Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
527 participants
INTERVENTIONAL
2017-08-23
2024-07-22
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Placebo
Encapsulated masked placebo
Masked Placebo
Oral Placebo
Masked Oral Valacyclovir 1000 mg daily
Valacyclovir, 500 mg, oral pill, two 500mg pills daily
Masked Oral Valacyclovir
Oral Valacyclovir 1000 mg/day
Interventions
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Masked Placebo
Oral Placebo
Masked Oral Valacyclovir
Oral Valacyclovir 1000 mg/day
Other Intervention Names
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Eligibility Criteria
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Inclusion 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:
1. History of characteristic unilateral, usually vesicular, HZO rash in the dermatomal distribution of cranial nerve V1 or V2.
2. 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. 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).
Exclusion Criteria
1. History of immunocompromised status as defined by current CDC contraindications for the vaccine against zoster (44).
1. 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.
2. 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.
3. 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.
3. Renal insufficiency:
1. Requires dialysis or has history of renal transplant or
2. eGFR less than 45, determined within 3 months days 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 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 chronic suppressive antiviral treatment with these medications will be excluded.
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.
18 Years
ALL
No
Sponsors
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National Eye Institute (NEI)
NIH
National Institutes of Health (NIH)
NIH
NYU Langone Health
OTHER
Responsible Party
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Principal Investigators
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Elisabeth Cohen, MD
Role: STUDY_CHAIR
NYU Langone Health
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Mayo Clinic - Arizona
Scottsdale, Arizona, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Scripps Clinic
La Jolla, California, United States
Loma Linda University Eye Institute
Loma Linda, California, United States
Jules Stein Eye Clinic - UCLA
Los Angeles, California, United States
Byers Eye Institute at Stanford University
Palo Alto, California, United States
UCSF- Francis I. Proctor Foundation
San Francisco, California, United States
Pacific Eye Surgeons, Inc.
San Luis Obispo, California, United States
University of Colorado
Aurora, Colorado, United States
Colorado Cornea Consultants P.C.
Littleton, Colorado, United States
Medstar Georgetown University Hospital
Washington D.C., District of Columbia, United States
Delray Eye Associates, PA
Delray Beach, Florida, United States
University of Florida
Gainesville, Florida, United States
Florida Eye Specialists
Jacksonville, Florida, United States
University of Miami - Bascom Palmer Eye Institute
Miami, Florida, United States
Eye Consultants of Atlanta, PC
Atlanta, Georgia, United States
University of Illinois
Chicago, Illinois, United States
NorthShore University Health System
Glenview, Illinois, United States
Case Western Reserve University
Cleveland, Indiana, United States
Indiana University - Glick Eye Institute
Indianapolis, Indiana, United States
University of Kansas Medical Center
Prairie Village, Kansas, United States
University of Kentucky
Lexington, Kentucky, United States
LSU Health Science Center
New Orleans, Louisiana, United States
Shreveport Eye Clinic
Shreveport, Louisiana, United States
University of Maryland
Baltimore, Maryland, United States
The Krieger Eye Institute
Baltimore, Maryland, United States
Wilmer Eye Institute John Hopkins
Bethesda, Maryland, United States
Crossroads Eye Physician
Owings Mills, Maryland, United States
Tufts Medical Center
Boston, Massachusetts, United States
Massachusetts Eye and Ear Infirmary
Boston, Massachusetts, United States
Boston Medical Center
Boston, Massachusetts, United States
Lahey Medical Center
Peabody, Massachusetts, United States
Eye Health Services
Weymouth, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Verdier Eye Center
Grand Rapids, Michigan, United States
Northwest Eye Clinic
