Systemic and Topical Antivirals for Control of Cytomegalovirus Anterior Uveitis: Treatment
Phase: PHASE2
Conditions: Cytomegalovirus Anterior Uveitis
Sponsor: University of California, San Francisco

Systemic and Topical Antiviral Control of 
Cytomegalovirus Anterior uveitis: Treatment 
Outcomes (STACCATO) - NCT03586284
Protocol Number: 1.0
Principal Investigators: John Gonzales 
Sponsor: University of California, San Francisco 
Version Number:  v1.3 
January 17, 2025 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 

  
Protocol for SOPRANO – v1.2 16 May 2022 
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Table of Contents 
1 STATEMENT OF COMPLIANCE ......................................................................................................................... 1 
2 PROTOCOL SUMMARY ....................................................................................................................................... 1 
1.1 Synopsis ........................................................................................................................................................... 1 
1.2 Schema ............................................................................................................................................................. 4 
Trial I 
4 
1.3 Schedule of Activities (SOA) .......................................................................................................................... 6 
(x)-if applicable ....................................................................................................................................................... 7 
2 INTRODUCTION .................................................................................................................................................... 7 
2.1 Background  ..................................................................................................................................................... 7 
2.2 Study Rationale and Significance ................................................................................................................. 8 
2.3 Risk/Benefit Assessment ................................................................................................................................ 9 
2.3.1 Known Potential Risks 9 
2.3.2 Known Potential Benefits ...................................................................................................................... 10 
2.3.3 Assessment of Potential Risks and Benefits ...................................................................................... 10 
3 OBJECTIVES AND ENDPOINTS ...................................................................................................................... 10 
4 STUDY DESIGN ................................................................................................................................................... 10 
4.1 Overall Design ............................................................................................................................................... 11 
4.1.1 . Study masking procedures (Exam #2 and 3) ................................................................................... 11 
4.2 Scientific Rationale for Study Design ......................................................................................................... 11 
4.3 End of Study Definition ................................................................................................................................. 12 
4.4 Adherence ...................................................................................................................................................... 12 
5 STUDY POPULATION ......................................................................................................................................... 12 
5.1 Inclusion Criteria ............................................................................................................................................ 12 
5.2 Exclusion Criteria ........................................................................................................................................... 12 
5.3 Strategies for Recruitment and Retention .................................................................................................. 13 
6 PARTICIPANT DISCONTINUATION/WITHDRAWAL .................................................................................... 14 
6.1 Participant Discontinuation/Withdrawal from the Study ........................................................................... 14 
7 STUDY ASSESSMENTS AND PROCEDURES .............................................................................................. 14 
7.1 Assessments and procedures ..................................................................................................................... 14 
7.1.1 Procedures 
14 
7.1.2 Specimens 
14 
7.1.3 Forms for data collection ....................................................................................................................... 15 
7.2 Adverse Events and Serious Adverse Events ........................................................................................... 15 
7.2.1 Non-serious adverse events ................................................................................................................. 15 
7.2.2 Dose reduction due to safety ................................................................................................................ 16 
7.2.3 Serious adverse event (SAE) ............................................................................................................... 16 
7.2.4 Medication cessation 16 
7.2.5 Adverse event reporting ........................................................................................................................ 16 
7.3 Unanticipated Problems ............................................................................................................................... 17 
7.3.1 Definition of Unanticipated Problems (UP) ......................................................................................... 17 

  
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7.3.2 Unanticipated Problem Reporting ........................................................................................................ 17 
7.3.3 Reporting Unanticipated Problems to Participants ............................................................................ 18 
8 STATISTICAL CONSIDERATIONS ................................................................................................................... 18 
8.1 Statistical Hypotheses .................................................................................................................................. 18 
8.2 Sample Size Determination ......................................................................................................................... 19 
8.3 Statistical Analyses ....................................................................................................................................... 20 
8.3.1 Safety Analyses 
21 
9 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....................................... 22 
9.1 Regulatory, Ethical, and Study Oversight Considerations ....................................................................... 22 
9.1.1 Informed Consent Process ................................................................................................................... 22 
9.2 Study Discontinuation and Closure ............................................................................................................. 23 
9.3 Confidentiality and Privacy ........................................................................................................................... 23 
9.3.1 Certificate of Confidentiality .................................................................................................................. 24 
9.4 Future Use of Stored Specimens and Data ............................................................................................... 24 
10 Key Roles and Study Governance ................................................................................................................... 24 
10.1 Safety Oversight .......................................................................................................................................... 24 
10.2 Clinical Monitoring ....................................................................................................................................... 25 
10.3 Quality Assurance and Quality Control .................................................................................................... 25 
11 Data Handling and Record Keeping ................................................................................................................ 25 
11.1 Data Collection and Management Responsibilities ................................................................................ 25 
11.2 Study Records Retention ........................................................................................................................... 26 
11.3 Protocol Deviations ..................................................................................................................................... 26 
11.4 Publication and Data Sharing Policy ........................................................................................................ 26 
11.5 Conflict of Interest Policy ............................................................................................................................ 26 
11.6 Additional Considerations .......................................................................................................................... 27 
12 Abbreviations ...................................................................................................................................................... 27 
13 Protocol Amendment History ............................................................................................................................ 28 
14 REFERENCES ................................................................................................................................................... 28 
 
 
 
 
 
 
 
 
 

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1 STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 
and/or 21 CFR Part 812) 
  
All site staff responsible for the conduct, management, or oversight of the study has 
completed Human Subjects Protection Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Institutional Review Board (IRB) for review and 
approval. Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
2 PROTOCOL SUMMARY 
1.1 Synopsis  
Title: 
Systemic and Topical Antiviral Control of Cytomegalovirus Anterior 
uveitis: Treatment Outcomes (STACCATO) 
 
Study Description: 
Systemic and Topical Antiviral Control of Cytomegalovirus Anterior 
uveitis: Treatment Outcomes (STACCATO) study is a sequential 
double-masked randomized clinical trial comparing the efficacy of 
oral valganciclovir, topical ganciclovir 2%, and placebo for the 
treatment of PCR-proven CMV anterior uveitis (also known as 
keratouveitis) in Trial I. After participants achieve control of their 
inflammation, they will enter Trial II, where they will be re-
randomized to one of three arms (oral valganciclovir prophylaxis, 
topical ganciclovir prophylaxis, or placebo) to determine which 
therapeutic and route of administration reduces recurrences of CMV 
anterior uveitis. Recurrences of inflammation in Trial II will be 
assessed for viral load to determine if recurrences are mediated by 
active viral replication. Participants who initially present with anterior 
uveitis suspected to be due to a viral aetiology and meet all eligibility 
criteria will be recruited from the clinic. Chulalongkorn University, 
Khon Kaen University, and Chiang Mai University (all in Thailand) 
along with the Francis I. Proctor Foundation at the University of 
California, San Francisco (UCSF) will jointly execute this clinical trial. 
UCSF will serve as the clinical and data coordinating center. 
 
Objectives: 
 
Specific Aim 1 (Trial I): To compare CMV viral load and inflammation 
after randomization to oral valganciclovir, topical ganciclovir, or 
placebo.  

