are standard care. 
 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Not applicable. 
 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Until a possible primary outcome is reached open label treatment of HZO eye disease with oral valacyclovir, 
acyclovir, or famciclovir is prohibited for duration of the study (i.e. 18 months).  
 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Not applicable. 
 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
Not applicable. 
 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
 
Following completion of the 18-month study the study participant will return to the care of their ophthalmologist 
and treated at their physician’s discretion. 


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8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
It is the responsibility of the PCC Principal Investigator (PI) to oversee the safety of the study at his/her center. 
This safety monitoring will include training, careful assessment and appropriate reporting of serious adverse 
events (see MOP). 
 
The CC monitoring of serious adverse events will be reviewed by masked medical monitors. These medical 
monitors will also have the ability to unmask treatment if required in an emergency for study participant safety 
(see MOP). 
 
At each contact with the study participant, the PCC study investigator or designated study team member will 
assess for possible medical events of interest, possible primary endpoints and for possible SAEs (see MOP).  
 
8.1.1 
COLLECTION OF SELECTED ADVERSE EVENTS (AE) 
 
Adverse events that result in temporary or permanent discontinuation of study medication will be required to be 
reported by the PCC to the CC as appropriate.  
 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
  
Serious, unexpected adverse events related to the study treatment will be primary safety endpoints. A serious 
adverse event is any untoward occurrence that: 
 
 
Results in death. 
 
Is life threatening; (a nonlife-threatening event which, had it been more severe, might have become 
life-threatening, is not necessarily considered a serious adverse event). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
Is a congenital anomaly or birth defect. 
 
Is considered a significant medical event by the study investigator based on medical judgment (e.g., 
may jeopardize the study participant or may require medical/surgical intervention to prevent one of 
the outcomes listed above). 
 
The occurrence of the SAE acute kidney failure, defined as requiring temporary or permanent 
dialysis, will be a safety endpoint.  
 
8.1.3 
DEFINITION OF UNANTICIPATED (UNEXPECTED) PROBLEMS  
 
OHRP considers unanticipated problems involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria:  
 


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 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied;  
 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research). 
 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.  
 
This study will use the OHRP definition of unexpected/unanticipated problems.  
 
The determination that a serious adverse event is related to the study treatment is initially made by the study 
investigator, reviewed by the medical monitor and DSMC. 
 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 
SEVERITY OF EVENT 
 
Events that result in temporary or permanent discontinuation of study medication will be recorded on 
appropriate study eCRF (See MOP).  
 
The intensity (or severity) of events will be rated on a three-point scale:  
 
Mild: Events that require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
 
Moderate: Events that result in a low level or inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. Mild or moderates side 
effects to study medication may result in temporary or permanent discontinuation without being a 
serious adverse event.  
 
Severe: Events that interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event is not necessarily 
serious. For example, itching for several days may be rated as severe, but may not be clinically serious. 
 
8.2.2 
RELATIONSHIP TO STUDY AGENT 
 
The study investigator will assess the relationship of any serious adverse event or adverse events that lead to 
discontinuation of study medication to be related or unrelated by determining if there is a reasonable possibility 
that the reported event may have been caused by the treatment. To ensure consistency of AE/SAE causality 
assessments, study investigators should apply the following general guideline when determining whether an 
AE/SAE is related: 
 
 
Related:  There is a plausible temporal relationship between the onset of the event and 
administration of the study treatment, and the event cannot be readily explained by the participant’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the event follows a known pattern 


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of response to the study treatment; and/or the event abates or resolves upon discontinuation of the 
study treatment or dose reduction and, if applicable, reappears upon re-challenge. 
 
Not related:  Evidence exists that the event has an etiology other than the study treatment (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the event has no plausible temporal relationship to study treatment administration (e.g., 
cancer diagnosed 2 days after first dose of study drug); and/or an alternate etiology has been 
established. 
 
If necessary, the PCC PI or investigator will consult with CC in order to determine the relatedness of an 
AE/SAE. 
 
8.2.3 
EXPECTEDNESS  
 
The PCC PIs will be responsible for determining whether of any serious adverse event or adverse events that 
lead to discontinuation of study medication is expected or unexpected.  An AE/SAE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study agent in the package insert.  If necessary, the PCC PI or investigator will 
consult with CC in order to determine the expectedness of an AE/SAE. 
 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Serious adverse events (SAEs) occurring during the study period must be recorded.  SAEs that are related to 
the study medication that are still ongoing at the end of the study period must be followed up to determine the 
final outcome.  SAEs that occur within 30 days after study drug discontinuation will occur within the period of 
long-term follow-up as specified by the protocol. SAEs will be reported on a SAE form in the EDC system (see 
MOP). 
 