Golden Valley, Minnesota, United States
Jennifer Burdick
Minnetonka, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Washington University Opthalmology
St Louis, Missouri, United States
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States
EyeCare MD of NJ
Morristown, New Jersey, United States
Albany Stratton VA Medical Center
Albany, New York, United States
Finger Lakes Ophthalmology /The Eye Care Center
Canandaigua, New York, United States
Stony Brook Ophthalmology
East Setauket, New York, United States
Northwell Health
Great Neck, New York, United States
New York Eye and Ear Infirmary
New York, New York, United States
NYU Langone Health
New York, New York, United States
Weill Cornell Ophthalmology
New York, New York, United States
Duke University
Durham, North Carolina, United States
Cincinnati Eye Institute
Cincinnati, Ohio, United States
Case Western Reserve University
Cleveland, Ohio, United States
Devers Eye Institute
Portland, Oregon, United States
Casey Eye Institute - Oregon Health and Science University
Portland, Oregon, United States
Vantage Eye Care Center, LLC
Bala-Cynwyd, Pennsylvania, United States
Geisinger Eye Clinic
Danville, Pennsylvania, United States
University of Pennsylvania
Philadelphia, Pennsylvania, United States
Corneal Associates at Wills Eye Hospital
Philadelphia, Pennsylvania, United States
University of Tennessee - Hamilton Eye Institute
Memphis, Tennessee, United States
Cornea and Cataract Consultants of Nashville
Nashville, Tennessee, United States
Vanderbilt Eye Institute
Nashville, Tennessee, United States
Cornea Associates of Texas
Dallas, Texas, United States
University of Texas Southwestern
Dallas, Texas, United States
Cornea Consultants of Texas
Fort Worth, Texas, United States
Alkek Eye Center - Baylor College of Medicine
Houston, Texas, United States
R and R Eye Research, LLC
San Antonio, Texas, United States
University of Utah - Moran Eye Center
Salt Lake City, Utah, United States
Virginia Eye Institute
Richmond, Virginia, United States
Virginia Mason Medical Center
Seattle, Washington, United States
NY Eye Surgeons
Seattle, Washington, United States
University of Wisconsin - Madison
Madison, Wisconsin, United States
Royal Alexandra Hospital
Edmonton, Alberta, Canada
University of British Columbia/Vancouver General Hospital Eye Care Centre
Vancouver, British Columbia, Canada
Kingston Health Sciences Centre-HDH Site and Queen's University
Kingston, Ontario, Canada
Prism Eye Institute
Oakville, Ontario, Canada
Centre Hospitalier de l'Université de Montréal (CHUM)
Montreal, Quebec, Canada
The Research Institute of the McGill University Health Centre/McGill Academic Eye Centre
Montreal, Quebec, Canada
Clinique Axe Visuel
Sherbrooke, Quebec, Canada
Countries
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References
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Warner DB, Jeng BH, Kim J, Liu M, Troxel AB, Hochman JS, Baratz KH, Mian SI, Choulakian MY, Meyer JJ, Lu Y, Twi-Yeboah A, Lee TF, Lopez-Jimenez C, Laury SC, Cohen EJ; ZEDS Trial Research Group. Low-Dose Valacyclovir for Postherpetic Neuralgia in the Zoster Eye Disease Study: A Randomized Clinical Trial. JAMA Ophthalmol. 2025 Apr 1;143(4):277-285. doi: 10.1001/jamaophthalmol.2024.6113.
Cohen EJ, Troxel AB, Liu M, Hochman JS, Baratz KH, Mian SI, Choulakian MY, Warner DB, Lu Y, Twi-Yeboah A, Lee TF, Kim J, Lopez-Jimenez C, Laury SC, Jeng BH; ZEDS Trial Research Group. Low-Dose Valacyclovir in Herpes Zoster Ophthalmicus: The Zoster Eye Disease Randomized Clinical Trial. JAMA Ophthalmol. 2025 Apr 1;143(4):269-276. doi: 10.1001/jamaophthalmol.2024.6114.
Prescott CR, Cohen EJ, Hochman JS, Troxel AB, Lu Y, Twi-Yeboah A, Jimenez CL, Mian SI, Mazen CY, Warner DB, Baratz KH, Jeng BH; ZEDS Trial Research Group. Baseline Participant Characteristics at Enrollment in the Zoster Eye Disease Study. Cornea. 2024 Dec 1;43(12):1473-1480. doi: 10.1097/ICO.0000000000003497.
Cohen EJ, Hochman JS, Troxel AB, Colby KA, Jeng BH; ZEDS Trial Research Group. Zoster Eye Disease Study: Rationale and Design. Cornea. 2022 May 1;41(5):562-571. doi: 10.1097/ICO.0000000000002743.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Study website
Other Identifiers
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16-00463
Identifier Type: -
Identifier Source: org_study_id
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