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1a: We hypothesize that participants randomized to oral 
valganciclovir will have a lower viral load after 7 days compared to 
those randomized to either topical ganciclovir 2% or placebo (Trial I 
primary outcome).  
1b: We hypothesize that a greater proportion of participants 
randomized to oral valganciclovir will have controlled inflammation 
compared to those randomized to either topical ganciclovir 2% or 
placebo. 
 
Specific Aim 2 (Trial II): To compare the effect of long-term antiviral 
suppression on recurrence rate of inflammation.  
2a: We hypothesize that participants randomized to placebo will 
have fewer recurrences over 12 months compared to those 
randomized to either oral valganciclovir or topical ganciclovir 2% 
(Trial II primary outcome).  
2b: We hypothesize that aqueous obtained at the time of a 
recurrence of inflammation will demonstrate a detectable viral load 
and will correlate with level of inflammation. 
 
Specific Aim 3 (samples from Trials I and II): To characterize host 
transcriptional signatures and viral genomic features in CMV anterior 
uveitis using RNA sequencing of aqueous samples. 
 
3a: We hypothesize participants completing both trials who exhibit 
recurrent inflammation after antiviral suppression (Trial II) will have a 
higher prevalence of CMV mutations associated with antiviral 
resistance compared to baseline samples (Trial I). 
3b: We hypothesize that (i) host transcriptional profiles will 
distinguish CMV anterior uveitis from anterior uveitis cases negative 
for CMV and unable to enter Trial I, (ii) we will identify non-CMV 
pathogens in cases unable to enter Trial I, and (iii) we will identify 
unique signatures associated with recurrent inflammation in Trial II 
participants. 
 
 
 
Study Population: 
We plan to enroll 117 participants (39 participants per arm) across 
all sites. 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Participants will be enrolled at 6 sites centered in the United States, 
Thailand and Taiwan. In Thailand, participants will be enrolled at 
Chulalongkorn University in Bangkok, Thailand, Khon Kaen 
University in Khon Kaen, Thailand and Chiang Mai University in 
Chiang Mai, Thailand. In Taiwan, participants will be enrolled at 

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Chang Gung Memorial Hospital. In the United States, participants 
will be enrolled at the Francis I. Proctor Foundation/UCSF and the 
University of California, Los Angeles. UCSF will serve as the clinical 
and data coordinating center. 
 
Outcomes: 
Trial I: Primary Endpoint: Viral load after 7 days of treatment 
Secondary Endpoints: 
• 
Clinical quiescence 
Trial II: Primary Endpoint: Recurrence of inflammation over 12 
months 
Secondary Endpoints: 
• 
Prevalence of mutations conferring antiviral resistance 
 

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Schema 
Trial I 
Pre-study 
visit (Exam 0) 
 
 
 
 
 
 
 
 
 
Exam 1 
Randomization 
and 
Procedures 
 
 
 
Randomization 
to 1 of 3 arms 
 
 
 
 
 
 
 
 
Exam 2 (Day 7) 
Follow-up 
 
 
 
 
 
 
Exam 3 
(Day 21)  
Final visit 
for trial I 
 
 
Ø Review of results of in- house CMV PCR and laboratory results 
Ø Consent, enrollment, randomization to treatment arm if participants meet eligibility 
criteria 
Ø Clinical eye examination (in the following order: visual acuity, slit lamp examination of 
anterior segment, intraocular pressure assessment, confocal microscopy) 
Group 1: 
Oral valganciclovir 
N=39 
Ø Clinical eye examination (in the following order: visual acuity, slit lamp examination of 
anterior segment, intraocular pressure assessment) 
Ø Anterior chamber paracentesis #2 
Ø Assessment of clinical quiescence (grading anterior chamber cell) 
Ø Laboratory monitoring orders (complete blood count, complete metabolic panel) 
Randomize 
Group 3: 
Placebo 
N=39 
Group 2: Topical 
ganciclovir 2% 
N=39 
Ø Clinical eye examination (in the following order: visual acuity, slit lamp examination of 
anterior segment, intraocular pressure assessment) 
Ø Assessment of clinical quiescence (grading anterior chamber cell) 
Ø Laboratory monitoring orders (complete blood count, complete metabolic panel) 
Clinical eye examination reveals active anterior uveitis (≥1+ AC cell) and suggests a viral 
aetiology  
Ø Anterior chamber paracentesis is performed to establish a viral aetiology 
– Half of fluid will be used for in- house directed PCR for HSV, VZV and CMV 
– At least 50 μL of fluid will be preserved and used for quantitative CMV PCR to be 
conducted at a single US laboratory in eligible participants 
Ø Laboratory screening orders (CBC, chemistry panel, pregnancy test, HIV status) 
Ø Patients will be prescribed topical corticosteroid (prednisolone acetate 1%) to be used one 
drop in affected eye four times per day (this is typical standard of care) 
Ø Patients requiring management of elevated IOP will be prescribed IOP-lowering medication 
according to treating ophthalmologist’s discretion and best medical judgment 

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Trial II 
 
 
Exam 1 
(Re-randomization) 
 
 
 
 
 
 
 
 
 
Exam 2  
(1 month after 
randomization) 
 
 
Exam 3  
(3 months after 
randomization) 
 
 
 
 
Exam 4  
(5 months after 
randomization) 
 
 
 
 
Exam 5  
(7 months after 
randomization) 
 
 
 
 
 
Exam 6  
(9 months after 
randomization) 
 
 
 
Exam 7  
(11 months after 
randomization) 
 
 
Clinically inactive (< 1+ anterior chamber cell) 
for at least 2 weeks with at least 2 weeks 
wash-out period (no antivirals) 
Group 1: Oral 
valganciclovir N=35 
Group 3: Placebo 
N=35 
Group 2: Topical 
ganciclovir 2% N=35 
Ø Clinical eye examination (in the following order, VA, slit lamp examination of 
anterior segment, IOP) 
Ø Suppressive treatment initiation (randomized to 1 of 3 arms) 
Ø
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Confocal or specular microscopy if recurrent 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Confocal or specular microscopy if recurrent 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 
Ø
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Confocal or specular microscopy if recurrent 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Confocal or specular microscopy if recurrent 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 
Ø 
Clinical eye examination (in following order, VA, slit lamp examination of anterior segment, IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 

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Exam 8 
(12 months after 
randomization, 
Final Visit) 
 
 
Note that participants will be advised to contact their local site clinical coordinator or study 
ophthalmologist if they are having symptoms of recurrent inflammation. Recurrent inflammation is typically 
symptomatic (characterized by ocular redness, decreased vision, light sensitivity, and pain). Thus, 
participants will be evaluated for symptoms of recurrent inflammation, which may occur between study 
visits, during which they would have clinical eye examination, anterior chamber paracentesis #3 (if there 
is recurrent (active) inflammation). 
 