8.4 
REPORTING PROCEDURES 
 
8.4.1 
ADVERSE EVENT REPORTING  
 
Each PCC PI is responsible for adhering to the oversight and safety reporting requirements of their center’s 
Institutional Review Board or the central IRB. 
 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING  
 
Unexpected, related serious events must be reported to the CC immediately after the event comes to PCC 
staff attention via completion of the EDC SAE form.  If the study participant required hospitalization, the 
hospital discharge summary must also be sent to the CC.  In the event of problems with the online SAE form, 
the PCC PI or investigator will contact the CC.  CC staff will report these events to the applicable regulatory 
authorities within the required timelines (see MOP for details). 
 
Unexpected, related SAEs are reviewed by the Medical Monitor to verify the coding and the reporting that is 
required. These and all other reported SAEs are reviewed by the DSMC.  MedDRA coding conventions will be 
used. The CC will notify all PCC PIs of the DSMC findings and recommendations.   


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8.4.3 
UNEXPECTED/UNANTICIPATED PROBLEM REPORTING  
 
Incidents or events that meet the OHRP criteria for unexpected/ unanticipated problems require the notification 
of the CC. It is the site investigator’s responsibility to report unexpected/ unanticipated problems s to their IRB 
and to the CC.  
 
To satisfy the requirement for prompt reporting, unexpected/ unanticipated problems will be reported using the 
following timeline:  
 
unexpected/unanticipated problems that are SAEs will be reported to the CC within 24 hours of the 
investigator becoming aware of the event.  
 
It is the PCC PI’s responsibility to notify institutional officials and/or the IRB of unexpected/ 
unanticipated problems that are SAEs, as required. 
 
8.4.4 
EVENTS OF SPECIAL INTEREST  
 
Not applicable. 
 
8.4.5 
REPORTING OF PREGNANCY  
 
Women of child bearing will have a pregnancy test prior to enrollment, if it is positive they will be ineligible for 
the study. If a study participant thinks she may be pregnant the study staff will request that she immediately 
stop the study medication and have a pregnancy test. If the pregnancy test is positive the study medication will 
be stopped permanently; the study participant will be referred to see her doctor and will continue to be followed 
by the study staff. The study investigator will notify their PCC PI who will notify their IRB and the CC within 
seven (7) days. The CC will notify the DSMC and FDA within fifteen (15) days.  
 
The study investigator will have permission to follow the pregnant study participant to determine pregnancy 
outcome. 
 
8.5 
STUDY HALTING RULES  
 
A formal interim analysis is proposed and is described in the SAP.  In addition, a continuous sequential safety 
stopping rule is planned to monitor the study based on unexpected events.  In this study, the predominant 
safety concern is acute kidney failure.  The DSMC may recommend halting the study for safety, efficacy or 
other reasons (SAP). 
 
8.6 
SAFETY OVERSIGHT 
 
A DSMC has been appointed by the National Eye Institute (NEI) to monitor safety unmasked to treatment at 
regular intervals (at least once/6months). 
 
Safety oversight will be under the direction of the DSMC that is composed of individuals with the appropriate 
expertise, including ophthalmology, statistics, clinical trials and ethics.  The DSMC will meet at least 
semiannually to assess safety and efficacy data on each group of the study.  The DMSC will operate under the 


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rules of an approved charter that outlines the operating guidelines for the committee and the procedures for the 
interim evaluations of study data and will be written and reviewed at the organizational meeting of the DSMC. 
At this time, each data element that the DSMC needs to assess will be clearly defined.  The DSMC will provide 
advice to NEI.  The DSMC will monitor study participant safety and review performance of the trial. Reports will 
be prepared regularly in accordance with the plan outlined in the charter and as requested by the DSMC chair, 
and will include interim analysis(es) of primary and secondary endpoints; additional safety events; and other 
information as requested by the committee.  After each meeting, the DSMC will give advice to the NEI about 
the continuation of the study.  After approval by the NEI, a summary of the DSMC report and recommendations 
will be forwarded by the CC to investigators for submission to their local and central IRBs, as applicable.  
DSMC reports will be the primary mechanism for reporting safety concerns to NEI and IRBs. 
 
