Zoster Eye Disease Study

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

Specific Aims

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

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

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

• Masked Placebo (Drug): Oral Placebo
• Masked Oral Valacyclovir (Drug), also known as Valtrex: Oral Valacyclovir 1000 mg/day

Primary outcomes

• Number of Participants With the First Occurrence of New or Worsening Stromal Keratitis Without Ulceration (SK), Endothelial Keratitis (EK), Iritis (IR), Dendriform Epithelial Keratitis (DEK), or Stromal Keratitis With Ulceration (SKU) [Month 12]: The number of participants with the first confirmed endpoint (new or worsening SK, EK, IR, DEK or SKU associated with pre-specified definitions of these disease manifestations and associated treatment requirements within 12 months in study participants assigned to valacyclovir compared to placebo. Diagnostic criteria were defined using the classification for SK, EK, SKU, and DEK caused by Herpes Simplex Virus (HSV) and standardization of uveitis nomenclature (SUN) for IR. A substantial increase in topical steroid treatment, defined as starting, shifting from a lower to higher potency steroid, or doubling frequency of steroid at one visit (new) or gradually within 3 months (worsening) was required for SK, EK, IR, and SKU.

Secondary outcomes

• Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment [Month 18 (6 months post treatment)]: A secondary endpoint, at 18 months, assessed whether the treatment effect persisted 6 months after treatment. Diagnostic criteria were defined using the classification for SK, EK, SKU, and DEK caused by HSV and standardization of uveitis nomenclature (SUN) for IR. A substantial increase in topical steroid treatment, defined as starting, shifting from a lower to higher potency steroid, or doubling frequency of steroid at one visit (new) or gradually within 3 months (worsening) was required for SK, EK, IR, and SKU.
• Number of Postherpetic Neuralgia (PHN) Episodes [Month 12]: PHN was defined by a Zoster Brief Pain Inventory (ZBPI) score of ≥ 3 (the level at which pain interferes with normal activities), persisting, occurring, or reoccurring 3 or more months after the onset of Herpes Zoster Ophthalmicus (HZO).
• Number of Postherpetic Neuralgia (PHN) Episodes [Month 18 (6 months post treatment)]: PHN was defined by a ZBPI score of ≥ 3 (the level at which pain interferes with normal activities), persisting, occurring, or reoccurring 3 or more months after the onset of HZO
• Average Duration of Postherpetic Neuralgia (PHN) Pain [Month 24 (12 months post-treatment)]: The duration of pain after zoster is obtained at every visit when they reported pain. Outcome measure was obtained using the Zoster Brief Pain Inventory (ZBPI) score of worst pain in last 24 hours of 3/10 (the level at which pain interferes with normal activities) or more occurring 3 or more months after HZO onset was used to determine the prevalence, severity and duration of PHN.
• Average Duration of Postherpetic Neuralgia (PHN) Pain [Month 30 (18 months post treatment)]: The duration of pain after zoster is obtained at every visit when they reported pain. Outcome measure was obtained using the Zoster Brief Pain Inventory (ZBPI) score of worst pain in last 24 hours of 3/10 (the level at which pain interferes with normal activities) or more occurring 3 or more months after HZO onset was used to determine the prevalence, severity and duration of PHN.

Sex: All, ages: 18 Years to any

PARTICIPANT INCLUSION CRITERIA

To be eligible for study participation, an individual must meet all of the following criteria:

1. Ability to understand, and willingness and ability to read and sign, the informed consent form.
2. Ability to understand and follow instructions and study procedures.
3. Willingness to comply with all study procedures and be available for the duration of the study.
4. Ability to take oral medication, and are willing to adhere to study medication regimen.
5. Age 18 years or older.
6. Diagnosed with HZO in one eye based on both of these criteria:

   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).

PARTICIPANT EXCLUSION CRITERIA

An individual who meets any of the following criteria will be excluded from participation in this study:

1. History of immunocompromised status as defined by current CDC contraindications for the vaccine against zoster (44).

   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.
2. Medical history of a systemic disease and thought likely to meet one of the exclusion criteria listed in exclusion criterion #1 during the 18-month study period.
3. Renal insufficiency:

   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.

Participant flow

Outcome results

• Number of Participants With the First Occurrence of New or Worsening Stromal Keratitis Without Ulceration (SK), Endothelial Keratitis (EK), Iritis (IR), Dendriform Epithelial Keratitis (DEK), or Stromal Keratitis With Ulceration (SKU) (Primary), Count of participants, Participants: Placebo 86; Masked Oral Valacyclovir 1000 mg Daily 75
• Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment (Secondary), Count of participants, Participants: Placebo 104; Masked Oral Valacyclovir 1000 mg Daily 87
• Number of Postherpetic Neuralgia (PHN) Episodes (Secondary), Number, Number of PHN episodes: Placebo 24; Masked Oral Valacyclovir 1000 mg Daily 25
• Number of Postherpetic Neuralgia (PHN) Episodes (Secondary), Number, Number of PHN episodes: Placebo 20; Masked Oral Valacyclovir 1000 mg Daily 16
• Average Duration of Postherpetic Neuralgia (PHN) Pain (Secondary), Mean, Months: Placebo 14.3 (10.8 to 17.8); Masked Oral Valacyclovir 1000 mg Daily 13.6 (10.7 to 16.4)
• Average Duration of Postherpetic Neuralgia (PHN) Pain (Secondary), Mean, Months: Placebo 18.7 (13.6 to 23.7); Masked Oral Valacyclovir 1000 mg Daily 13.6 (11.6 to 15.6)

Adverse events

Time frame: 18 months

Serious adverse events by term

• Results publication: Mian SI, Kim J, Troxel AB, Cohen EJ, Jeng BH; ZEDS Trial Research Group. Outcomes of Recombinant Zoster Vaccination in Herpes Zoster Ophthalmicus: A Secondary Analysis of the Zoster Eye Disease Study. Cornea. 2026 Aug 4. doi: 10.1097/ICO.0000000000004253. Online ahead of print. PMID 42635062
• Results publication: Warner DB, Lee TF, Troxel AB, Prescott C, Cohen EJ, Jeng BH; ZEDS Trial Research Group. Time-Varying Effects of Valacyclovir Prophylaxis in the Zoster Eye Disease Study: A Post Hoc Exploratory Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2026 Aug 13:e263202. doi: 10.1001/jamaophthalmol.2026.3202. Online ahead of print. PMID 42593809
• Results publication: 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. PMID 40048191
• Results publication: 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. PMID 40048183
• Results publication: 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. PMID 38411973
• Results publication: 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. PMID 35090154

• Study Protocol and Statistical Analysis Plan (PDF, 2020-03-25)

• Elisabeth Cohen, MD, Study chair, NYU Langone Health

NIH grants: U10EY026869