 
1.2 Schedule of Activities (SOA) 
                               
 
Tasks/Forms 
 
Trial I Visits 
Trial II Visits 
Exam 
#0 
Enroll/ 
Randomize 
Exam #1 
 
Exam #2 
Exam #3 
Enroll/ 
Re-Randomize 
Exam #1 
 
Exam #2-7 
Exam #8 
Eligibility/ 
Screening Form 
 
X 
 
 
X 
 
 
Consent/HIPAA 
 
X 
 
 
X 
 
 
Baseline 
History Form 
 
X 
 
 
 
 
 
Clinical Eye 
Exam Form 
 
      X 
X 
X 
      X 
X 
X 
REDCap 
patient 
d
i
ti
 
      X 
 
 
      X 
 
 
Treatment 
initiation 
 
      X 
 
 
      X 
 
 
Laboratory 
orders (CBC, 
Cr, pregnancy 
test)
X 
 
X 
X 
 
X 
X 
SAE/side effect 
evaluation 
 
 
X 
X 
 
X 
X 
Calendar/ 
medication 
log*** 
 
 
X 
X 
 
X 
X 
Patient Dropout 
 
 
(x) 
(x) 
(x) 
 
(x) 
(x) 
Protocol 
Deviation Form 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
Adverse Event 
Narrative/Log 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
(x) 
AC 
paracentesis 
X 
 
X 
 
 
(x) 
(x) 
Ø 
Clinical eye examination (in the following order, VA, slit lamp examination of anterior segment, 
IOP) 
Ø 
Assessment for recurrence of inflammation 
Ø 
Anterior chamber paracentesis #3 if recurrent inflammation (participant exits study if recurrent 
inflammation) 

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Confocal 
microscopy 
 
 
 
X 
 
 
X 
(x)-if applicable 
 
2 INTRODUCTION 
2.1 Background  
Immunocompetence does not protect one from cytomegalovirus (CMV) ocular inflammation 
(uveitis). While CMV retinitis causes blindness in patients with HIV/AIDS, recurrent and chronic 
inflammation anterior uveitis in immunocompetent individuals can also lead to blindness by 
causing glaucoma and corneal decompensation.  
There is debate whether each case of active CMV anterior uveitis requires treatment.1,2 
Nevertheless, treatment strategies include oral antiviral and topical antiviral therapy.3-5 There is 
relative equipoise as to whether oral or topical antiviral treatment and management of CMV 
anterior uveitis is most effective.6  
Once CMV anterior uveitis is controlled long-term antiviral prophylaxis has been suggested to 
decrease recurrences, but is not uniformly used.7 There are no prospective randomized trials 
demonstrating whether long-term antiviral prophylaxis reduces recurrences and associated 
sequela of corneal decompensation or glaucoma.3,4 
Clinical features of inflammation are the primary way that disease activity is assessed and 
monitored, but whether each recurrence is mediated by active viral replication and whether viral 
genome mutations and polymorphisms play a role in persistence and recurrence is largely 
unknown.  
This proposal leverage’s our team’s expertise in metagenomic deep sequencing and the design 
and implementation of randomized controlled trials. We have led randomized placebo-controlled 
trials in infectious keratitis in the Steroids for Corneal Ulcers Trial (SCUT, U10 EY015114) and 
in non-infectious uveitis in the First-line Antimetabolites for Steroid-sparing Therapy (FAST, U10 
EY021125) trial. Our group has significant prowess in identifying the entire genome of infectious 
pathogens as well as identifying mutations that confer resistance to medications.8-10 Additionally, 
our group has characterized host transcriptome features in a variety of inflammatory 
conditions.9,11 We also have substantial experience in conducting successful multicenter, 
international randomized trials. Including prior trials such as SCUT, FAST, the Mycotic Ulcer 
Treatment Trial (MUTT, U10 EY018573) and currently active trials like Azithromycin Reduction 
to Reaching Elimination of Trachoma (ARRET, UG1 EY030833), Adalimumab in JIA-associated 
Uveitis Stopping Trial (ADJUST, UG1 EY029658), and the Village-Integrated Eye Worker Trial 
(VIEW, UG1 EY028097). 
There are no clear guidelines regarding the treatment for acute inflammation in CMV anterior 
uveitis and no guidelines regarding the most effective strategy for preventing recurrences of 
CMV anterior uveitis once clinical control is achieved. We seek to enroll participants with PCR-
proven CMV anterior uveitis into a sequential double-masked placebo-controlled randomized 
clinical trial in the US and Asia.  

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2.2 Study Rationale and Significance 
Cytomegalovirus made headlines in medicine and ophthalmology as a major cause of blindness 
during the HIV/AIDS epidemic. CMV retinitis causes a coagulative retinal necrosis of the 
peripheral and macular retina and can involve the optic nerve, all of which can lead to 
irreversible blindness. The risk factors for CMV retinitis are well known. Patients with CD4 
counts lower than 50 cells/microliter have a 4-fold higher risk for developing CMV retinitis 
compared to those with CD4 counts greater than 100 cells/microliter. While the HIV/AIDS 
epidemic is over in developed countries, CMV retinitis is still encountered in patients with a 
variety of immunodeficient states or with advanced age.12 The management for CMV retinitis is 
well developed. Systemic therapy consists of intravenous administration of antiviral medication 
that targets the viral kinases of CMV, which is necessary for its replication. Additionally, 
intraocular injection therapy using antivirals has been a standard approach, including, for a time, 
a ganciclovir-eluting implant. There is, however, no defined therapeutic regimen for 
managing acutely active CMV anterior uveitis or whether long-term antiviral prophylaxis 
prevents recurrences.  
Antiviral resistance mutations play a role in CMV infection, particularly in HIV/AIDS and in organ 
transplant patients. The chronic exposure to prophylactic dosing of antiviral in an 
immunodeficient host plays a role in the development of CMV antiviral resistance.13 This has 
implications for the eye as up to nearly 30% of patients on long-term antiviral prophylaxis for a 
history of CMV retinitis are found to have CMV resistant to standard antiviral therapy, which is 
associated with more areas of retinitis and worse vision as well as putting the other eye at risk 
for the development of CMV retinitis.14,15 Additionally, plasma CMV viral loads >  >400 
copies/mL is associated with antiviral resistance due to mutations in the UL97 and UL54 
genes.16 Does long-term antiviral prophylaxis for CMV anterior uveitis also promote the 
development of antiviral resistance? 
A detectable CMV viral load in the blood predicts the development of CMV disease (including 
retinitis) as well as death with or without antiretroviral therapy. Plasma CMV loads >400 
copies/mL is associated with an increased risk of CMV retinitis progression.16 Moreover, the 
viral load in the eye (as assessed from the aqueous or vitreous fluid in patients with CMV 
retinitis) is correlated with the area of retinitis involvement.17 CMV viral load may be correlated 
with disease severity in CMV anterior uveitis.  
CMV anterior uveitis may be characterized by a self-limiting course even without therapy, by 
frequently recurrent disease, or chronic inflammation. Such a wide array of phenotypes has led 
to a lack of precise treatment protocols. Whether treatment of CMV anterior uveitis acutely 
with antiviral medication results in a more significant reduction in viral load, which may 
be associated with improved outcomes with respect to corneal endothelial cell count, 
intraocular pressure, incidence or progressive glaucoma, and, visual acuity is unknown.  
Long-term antiviral prophylaxis can beget the development of antiviral resistant CMV – in 
immunodeficient patients. In patient with acquired immunodeficiencies, such as HIV/AIDS, or 
organ transplant patients iatrogenically immunosuppressed to prevent graft rejection, antiviral 
resistant CMV may develop. Antiviral resistant CMV can be found in 19.5% of patients with 