Sequential safety procedures (54) for life-threatening conditions in clinical trials will be employed. The 
unmasked study statisticians will be responsible for the oversight and implementation of this plan. Results will 
be provided to the DSMC.   
 
If study participant safety requires unmasking, such as in the event of overdose of study medication, 
unmasking will be available through a 24-hour helpline answered by a physician medical monitor.  Procedures 
for this unmasking and for its documentation are described in the MOP.  
 
9 
CLINICAL MONITORING 
 
PCC monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that the 
reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by ZEDS CC staff.  
 
The CC is the first line of contact for trial PCC staff and investigators regarding current protocol and CRF 
versions, forms, procedures, quality, monitoring, and other study components, ensuring PCC understanding 
and operationalization of the protocol, and successful identification of eligible patients for screening and 
enrollment, protocol adherence and study participant retention.  Substantial written correspondence and logs of 
phone conversations will be filed within the ZEDS mailbox.  All IRB related correspondence will be filed in the 
PCC’s file within the ZEDS Trial Master File (TMF).   
 
Study recruitment, enrollment, and retention are monitored based on reports generated by the data acquisition 
and management system.  Study screening information is reviewed by comparing the characteristics of study 
participants enrolled versus screened out, assisting with potential strategies to improve study enrollment. The 
ratio of screened to randomized participants is also reviewed.  Enrollment and visit attendance is also 
monitored on an ongoing basis by participant, by PCC, and for the overall study. 
   
Data performance indicators for each PCC and for the overall study are also reviewed. These include CRF-
level and field-level completeness, data accuracy, data entry timeliness, query resolution timeliness. Essential 
protocol adherence requirements are also monitored from the database.  Important components of adherence 
monitoring include ensuring that informed consents are signed and dated by the participant, confirming that 
study participants are re-consented in accordance with protocol specifications (if needed), and making sure 
that inclusion and exclusion criteria are met.  PCCs with study participants who have excessive missed  study 
visits, as well as data collected outside the permitted visit windows are identified, and participants who are not 


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adhering to protocol medication or treatment compliance requirements are identified and reported to the 
appropriate study personnel.  
 
A crucial part of data integrity monitoring is the ongoing review, monitoring and cleaning of study data for 
completeness and accuracy. During this process CC staff reviews trends in data collection patterns across 
centers.  Issues are flagged as they arise and resolved accordingly.  The data management staff will 
communicate these trends and data collection issues to NEI and study monitors at the CC to ensure that 
monitors are aware of the issues and can appropriately review and verify PCC data. 
 
This trial will utilize centralized, remote, and risk-based monitoring for regulatory, data and safety monitoring, 
along with onsite monitoring for specified source verification and risk management, for cause.  Initially the 
PCCs have been required to provide information related to the training of the study investigator, co-
investigators and coordinators, and past research experience.  The centers have also been assessed to 
determine the extent at which they have access to electronic medical records (EMR) and to electronic data 
capture (EDC).  If additional centers are added similar information will be obtained. 
 
The CC will ensure the training of monitoring personnel prior to initiation of study enrollment and as specified in 
MOP to ensure the monitoring plan is executed. This will include but not be limited to training of monitors on 
specific protocol requirements, monitoring plans, and standard operating procedures.  
  
Details of PCC monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP describes in detail 
who will conduct the monitoring, frequency of monitoring will be done, at what level of detail monitoring will be 
performed, and the distribution of monitoring reports. 
  
10 
STATISTICAL CONSIDERATIONS  
 
10.1 
STATISTICAL ANALYSIS PLAN 
 
A Statistical Analysis Plan provides a complete description of all statistical considerations and analysis plans 
(see SAP). 
 
10.2 
STATISTICAL HYPOTHESES 
 
The primary objective of this randomized controlled clinical trial is to test the hypothesis that long-term suppressive 
antiviral treatment for 1 year with oral valacyclovir 1000 mg daily delays the time to the first occurrence of new or 
worsening anterior segment ocular disease (dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, 
and/or iritis) compared to placebo by 12 months.   
 
The secondary objectives are (1) a) to test the hypothesis that long-term  suppressive antiviral treatment for 1 year 
with oral valacyclovir 1000 mg daily delays the time to the first occurrence of new or worsening anterior segment 
ocular disease (dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis) compared to 
placebo by 18 months; and b) to test the hypothesis that the occurrence of new or worsening disease in the 6 
months post treatment period is reduced for participants treated with valacyclovir compared to placebo; and (2) to 
test the hypothesis that suppressive treatment for 12 months with oral valacyclovir 1000 mg daily reduces the 


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incidence, severity and duration of post herpetic neuralgia (PHN) compared to placebo at 12 and 18 months in 
patients with HZO. 
 
To evaluate these hypotheses, the following endpoints will be evaluated:  
 
Primary Efficacy Endpoint: 
The primary endpoint is the time to first occurrence of new or worsening episode of dendriform epithelial 
keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to HZO, accompanied by pre-specified changes 
in treatment for the same disease manifestation of HZO (see MOP) during the twelve months of treatment. The 
primary endpoint is compared for participants randomized to study medication or placebo. 
 
To assess the primary objectives, study participants will be monitored at each visit for new or worsening any of 
the following conditions (see MOP for definitions): 
  
1. Dendriform epithelial keratitis: 
2. Stromal keratitis 
a. Without ulceration  
b. With ulceration  
3. Endothelial keratitis  
4. Iritis  
 
The endpoint of first occurrence of new or worsening dendriform epithelial keratitis, stromal keratitis, 
endothelial keratitis, and/or iritis will be determined by clinical examination accompanied by prespecified 
changes in treatment (see MOP), as there are no validated confirmatory biomarkers or other tests.   
 
Secondary Efficacy Endpoints: 
To assess the secondary objectives, the study participants will be monitored at each visit for the following: 
1. Time to development and number of episodes of new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis due to HZO, requiring pre-specified changes in 
treatment (see MOP), during the 18 months following randomization, that includes the 6 months 
following cessation of treatment; and during the 6 months following the end of the 12 month 
treatment period.  
2. The incidence, severity, and duration of PHN at one year of treatment, and after the 6 month post-
treatment follow up.   
3. Impact of vaccination against zoster with RZV on outcomes.  
4. Development of specific manifestations of HZO, classified as dendriform epithelial keratitis, stromal 
keratitis (all types), endothelial keratitis, iritis requiring pre-specified changes in treatment (see 
MOP), neurotrophic keratopathy with or without melting and/or microbial superinfection, episcleritis, 
and/or scleritis during the twelve months of treatment.  
5. Secondary glaucoma as determined by IOP and treatment required.  
 
Exploratory Efficacy Endpoints:  
1. Changes in strength and/or frequency of prescribed topical corticosteroids at 12 and 18 months.  
2. Occurrence of stroke 
3. Occurrence of temporal arteritis/giant cell arteritis 
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5. Occurrence of new or worsening malignancy 
a. Solid tumor (other than non-melanoma skin cancer) 
b. Hematologic malignancy 
c. Lymphoma.  
6. Time to development and number of episodes of new or worsening dendriform epithelial keratitis, 
stromal keratitis, endothelial keratitis, and/or iritis due to HZO, with a recent substantial reduction in 
treatment (see MOP) during 12 months of treatment.  
7. Impact of suppressive antiviral treatment prior to enrollment on outcomes during 12 months of study 
treatment.  
 
10.3 
ANALYSIS DATASETS 
All study participants who were randomized into the study will comprise the intent-to-treat population, the 
primary analysis population for efficacy.  Study participants who received at least one dose of the assigned 
study drug will comprise the as-treated population, the primary analysis population for safety.  Note, 
participants on either arm can receive off study valacyclovir or other antivirals after the primary endpoint is 
reached or for the occurrence of herpes simplex. During the time period that other antivirals are received, 
participants must be off study medication. Therefore, safety analyses will be conducted in this as-treated 
population until participants go off treatment at the end of the study or receive off treatment antiviral therapy for 
a primary endpoint or for herpes simplex.  For this subset of participants who receive antiviral therapy for these 
reasons, additional analyses of safety for the time period following resumption of study medication will be 
conducted.  Further supportive analyses of safety will be carried out for study participants who complete 12 
months of treatment.  Details provided in SAP.  
 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 
GENERAL APPROACH 
 
The ZEDS trial is a multicenter double-masked RCT that will enroll approximately 780 study participants with a 
medical record documentation of an episode of dendriform epithelial keratitis, stromal keratitis, endothelial 
keratitis, and/or iritis due to Herpes Zoster that was diagnosed in the past year.  Eligible study participants will 
be randomized via a computer IXRS system following confirmation of eligibility within PCC in 4 strata defined 
by age at HZO onset (less than 60 years, or 60 years and greater, at time of HZO onset) and by recent onset 
or chronic HZO (recent onset:  HZO diagnosed within 6 months of the enrollment/ randomization visit; chronic:  
HZO diagnosed 6 or more months prior to the enrollment/randomization visit). 
 