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HIV/AIDS and in 11.4% of organ transplant patients.13 Others have found that by 9 months of 
antiviral therapy, 27% of HIV/AIDS patients developed antiviral resistant CMV.18 Further studies 
have identified mutations or polymorphisms in the UL97 gene from the blood and vitreous in 
HIV/AIDS patients.19 Thus, mutant CMV in the peripheral blood is reflected in the replicating 
virus in patients with antiviral resistant CMV retinitis.  
Antiviral resistance is associated with progressive and new CMV ocular disease. In 
immunocompromised patients, the development of antiviral resistant CMV in their blood or urine 
portends poor clinical outcomes, including ocular disease as such patients develop progressive 
retinitis in those with prior CMV retinitis or development of retinitis in their previously affected 
contralateral eye.14,18,20 Antiviral resistance most commonly involves mutations in the genes 
encoding viral kinases (UL97 and UL54). Indeed, mutations in these two viral kinase genes is 
associated with a greater increase in the area of retina involved with CMV retinitis as well as a 
9-fold increased risk of having contralateral involvement with CMV retinitis.15 Whether recurrent 
CMV anterior uveitis is mediated by antiviral resistance is unknown. The present proposal will 
be able to identify such resistance. 
 
2.3 Risk/Benefit Assessment   
2.3.1 KNOWN POTENTIAL RISKS  
The Medication risks: 
Patients randomized to receive oral valganciclovir will be at risk of developing complications due 
to systemic toxicity. Although this drug is widely prescribed to treat CMV anterior uveitis in the 
United States, there are known adverse effects. Common ones include fever, headache, 
insomnia, diarrhea, nausea, vomiting, and abdominal pain. Rare side effects include 
hematologic abnormalities, acute renal failure, infertility, teratogenesis, and carcinogenesis. 
Patients randomized to receive topical ganciclovir eye drops will be subjected to the risks of 
topical toxicity. These include corneal epitheliopathy and conjunctivitis, both of which are almost 
always reversible upon discontinuation of the topical medication. 
Minimizing medication risks: 
Due to the potential complications associated with oral valganciclovir, patients will obtain 
pre-study labs, as well as monitoring labs throughout the study. The pre-study labs are 
to ascertain whether an individual is at greater risk of developing complications such as 
bone marrow suppression or acute renal failure. Patients identified as being high risk will 
be excluded from the study, as specified in our protocol. Patients enrolled in the study 
will receive regular laboratory tests in order to monitor CBC and renal function. Those 
that develop blood or renal abnormalities as specified in the protocol will be removed 
from the study. For patients that are randomized to receive topical antiviral therapy, the 
regular schedule of follow-up with clinical exam by a study ophthalmologist will provide 
ample opportunity to detect topical toxicity and discontinue medications as described in 
our protocol. 
Procedural risks: 
Although extremely rare, risks associated with anterior chamber paracentesis include 
endophthalmitis and traumatic cataract, both of which can lead to vision loss. In rare cases, 
endophthalmitis warrants need for eye removal. 

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Minimizing procedural risk: 
All study ophthalmologists are trained to safely utilize anterior chamber paracentesis 
techniques to access fluid in the anterior chamber. Sterilization drops will be used in 
order to minimize the risks of intra-ocular infection. 
2.3.2 KNOWN POTENTIAL BENEFITS  
The benefits to the participant include a potential for a positive health outcome due to closer 
follow-up than standard care. Knowledge will be gained about their personal health through 
objective microbiological outcomes, which may help direct their care after study completion. 
Additionally, these participants will be contributing to work that could potentially guide treatment 
of CMV anterior uveitis for patients around the world. These benefits, in addition to the others 
mentioned above are reasonably balanced with the risks of partaking in the study. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Knowledge gained from this study may help improve the treatment of CMV anterior uveitis 
around the world. Given the risks to participants in this study, we feel the benefits of the 
important knowledge we expect to gain from this study outweigh the risks.   
 
3 OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
Specific Aim 1: To 
compare CMV viral load 
and inflammation after 
randomization to oral 
valganciclovir, topical 
ganciclovir, or placebo. 
 
 
Reduction in log 
transformed viral load 
as measured by 
quantitative PCR at 7 
days of treatment. 
Viral load post 7 days of treatment 
using fluid from the eye is an 
important micro biologic outcome to 
compare the effect of treatment. 
This is primary outcome for Trial I  
Specific Aim 2: To 
compare the effect of long-
term antiviral suppression 
on recurrence of 
inflammation. 
Proportion of 
participants with 
recurrence at the end of 
6months. 
CMV recurrence is a clinical 
outcome indicating effect of long-
term treatment in controlling 
inflammation and preventing 
recurrence. This is primary outcome 
for Trial II  
Specific Aim 3: To 
determine if antiviral 
resistance mutations 
develop with exposure to 
long-term antiviral 
suppression. 
 
Prevalence of mutations 
associated with antiviral 
resistance 
Using aqueous fluid from the eye, 
comparing prevalence of mutations 
conferring antiviral resistance in at 
baseline (Trial I) and recurrent 
disease (Trial II) is important to 
determine the relationship between 
viral and host genome features that 
mediate inflammation in CMV 
anterior uveitis.  
 
 
4 STUDY DESIGN  

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4.1 Overall Design 
The Systemic and topical antiviral control of cytomegalovirus anterior uveitis: treatment 
outcomes (STACCATO) study will enroll participants with PCR-proven CMV anterior uveitis into 
a sequential double-masked randomized clinical trial in the US and Asia. In Trial I, participants 
will be randomized to one of the three treatment groups: 
 
Group 1: Valganciclovir tablets 900 mg PO BID (4 tablets daily) and Placebo drops 1 
drop 6 times daily  
Group 2: Topical ganciclovir 2% 1 drops 6 times daily and Placebo tablets 2 tablets PO 
BID (4 tablets daily) 
Group 3: Placebo tablets 2 tablets PO BID (4 tablets daily) and Placebo drops 1 drop 6 
times daily  
 
After participants achieve control of their inflammation, they will enter Trial II at which point they 
will be re-randomized to one of the three arms in Trial I at a prophylactic dosing. Additionally, 
patients with known CMV anterior uveitis, but who are inactive, may enter Trial II directly. 
Recurrences of inflammation in Trial II will be assessed for presence of detectable viral load. 
Those who agree to participate will be randomized at baseline and after achieving clinical 
quiescence, get re-randomized to one of the three treatment groups: 
 
Group 1: Valganciclovir tablets 450 mg PO BID (2 tablets daily) and Placebo drops 1 
drop BID 
Group 2: Topical ganciclovir 2% 1 drop BID and Placebo tablets 1 tablet PO BID (2 
tablets daily) 
Group 3: Placebo tablets 1 tablet PO BID (2 tablets daily) and Placebo drops 1 drop BID  
 
All study ophthalmologists and participants will remain masked to treatment assignment after 
enrollment. Due to the treatment design, all participants will receive both pills and eye drops. An 
interim analysis will be performed for both trials once primary outcome data is available for one 
third of the patients. 
4.1.1 . STUDY MASKING PROCEDURES (EXAM #2 AND 3) 
• 
The patient comes for the study visit and meets with the study coordinator before 
seeing their study doctor. This will facilitate masking of ophthalmologists and 
participants. All outcome assessors including lab technicians for trial I and 
ophthalmologists for trial II will remain masked. To facilitate interim and safety 
analysis, a data team member may also be unmasked. 
• 
The patient’s medication bottles are immediately placed in a secure, black bag and 
left at the study coordinators desk for the remainder of the visit. Patient medication 
calendars should also be placed in the black bag.  
• 
The study coordinator will check-in with the patient and complete the following in any 
order:  
o Review of patient medication diaries 
o Review of adverse events since last visit*  
o Dispense new medication bottle (if applicable) 
 
4.2 Scientific Rationale for Study Design 
Randomized control trials are known to be the least biased form of evidence; we have chosen to 
do a randomized double- masked, placebo- controlled trial to reduce bias as much as possible. 