10.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is the time from randomization to development of the first occurrence of any new or 
worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to HZO, 
diagnosed by a change in clinical slit lamp biomicroscopy examination and accompanied by prespecified 
changes in treatment (see MOP) by 12 months of treatment with valacyclovir compared to placebo.   
 
The objective of the analysis of the primary endpoint is to compare cumulative failure rates (failure defined as 
an episode of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or 


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iritis) in the valacyclovir treated groups with the placebo treated group by 12 months (treatment completion). 
Kaplan-Meier curves will be plotted by treatment group (overall and within strata) and 95% confidence intervals 
(adjusted for interim analyses) for the difference between the 12-month cumulative failure rates will be 
estimated (overall and within strata). Results will also be plotted within strata and by baseline disease and 
study participant characteristics to provide descriptive summaries of the results. 
 
The primary study analysis will be based on a stratified log-rank (2-sided) test with adjustment for stratification 
factors (age, and recent onset vs. chronic disease).  
 
Details of all analyses, including sensitivity analyses are provided in the SAP. For example, analyses will be 
provided that incorporate adjustments of study medication to one 500 mg pill twice daily or one 500 mg pill 
daily instead of the standard 2 pills daily; and that evaluate the impact of study drug discontinuation by 
treatment group. 
 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints are listed in Section 10.2 above.  Methods for the analyses that compare these outcomes 
by randomized treatment group are described in the SAP.  
 
10.4.4 
EXPLORATORY ANALYSES 
 
Exploratory analyses to compare the rates of occurrence of each of the exploratory endpoints described above 
will be conducted as described in the SAP.  
  
10.4.5 
SAFETY ANALYSES 
All study participants who were randomized into the study will comprise the intent-to-treat population, the 
primary analysis population for efficacy.  Study participants who received at least one dose of the assigned 
study drug will comprise the as-treated population, the primary analysis dataset for safety.  
The analysis datasets for safety are described in Section 10.3 (Analysis Datasets) above.  Details are provided 
in SAP.  
The occurrence of acute kidney failure, defined as requiring temporary or permanent dialysis, in these patients 
will be monitored using a safety monitoring rule as described in the SAP and compared between the two 
treatment groups.  
  
SAEs will be analyzed in a similar manner.  For all safety events, the rates of study drug termination will be 
summarized and compared by treatment group and strata. 
   
10.4.6 
ADHERENCE AND RETENTION ANALYSES  
 
Study recruitment, retention, and adherence will be monitored by PCC and randomization strata. For each 
PCC, numbers of patients screened, numbers randomized, numbers of ineligible patients, treatment 
compliance as measured by pill count for individual study participants, protocol deviations, timeliness of data 
reporting and query resolution, numbers of queries/study participant, and additional monitoring measures will 


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be provided by center and reviewed monthly.  All results will be summarized over time using descriptive 
statistics, graphical displays, and frequency distributions as appropriate.  Retention rates by PCC and strata 
will also be monitored over time.  
 
10.4.7  
BASELINE DESCRIPTIVE STATISTICS 
 
Plans for the comparison of baseline characteristics between the two randomized treatment groups are 
provided in the SAP. 
  
10.4.8 
PLANNED INTERIM ANALYSES  
 
The interim analysis plan is described in the SAP.  
 
10.4.8.1 SAFETY REVIEW 
 
For ethical reasons, an independent DSMC appointed by the National Eye Institute (NEI), will monitor study 
participant safety and review performance of the trial at regular intervals during the trial. The primary objective 
of these interim safety analyses is to ensure the safety of the study participants randomized in the trial.  This 
interim monitoring will involve a review of study participant recruitment, compliance with the study protocol, 
status of data collection, and other factors that reflect the overall progress and integrity of the study.  Formal 
interim analysis of efficacy will evaluate the accumulating endpoint data by treatment group.  The interim 
monitoring plan is described in the SAP.   
 
10.4.8.2 EFFICACY REVIEW 
. 
Interim analysis(es) for efficacy  by treatment group will focus on the primary endpoint is described in the SAP.     
 
Judgment concerning the continuation of the study will involve not only the magnitude of observed differences 
between randomized strategies and degree of statistical significance, but also careful consideration of many 
other important factors including the need for precise parameter estimation, the overall progress and integrity 
of the trial including the frequency of serious adverse events associated with active study medication, and 
information available from other studies at the time of DSMC deliberations. 
 
10.4.9 
ADDITIONAL SUB-GROUP ANALYSES 
 
Analyses of primary and secondary endpoints will be presented by strata, by covariates including comorbidities 
such as diabetes, cancer among others, and by Zoster vaccination status as well as by gender. Details are 
provided in the SAP.  Pre-specified subgroup analyses will be provided in the SAP.  
 
10.4.10 
MULTIPLE COMPARISON/MULTIPLICITY 
 
A statistical adjustment for interim efficacy analyses is incorporated into for the analysis of the primary 
endpoint. No further adjustments for multiplicity are incorporated; any adjustments for multiplicity developed for 
the secondary analyses for the final study protocol will be incorporated into the SAP prior to unmasking and 
analysis of results. 


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10.4.11 
EXPLORATORY ANALYSES 
 
Exploratory analyses to compare the rates of occurrence of each of the exploratory endpoints described above 
will be conducted as described in the SAP.   
 
10.5 
SAMPLE SIZE 
 
The overall study sample size is based on the primary endpoint of episode of new or worsening dendriform 
epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis accompanied by pre-specified changes in 
treatment (see MOP) by 12 months for the ZEDS RCT as described above.  On the basis of available data, the 
12-month cumulative failure rate for the primary endpoint in the placebo group was estimated at 30% among 
study participants.  
 
Under the assumption that the cumulative 12 month failure rate in the placebo group is 30% with approximately 
390 study participants randomized to each of the two treatment groups, (including a planned interim analysis) 
we can detect a difference between the placebo and valacyclovir treated groups in failure rate at 12 months 
(treatment completion) of +/-8.7% (to 21.3% in the valacyclovir group), an approximately 30% treatment effect, 
with a two-sided alpha = 0.05 and 80% power (without adjustment for interim analyses)  These considerations 
are equivalent to a detectable hazard ratio for failure on valacyclovir relative to placebo of 0.67 based on a 
logrank-test for the comparison of the distributions of failure times between the two groups. [Calculations from 
EAST 6.5, Cytel, 2018] We estimate that approximately 780 study participants can be randomized into this 
study over an estimated 7-year accrual period.  All randomized study participants will be included in the intent-
to-treat analysis to compare cumulative failure rates by 12 months (failure time is defined as from 
randomization to the development of first episode of new or worsening dendriform epithelial keratitis, stromal 
keratitis, endothelial keratitis, and/or iritis) in the valacyclovir arm and placebo arm.  [ZEDS SAP provides a 
complete description of the approach].  
 
Sample size may be re-estimated using aggregate event rates as described in the SAP.   
 
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 
ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
 
Eligible study participants will be randomized centrally using the IXRS web-based interactive computerized 
system (see MOP). Study participants will be randomized following confirmation of eligibility by the system 
within center in the four strata, defined by age at onset of HZO (less than 60 years or 60 years and greater) 
and by recent onset or chronic HZO (recent onset defined as HZO diagnosed within 6 months of enrollment/ 
randomization, or chronic defined as HZO diagnosed 6 months or more prior to enrollment/randomization). The 
IXRS system allows PCC staff to log in and obtain the masked randomization assignment and supply 
assignment for individual study participants after on-line confirmation of eligibility and informed consent is 
obtained.  The IXRS will provide electronic files with randomization numbers to the DCC for supply labeling 
prior to sending supplies to centers. Confirmation of eligibility and randomization and supply assignments are 
then incorporated into the) Electronic Data Capture clinical trials database and become part of the study files.  


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Note that all data management staff in the CC are masked to treatment assignments throughout the study 
process.  The only exceptions to this are the unmasked statisticians. 
 
10.6.2 
 EVALUATION OF SUCCESS OF BLINDING  
 
Not applicable. 
 
10.6.3 
BREAKING THE STUDY BLIND/PARTICIPANT CODE 
 
A 24-7 helpline will be available for unmasking by the medical monitor in the event of a medical emergency 
that requires unmasking for the safety of the study participant. (See MOP) 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Each PCC will maintain appropriate medical and research records for this trial, in compliance with ICH E6, and 
regulatory and institutional requirements for the protection of confidentiality of participants. 
 
Source documents contain source data and include medical records, paper CRFs and images and all other 
information necessary to reconstruct and evaluate the clinical trial (see MOP).  
 