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4.3 End of Study Definition 
A participant is considered to have completed the study if he or she has completed all visits and 
procedures and exams of the study described in Assessments and Procedures Section 7.1. 
 
4.4 Adherence 
Participants will be given a treatment diary in the form of a weekly calendar on which they will 
be asked to record adherence as well as reasons for missed doses. At each study visit, the 
study coordinator will review with the participant their treatment calendar, and document 
findings in the Medication Log in each participant file. Pill counting and medication bottle 
weighing will also be done for an objective measure of adherence. Participants who miss a 
scheduled dose of medication will be instructed to skip that dose and continue with their next 
scheduled dose of tablets or eye drops. 
 
5 STUDY POPULATION 
5.1 Inclusion Criteria 
In order to be eligible to participate in Trial I of this study, an individual must meet all of the 
following criteria: 
• 
CMV positivity by nucleic acid amplification test (e.g., polymerase chain reaction) 
from aqueous humor obtained via anterior chamber paracentesis obtained during an 
active flare of inflammation (uveitis) preceding enrollment into study 
• 
Active anterior uveitis using Standardisation of Uveitis 
Nomenclature (SUN) Working group with clinical impression of CMV as the etiologic 
agent defined as ≥1+ anterior chamber cell21 
• 
Participant willingness to use an acceptable method of contraception during the 
study period (i.e., pharmacologic, barrier methods or abstinence). 
• 
Age over 18 years 
• 
Basic understanding of the study as determined by the physician 
• 
Commitment to return for follow up visits 
 
To be eligible for Trial II, an individual must: 
• 
Have a history of being CMV positive by nucleic acid amplification test (e.g., 
polymerase chain reaction) from aqueous humor obtained via anterior chamber 
paracentesis during an active flare of inflammation (uveitis) 
• 
Have inactive inflammation (<1+ anterior chamber cell) for at least 2 weeks 
• 
Have a period of 2 weeks of no antiviral prior to long-term treatment initiation 
 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
Trial I 

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• 
Negative for CMV by nucleic acid amplification test (e.g., polymerase chain reaction) 
of aqueous humor obtained via anterior chamber paracentesis during an active flare 
of inflammation (uveitis) preceding enrollment into study 
• 
Participants <18 years of age 
• 
Inactive anterior uveitis 
• 
Active intermediate or posterior inflammation (involvement of vitreous, choroid or 
retina) 
• 
Participants who have received antiviral therapy <14 days prior to enrolment 
• 
Participants who have received periocular or intraocular corticosteroid injection <8 
weeks prior to enrolment 
• 
Current use of oral corticosteroids 
• 
Immunocompromised participants (primary or secondary immunodeficiency 
disorders) 
• 
Prior immunosuppressive therapy in the past 3 months 
• 
Directed PCR testing positive for HSV or VZV 
• 
Plans to conceive during the study period, pregnant or breastfeeding mothers (blood 
or urine pregnancy test for all females of childbearing age is mandatory within 4 
weeks prior to enrolment) 
• 
Complete blood count with white blood cell, absolute neutrophil or platelet count 
lower than the lower limit of reference laboratory normal 
• 
Blood urea nitrogen or creatinine above the upper limit of reference laboratory 
normal 
• 
Recent ocular surgery within the past 30 days or planned surgery within the next 45 
days 
• 
Systemic autoimmune disease or ocular condition (besides anterior uveitis) 
anticipated to dictate or alter treatment course 
 
In Trial II, participants will be excluded if 
 
• 
They have not had prior positive CMV by nucleic acid amplification test (e.g., 
polymerase chain reaction) of aqueous humor obtained via anterior chamber 
paracentesis during active flare of inflammation (uveitis)  
• 
Have active inflammation 
• 
Did not have a 2-week period of no antiviral (treatment) prior to randomization to 
long-term prophylaxis 
 
 
5.3 Strategies for Recruitment and Retention 
The investigating ophthalmologist is conducting the search for potential participants by 
reviewing results of the nucleic acid amplification test (e.g., polymerase chain reaction) 
performed on aqueous fluid obtained from anterior chamber paracentesis. He or she will then 
determine if the patient meets all non-laboratory eligibility criteria. If so, the patient will be 
approached and participation in the study will be discussed. If consent is obtained, the patient 
will be formally enrolled into the study and randomized to one of the 3 treatment groups by the 
study coordinator. These patients will be coming from the study sites' patient population, 
including patients referred for evaluation of a possible infectious cause of their uveitis. 
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stay on that suppressive therapy for 12 months. 
6 PARTICIPANT DISCONTINUATION/WITHDRAWAL 
6.1 Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. The 
reason for participant discontinuation or withdrawal from the study will be recorded on the final 
form. Subjects who sign the informed consent form and are randomized but do not receive the 
study intervention may not be replaced and will be included in the intent to treat analysis. 
Subjects who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, will 
not be replaced and will be included in the primary analysis. 
 
7 STUDY ASSESSMENTS AND PROCEDURES 
7.1 Assessments and procedures 
7.1.1 PROCEDURES 
• 
Visual acuity (best-spectacle correction using Snellen) 
• 
Clinical eye exam (including slit lamp examination to examine cornea, evaluate for 
keratic precipitates and their morphology and location, to assess for anterior 
chamber cell and flare) 
• 
Intraocular pressure assessment 
• 
Anterior chamber paracentesis: Trial I-Exam 0 (pre-study visit) and Exam 2 (day 7), 
and Trial II- during recurrence 
• 
Endothelial cell morphology and density using specular microscopy or confocal 
microscopy: Trial I- Exam 1 and Trial II- Exam 7 
• 
Laboratory screening/monitoring orders (complete blood count, CBC, and complete 
metabolic panel, CMP): Trial I-Exam 0,2, and 3 and Trial II- Exam 2-7 
 
7.1.2 SPECIMENS 
The following specimens will be collected  
• 
Anterior chamber aqueous fluid for CMV quantitative PCR: Trial I- at Exam 0 and 
Exam 2, Trial II- during recurrence 
o Aqueous humor from Exam 0 will be divided into two parts, some of fluid will 
be used for in-house directed PCR for HSV, VZV, and CMV. The results will 
determine study eligibility. 50 microliters of fluid will be preserved in the 
event the patient is CMV positive, and amenable to participating in the trial, 
ultimately to be used for quantitative CMV PCR to be conducted at Proctor 
Foundation/UCSF. 
o Aqueous humor from Exam 2 in trial I and during recurrence in trial II 
designated for CMV quantitative PCR and RNA sequencing will be 
immediately labeled and frozen on site. Once all enrolled participants at the 
site have completed the study, their aqueous samples will be packaged 
together with sufficient dry ice and shipped to UCSF for testing.  
 
• 
The following specimens will be collected for laboratory measurements after Exam #0 
and prior to enrollment and randomization (Day #1 of clinical trial) 

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o Blood for complete blood count (CBC with differential)  
o Blood for serum chemistry panel (complete metabolic panel)  
o Blood or urine pregnancy test (all female participants of child-bearing age) 
o Blood for HIV testing (unless HIV status is known) 
 
• 
Blood for complete blood count (CBC with differential) and chemistry (complete 
metabolic panel): (Trial I; Exam 2 and 3, Trial II Exam 2-7) 
 
7.1.3 FORMS FOR DATA COLLECTION 
• 
Patient Consent Forms for AC paracentesis- Trial I- at Exam 0 and Exam 2, trial II- 
during recurrence 
• 
Eligibility/screening form: Trial I-Exam 1 and Trial II-Exam 1 
• 
Patient Consent Forms for clinical trial: Trial I-Exam 1 and Trial II-Exam 1 (for new 
participants) 
• 
Baseline History Form: Trial I-Exam 1 
• 
Clinical Eye Exam Form: All Exams in Trial I and Trial II 
• 
Medication Log (to be completed by patient): Trial I- Exam 2, and 3, Trial II- Exam 2-
7 
• 
Serious Adverse Event Narrative (if applicable): All Exams in Trial I and Trial II 
• 
Patient Dropout Form (if applicable): Trial I- Exam 2, and 3, Trial II- Exam 2-7 
• 
Protocol Deviation Form (if applicable): All Exams in Trial I and Trial II 
 
7.2 Adverse Events and Serious Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
7.2.1 NON-SERIOUS ADVERSE EVENTS 
Non-serious adverse events may include any unfavorable medical occurrences in patients who 
have ever received study medication, regardless of any causal relationship with treatment. 
Examples may include: 
1. Increased intraocular pressure (>24 mm Hg) 
2. Abnormal lab findings (rise in creatinine to ≥ 1.5 to < 2 mg/dL, reduction of white blood 
cell count to below 2.5) 
3. Concurrent accident or illness 
4. Increase in the frequency and severity of symptoms of a pre-existing condition 
5. Side effects intolerable to patient (gastrointestinal upset, nausea, vomiting, fatigue)  
6. Signs of corneal or conjunctival toxicity (epitheliopathy, conjunctivitis) 

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7.2.2 DOSE REDUCTION DUE TO SAFETY 
In the event of a non-serious adverse event in the form of a laboratory abnormality, dose 
reductions in study treatments should be made. This will entail decreasing the dose of 
valganciclovir to 450 mg PO BID. Topical drop frequency will be decreased to 3 times daily. In 
the event of a non-serious lab abnormality, repeat testing should be ordered at 7 days of 
treatment with the reduced dose in order to monitor for resolution. 
7.2.3 SERIOUS ADVERSE EVENT (SAE) 
Serious adverse events include any medical occurrence that results in the following outcomes, 
or any other adverse event classified as severe*: 
1. Cr ≥ 2 mg/dL, leukocytes ≤ 1,000/ L, platelets < 20,000/ L, or hemoglobin < 6.5 g/dL  
2. Death 
3. Non-elective surgery or hospitalization for any reason 
4. Myocardial infarction or stroke 
5. Corneal perforation 
6. Life-threatening adverse drug experience or any life-threatening event  
7. Persistent or significant disability or incapacity 
8. Cancer 
9. Seizure 
10. Congenital anomaly/birth defect 
11. Disability or permanent damage 
12. Required intervention to prevent permanent impairment/damage 
 
7.2.4 MEDICATION CESSATION 
In the event of a serious adverse event, all study medications should be stopped and the 
medical monitor should be informed via a protocol deviation form. Further medical management 
will be at the discretion of the treating ophthalmologist and any consulting services. These 
patients should continue with scheduled study visits if possible. 
7.2.5 ADVERSE EVENT REPORTING 
Non-serious and serious adverse events will be noted at each study visit by the study 
coordinator while meeting with the patient at the beginning of each study visit. If there are any 
reported symptoms (not only severe symptoms), the study physician will review them with the 
patient while remaining masked to determine if any action is needed. 
In case of a Serious Adverse Event (SAE), the Investigator needs to write a summary of the 
SAE and submit to the Medical Monitor (Dr. Gerami Seitzman; gerami.seitzman@ucsf.edu), and 
Principal Investigator (Dr. John Gonzales; john.gonzales@ucsf.edu) within 24 hours of the SAE. 
Information recorded in this message will include the nature of the event, date of onset, date of 
resolution, date of notification to Medical Monitor, and action taken. The Medical Monitor will 
review and decide if the serious adverse event was related to the study drug and collect 
additional information if needed. 
The Medical Monitor will determine two things: 
1) Whether this is a true adverse event and 
2) Whether this is likely related to the study drug. 

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If the investigator thinks the SAE is related to the study drug, he/she can stop the study 
medication anytime (including prior to investigation by the medical monitor). 
Any significant study drug-related adverse events will be reported by the coordinating center to 
the FDA and CHR office as appropriate. The principal statistician will inform the DSMC of 
serious adverse events by arm every month. 
Any complications will be reported within 24 hours to the Principal Investigator (Dr. John 
Gonzales, john.gonzales@ucsf.edu). 
7.3 Unanticipated Problems 
7.3.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (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: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (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); and 
• 
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. 
 
7.3.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP 
report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP. 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study sponsor within 7 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 30 days of 
the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 

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and the Office for Human Research Protections (OHRP) within 30 days of the IRB’s 
receipt of the report of the problem from the investigator.] 
 
7.3.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Participants will be notified of UPs in aggregate. When UPs affect an individual, they will be 
notified individually by the treating physician.  
 
8 STATISTICAL CONSIDERATIONS  
8.1 Statistical Hypotheses 
Specific Aim 1 (Trial I): To compare CMV viral load and inflammation after randomization 
to 7 days of oral valganciclovir, topical ganciclovir 2%, or placebo.  
1a: We hypothesize that participants randomized to oral valganciclovir will have a lower viral 
load after 7 days compared to those randomized to either topical ganciclovir 2% or placebo 
(Trial I primary outcome).  
1b: We hypothesize that a greater proportion of participants randomized to oral valganciclovir 
will have controlled inflammation compared to those randomized to either topical ganciclovir 2% 
or placebo.  
Specific Aim 2 (Trial II): To compare the effect of long-term antiviral suppression on 
recurrence rate of inflammation.  
2a: We hypothesize that participants randomized to placebo will have fewer recurrences over 12 
months compared to those randomized to either oral valganciclovir or topical ganciclovir 2% 
(Trial II primary outcome).  
2b: We hypothesize that aqueous obtained at the time of a recurrence of inflammation will 
demonstrate a detectable viral load and will correlate with level of inflammation. 
Specific Aim 3 (samples from Trials I and II: To characterize host transcriptional 
signatures and viral genomic features in CMV anterior uveitis using RNA sequencing of 
aqueous samples. 
3a: We hypothesize participants completing both trials who exhibit recurrent inflammation after 
antiviral suppression (Trial II) will have a higher prevalence of CMV mutations associated with 
antiviral resistance compared to baseline samples (Trial I). 
3b: We hypothesize that host transcriptional profiles will (i) distinguish CMV anterior uveitis from 
anterior uveitis cases negative for CMV and unable to enter Trial I, (ii) we will identify non-CMV 
pathogens in cases unable to enter Trial I, and (iii) identify unique signatures associated with 
recurrent inflammation in Trial II participants. 
 