The study investigators will permit study-related monitoring, audits, and inspections by the IRB, the NEI, 
government regulatory agencies, and NYULMC staff of all study-related documents and the capability for 
inspections of study-related facilities.  
 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control procedures will be implemented beginning with the data entry system and data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., regulations of the National Eye Institute of the National Institutes of Health (NEI/NIH), the 
Food And Drug Administration (FDA) and the International Council for Harmonisation (ICH)). 
 
The PCCs will provide direct access to all study related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the CC, NEI, and inspection by local and regulatory authorities. 
 
See MOP for details on QA and QC processes. 
 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
 


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This study is to be conducted in accordance with applicable US government regulations and institutional 
research policies and procedures. The protocol and any amendments will be submitted to a properly 
constituted Central Institutional Review Board (CIRB) or, as required, to IRBs at PCCs for formal approval of 
the study conduct. The decision of the IRB concerning the conduct of the study will be made in writing to the 
study investigators and a copy of this decision will be provided to the CC before commencement of the study. 
Annual renewals will be submitted to the CC. 
 
13.2 
INSTITUTIONAL REVIEW BOARD  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval.  Approval of both the protocol and the consent form must be obtained before 
any study participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether previously consented participants need to be re-consented. 
 
Withdrawal of IRB Approval 
A study investigator shall report to the CC a withdrawal of approval by the investigator’s reviewing IRB as soon 
as a possible, but no later than 5 working days of the IRB notification of withdrawal of approval. 
 
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 
CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study agent, study procedures, and risks will be given to the participant 
and written documentation of informed consent is required prior to any study-related activities taking place. 
 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation.  Written informed consent will be obtained from all 
potential study participants on an approved consent form.   Potential study participants will be provided 
sufficient information to make an informed decision about their participation in the study.  The investigator will 
explain the research study to the potential study participant and answer any questions that may arise.  All 
potential study participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  Potential 
study participants will have the opportunity to carefully review the written consent form and ask questions prior 
to signing.  The potential study participants should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. The formal consent of a study participant, using the 
IRB approved consent form, must be obtained before that study participant undergoes any study procedure.  
The consent form must be signed and dated by the study participant and the study investigator-designated 
research professional obtaining the consent.  A copy of the informed consent document will be given to the 
participants for their records.  The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in the 
study. 


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A study participant informed consent form has been approved by the NYUSoM IRB. This consent form will be 
submitted with the protocol for review and approval by CIRB or the IRB at the PCCs for this study.  Any 
changes made to the informed consent form at the PCCs will be reviewed by the CC staff.  
 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
 
To protect against the risk of loss of confidentiality, the study will follow the procedures specified by the 
NYULMC IRB, central IRB or IRBs of the PCCs.  Study participants will be assigned a unique identification 
number using no identifying information. Personal identifying information such as name, address, driver’s 
license, or Social Security Number will not be entered into the database.  The CC at NYULMC is IRB approved 
and has experience in managing PHI and are extremely prudent in keeping study participant data secure and 
confidential through a number of standard operating procedures.  Transmission of informed consent forms and 
records with any PHI for central source document verification by CC monitors will occur by SafeSend email, or 
secure fax, or mail.  The control of access to databases will be managed centrally by the CC through user 
passwords linked to appropriate access privileges.  This protects data from unauthorized view and 
modifications and from inadvertent loss or damage.  The CC has an extensive data security infrastructure. 
Materials that contain PHI will be stored securely at PCCs.  This information will be retained by each individual 
center and will not be entered into the any of the study databases.  If a PCC closes and cannot continue to 
follow enrolled participants, they may be transferred, with the study participant’s consent, to another PCC. 
 
Information about study participants will be managed according to the requirements of the Health Insurance 
Portability and Accountability Act (HIPAA), including obtaining written authorization to collect and use protected 
health information (PHI).  In the event that a study participant revokes authorization to collect or use PHI, the 
study investigator retains the ability to use all information collected prior to this revocation.  In this situation, the 
study investigator should attempt to obtain permission to collect at least information that the study participant is 
alive at the end of their scheduled study period.  
 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
 
Not applicable. 
 
13.5 FUTURE USE OF STORED SPECIMENS  
 
Not applicable. 
 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
PCC staff will be trained in the proper collection, storage and transmission of study data.  All established 
procedures will be readily available to PCCs in the MOP.  Informed consent forms and all source documents 
with PHI to be stored with any study records must be in a double-locked secure location and/or password 


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protected, encrypted electronic files at each PCC in compliance with local IRB PHI will be redacted before 
submission for central monitoring (see MOP and SAP). 
 
CC staff will provide the PCC staff with a visit checklist to ensure that all required data are collected at each 
visit and in the preferred order of data collection.  A secure, compliant, web based electronic data capture 
(EDC) system will be developed to process, edit and store all study data in a centralized database. PCC staff 
will document relevant information on source documents and enter data into the EDC system.  A 
comprehensive data management methodology will be implemented.  All data will be reviewed for 
completeness, accuracy and logical consistency though out the duration of the study.  Final data cleanup will 
be completed shortly after the last study participant visit, at which time the study database will be locked and 
provided to the study statistician for analyses. 
 
14.2 
STUDY RECORDS RETENTION  
 
It is the study investigator’s responsibility to retain all study documents in accordance with federal regulations 
and any applicable local state and institutional requirements after the investigator has been informed by the CC 
that the study analyses have been completed and the study has been closed.   
 
14.3 
PROTOCOL DEVIATIONS  
 
Protocol Deviations: 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical Practice, or MOP 
requirements. The noncompliance may be on the part of the study participant, the investigator, or PCC study 
staff. As a result of deviations, corrective actions are to be developed by the PCC and implemented promptly. 
 
These practices are consistent with ICH E6: 
 
Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4. 
 
Quality Assurance and Quality Control, Section 5.1.1 
 
Noncompliance, Sections 5.20.1 and 5.20.2. 
 
All deviations from the protocol must be addressed in study participant’s source documents and promptly 
reported within the EDC system. Protocol deviations must be reported to the PCC’s responsible IRB per their 
guidelines and the DSMC at each review. Further details about the handling of protocol deviations are included 
in the MOP. 
 
14.4 
PUBLICATION AND DATA SHARING POLICY 
 
The Publications Committee will authorize access to study data.  
 
All data access will follow guidelines described in the NIH Data Sharing Policy 
(http://grants.nih.gov/grants/gwas/index.htm), the Food and Drug Administration Amendments Act of 2007 
(FDAAA), and ClinicalTrials.gov. 
 


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The Study Chair, Study Co-Chair and PIs of the CC at NYULMC have the primary responsibility for the 
publication of the results of the study.  The DSMC will review the report of the primary results of the study prior 
to submission for publication.   
 
Any PCC investigator involved with this study is obligated to provide the sponsor (NYULMC) with complete test 
results and all data derived from the study.  Primary and secondary reports of study findings will be published 
in peer-reviewed journals.  Proposals for presentations and publications incorporating study data must be 
submitted for review by the publications committee.  
 
No PCC investigator is permitted to present or publish data obtained during the conduct of this trial without 
prior approval from the publications committee.  PCC investigators must submit a proposal requesting access 
to trial data.   
 
The full publications policy may be found in the MOP.  
 
15 
STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
 
The study is sponsored by the US National Eye Institute. The Study Chair and Study Co-Chair, supported by 
the CC maintain responsibility for the overall conduct of the study, including site management and site 
monitoring analysis and reporting.  The Statistics and Data Management Leadership is responsible for the 
receipt and processing of data collected by the PCCs, quality control programs, and statistical analysis and 
reporting. Members of the NEI will participate in the study leadership. Details regarding the CC may be found 
in the MOP.  
 
Details of the Committees, e.g. Executive Committee and Clinical Event Review Committee, their charge, and 
membership may be found in the MOP.   
 
16 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence is critical. Therefore any actual conflict 
of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial 
will be disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the trial. The study 
leadership in conjunction with the NEI has established policies and procedures for all study group members to 
disclose all conflicts.  Details are in the MOP.  
 
17  
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APPENDIX 
 
Version 
Date 
Significant Revisions  
1.0 
March 10, 2017 
Original release 
1.1 
August 7, 2017 
Clarification of the use of divided dose and reduced dose of 
the study medication. 
Correction of the Schedule of Events table. 
2.0 
February 12, 2018 
Clarification of secondary endpoints 1 and 3. 
Addition of new exploratory endpoint. 
Clarification of inclusion criterion 6. 
Clarification of exclusion criterion 5 to include usually 
vesicular rash. 
Clarification of exclusion 6 to include use of the new zoster 
vaccine and temporary discontinuation of study 
medication when study participant takes the new 
vaccine. 
Clarification of the discontinuation of study medication 
when study participant develops a contraindication to 
valacyclovir. 
Clarification of the discontinuation of study medication due 
to use of open label antiviral medication. 
Correction of the use of participant diaries. 
Clarification of the review of SAEs by medical monitors and 
the DSMC.