Primary Outcome:  

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• 
Viral load after 7 days of treatment (Trial I) 
• 
Recurrence of inflammation over 12 months (Trial II) 
 
Secondary outcomes: 
• 
Anterior chamber cell (Trials I and II) 
• 
Intraocular pressure (Trials I and II) 
• 
Visual acuity (Trials I and II) 
• 
Corneal endothelial cell count and morphology (Trials I and II) 
• 
Number of glaucoma medications (ocular hypertensive medication) (Trials I and II) 
• 
Prevalence of mutations conferring antiviral resistance (Trials I and II) 
 
8.2 Sample Size Determination 
Primary analysis for Trial I. We power the study for each pairwise comparison. We will be 
comparing each arm against the others: oral valganciclovir vs placebo, topical ganciclovir 2% 
vs. placebo and oral valganciclovir vs. topical ganciclovir 2%. The power calculation was based 
on the primary outcome, log-transformed CMV viral load. We informed the calculation with viral 
loads from the pilot study, STACCATO. The STACCATO trial measured viral load at baseline 
and 7 days post-treatment. The standard deviation (SD) of log-transformed viral load 7 days 
post-treatment in STACCATO was 0.98. Since the primary analysis will adjust for baseline viral 
load, we used an estimate of the residual standard deviation, which is 𝑆𝐷! = 𝑆𝐷√1 −𝑟", where r 
is the correlation between the baseline measure and primary endpoint. In STACCATO, the 
correlation between baseline and post-treatment viral load was 0.50. Assuming a significance 
level of 0.05/2=0.025 to account for multiple comparisons and an SDr of 0.66 in log10 viral load, 
we estimate that we will have 80% power to detect a difference of 0.50 in log10 viral load (from 
3.11 to 2.61) between arms with 35 study participants per arm (117 total allowing for 
approximately 10% loss to follow up). This calculation is based on the standard power formula 
for the T-test using an estimated residual standard deviation. While a global test of any 
difference between the three arms is possible, it is not clinically informative and the 2 pair-wise 
comparisons are of highest clinical interest. The proposed max-T procedure for P-value and 
simultaneous confidence interval estimation are a correct, valid approach for the two 
comparisons.22 
Primary analysis for Trial II. The primary outcome for Trial II is recurrence of inflammation 
(≥1+anterior chamber cell) over 12 months. We calculated the effect size we would be able to 
observe with 80% power, a two-sided alpha of 0.05/2, and 28 participants per arm (105 total 
from Trial I with 20% loss to follow-up) based on a two-sample z-test for proportions. Assuming 
the risk of recurrence is 25% in the placebo group, we can detect a difference of 36 percentage 
points between the oral valganciclovir and the placebo groups. We acknowledge that having 
fewer recurrences in the placebo group compared to oral antiviral group may be contradictory to 
what one might think would typically occur with exposure to antivirals. However, it is well 
documented in the literature that long-term suppressive-level dosing of antiviral in an 
immunodeficient host or in an immunologically privileged organ (such as the eye) can create an 
environment permissive to the development of antiviral resistance.13-15,18,20 

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For Specific Aim 3, we estimated the minimum detectable effect for the difference in 
prevalence of infections that have antiviral resistance mutations among recurrent infections in 
Trial II among patients who receive long-term antiviral prophylaxis compared with their 
infections at baseline. Aim 3 will focus on patients in the two active treatment arms in Trial II, 
because we would expect long-term use of topical and oral antivirals to lead to similar selection 
for antiviral resistance. From 117 participants enrolled, we conservatively assumed that 72% of 
patients would complete both Trial I and Trial II (n=84). We further assumed that 60% of 
patients will develop a recurrent infection over the monitoring period during the trials (Table 1)7. 
Participants who receive active treatment in Trial II (treatment regimens C+D) will contribute to 
the Aim 3 analysis (n=34). The analysis will be a paired analysis, comparing the proportion of 
recurrent infections with antiviral resistance mutations with that same proportion at baseline. 
Please refer to the Statistical Analysis Plan (SAP) for further details. 
Randomization 
For both trials, individuals will be randomized to the three arms in a 1:1:1 ratio. Randomization 
will be stratified by site. Stratified, block randomization will ensure that an approximately equal 
number of patients are randomized to each treatment arm by site. UCSF biostatistician will 
prepare the randomization and it will be implemented in REDCap. 
 
8.3 Statistical Analyses 
1a. The Aim 1 primary outcome viral load after 7 days of treatment will use the results from 
quantitative PCR at 7 days of treatment or placebo therapy (day 7 of trial). All quantitative PCR 
viral loads will undergo log transformation, with units converting from IU/mL to log IU/mL. 
1b. Clinical inactivity of inflammation: At each study visit patients will be clinically examined, 
and a study ophthalmologist will make a clinical determination as to whether the patient’s 
inflammation is considered inactive (defined as ≤0.5+ anterior chamber cell). The proportion of 
participants that achieve clinically inactive inflammation by day 7 and 21 will be compared by 
arm. Patients will also be administered a questionnaire querying when they felt symptomatic 
improvement in their condition. This analysis will be viewed as hypothesis generating and will be 
treated as supplementary and in addition to the main finding.  
2a. Recurrence of inflammation over 12 months: After achieving clinical quiescence, 
participants will be offered enrollment into Trial II where they would be re-randomized to long-
term suppressive treatment to study the effect on recurrence of inflammation (defined as ≥1+ 
anterior chamber cell). Each participant will be assessed for recurrence at each visit. 
Alternatively, if participants experience symptoms of a flare up, they will be instructed to contact 
the local site clinical coordinator or study ophthalmologist for an examination within 3 days. If 
recurrence of inflammation occurs, aqueous chamber fluid will be collected (an anterior 
chamber paracentesis will be performed) from participant to quantify viral load. 
3a. Prevalence of mutations conferring antiviral resistance: The analysis population will 
include individuals enrolled in both Trials I and II who are randomized to receive oral or topical 
antivirals in Trial II and experience a recurrent infection. Among patients that experience a 

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recurrent infection (anticipated n=34, see Sample Size section 3.3 in SAP), we will compare the 
proportion of infections with antiviral mutations upon recurrence with the proportion with antiviral 
mutations at baseline. 
Interim Analysis 
The interim analysis for each trial should be conducted after one-third and before one-half of the 
patients have been enrolled; ideally when there are 15 patients per arm. 
 
8.3.1 SAFETY ANALYSES 
Interim reports for the DSMC will be prepared by the central Proctor site.  
The Data and Safety Monitoring Committee will meet to review the interim efficacy data when 
primary outcome data is available on one third of the study subjects.  The DSMC will make one 
of the following recommendations:  
• Continue the study without modifications  
• Continue the study with modifications  
• Terminate enrollment or treatment in the study because of safety concerns  
• Terminate enrollment or treatment in the trial because of futility  
The DSMC will determine the database closure dates for each report in advance; archival 
copies of the (a) main database, and (b) study analysis file as they exist at the time of each 
report will be maintained. All reports will be sent using secure email to the members of the 
DSMC two weeks prior to each meeting. 
The DSMC will make decisions with the benefit of pre-specified decision guidelines. These 
guidelines will be agreed upon at the initial meeting, and are expected to include (a) safety, (b) 
efficacy, (c) futility, (d) clinical importance, or (e) validity. 
Efficacy. Unmasked interim analyses will be conducted to determine whether or not sufficient 
evidence has accumulated to justify stopping the trial because one treatment is clearly superior 
(and therefore should be extended to all future cases). The guidelines for efficacy will use group 
sequential boundaries for judging the statistical significance of the primary outcome measure. 
The Lan and DeMets23 flexible alpha spending approach with a power function is suggested, 
with a*(t*)= a (t*)Ɵ, where q= 3.561 chosen so that the two-sided P-value to stop the trial for 
efficacy is 0.001.  
Harm.  Stopping for harm will be done at the judgment of the DSMC. Several endpoints will be 
examined, including adverse events, and especially abnormal lab results meeting the 
designated threshold of a serious adverse event.  
All subjects who provide informed consent will be accounted for in this study. We will present 
the number lost to follow-up and the number of protocol deviations by arm. The proportion of 

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subjects reporting adverse events and serious adverse events will be reported by arm to the 
DSMC and will be compared using a Fisher’s Exact Test. 
Futility.  Early discontinuation due to the unlikeliness of significant findings conditional on interim 
results may be considered, based on the original sample size considerations. For evaluating 
futility, we propose to use a simulation-based approach24 that estimates conditional power under 
the assumed design effect for the remainder of participants and under the current trend 
observed at the interim analysis. We propose that the DSMC consider discontinuation for futility 
if the conditional power to detect a difference in viral load in Trial I and recurrence in trial II 
drops below 20% at the interim analysis under the assumed design effect for the remainder of 
participants yet to be enrolled. 
Population for Analyses 
Individual level missing data (due to loss to follow-up or dropouts) is expected. Complete 
analysis will be reported. Missing values will be tabulated by treatment arm, and study site. 
Sensitivity analysis assigning outcomes to the missing values will be reported. Additionally, 
analyses will be reported in which we adjust for any baseline covariate known to be a predictor 
of missing outcome data. Please refer to the SAP for further details regarding analyses. 
 
9 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
9.1 Regulatory, Ethical, and Study Oversight Considerations 
9.1.1 INFORMED CONSENT PROCESS 
9.1.1.1 Consent/assent and Other Informational Documents Provided to participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
study procedures.  Consent forms will be given to the participant in their native language.  
 
9.1.1.2 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. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. 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 this study. 

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9.2 Study Discontinuation and Closure 
 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 study participants, 
investigator, funding agency, sponsor, and regulatory authorities.  If the study is prematurely 
terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, 
the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to study visit schedule. 
  
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 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
9.3 Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), or regulatory agencies may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the Data Coordinating Center. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry 
and study management systems used by clinical sites and by the Data Coordinating Center 
research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the Data Coordinating Center at UCSF. 
 

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9.3.1 CERTIFICATE OF CONFIDENTIALITY  
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality 
and privacy to participants. 
 
9.4 Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored at the Data Coordinating Center at 
UCSF. After the study is completed, the de-identified, archived data will be transmitted to and 
stored on the Research Electronic Data Capture system (REDCap).  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the enrollment site.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data will be provided through REDCap.  
 
10 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
John Gonzales, MD 
Associate Professor 
Gerami Seitzman, MD  
Professor of Ophthalmology 
Francis I. Proctor Foundation, University 
of California, San Francisco  
Francis I. Proctor Foundation, University 
of California, San Francisco  
490 Illinois street, second floor  
San Francisco, CA 94158 
490 Illinois street, second floor  
San Francisco, CA 94158 
415-476-1442 
415-476-1442 
john.gonzales@ucsf.edu 
gerami.seitzman @ucsf.edu 
 
10.1 Safety Oversight 
A Data and Safety Monitoring Committee (DSMC) will be empaneled by the NEI. The committee 
will meet in person at least once per year and will convene biannual teleconferences for 
progress reports. Ad hoc meetings as needed may also be convened. The committee will review 
information on data quality, enrollment, patient retention, and study outcomes, etc. Committee 
members will be unmasked and receive reports of the data with ARM information at one interim 
time-point (when 1/3rd of the primary outcome has been collected). All study protocols will be 
subject to review and approval by Institutional Review Boards.  

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10.2 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of study 
participants are protected, that the reported study data are accurate, complete, and verifiable, 
and that the conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and with applicable regulatory requirement(s).  
 
Clinical monitoring will be conducted by the Clinical Coordinating Center (CCC) at UCSF. One 
person will make site visits to all enrollment sites once a year to monitor study activities. During 
each visit the CCC will conduct a complete chart review of all patient charts to ensure data is 
being recorded in a complete fashion. The CCC will conduct regular off-site reviews of data 
entered at UCSF to ensure 100% data verification.  
 
10.3 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
 
Quality control (QC) 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 Standard Operating Procedures (SOPs), the monitors will verify that the study 
is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP)).  
 
The investigational site will provide direct access to all study related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
 
 
11 DATA HANDLING AND RECORD KEEPING  
11.1 Data Collection and Management Responsibilities  
Data collection is the responsibility of the study staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  Enrollment sites will 
upload these forms to Box.com, where the Data Coordinating Center at UCSF will access these 
forms for data entry. Data recorded in the electronic case report form (eCRF) derived from 
source documents should be consistent with the data recorded on the source documents.  
 

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Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Research Electronic Data 
Capture (REDCap), a 21 CFR Part 11-compliant data capture system provided by the Data 
Coordinating Center at UCSF. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be double data-entered directly from the source 
documents. 
 
11.2 Study Records Retention  
Study documents should be retained for a minimum of 2 years. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to 
inform the investigator when these documents no longer need to be retained. 
 
11.3 Protocol Deviations  
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working 
days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to National Eye Institute Program Official and the Coordinating 
Center at UCSF.  Protocol deviations must be sent to the reviewing Institutional Review Board 
(IRB) per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB requirements.  
 
11.4 Publication and Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy. In addition, every attempt will be made 
to publish results in peer-reviewed journals.  
 
11.5 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 design and conduct of this study.  The study 
leadership in conjunction with the National Eye Institute has established policies and procedures 

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for all study group members to disclose all conflicts of interest and will establish a mechanism 
for the management of all reported dualities of interest. 
 
11.6 Additional Considerations 
None 
12 ABBREVIATIONS 
 
AC 
Anterior Chamber 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
BID 
Twice a day 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CCC 
Clinical Coordinating Center 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus  
Cr 
Creatinine 
DCC 
Data Coordinating Center 
DSMC 
Data Safety Monitoring Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GLP 
Good Laboratory Practices 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes Simplex Virus 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
MOP 
Manual of Operations and Procedures 
NEI 
National Eye Institute 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PO 
By mouth 
QA 
Quality Assurance 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
UCSF 
University of California, San Francisco 
UP 
Unanticipated Problem 
US 
United States 
VA 
Visual Acuity 
VZV 
Varicella-zoster Virus 

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VA 
Visual Acuity 
 
13 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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