A Phase 4 interventional study of Masked Placebo and Masked Oral Valacyclovir in Herpes Zoster Ophthalmicus, sponsored by NYU Langone Health. Completed at 78 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-03-07.
Sponsored by NYU Langone Health · Phase 4, Interventional, and Treatment
This is a multi-center, randomized, double-masked, placebo-controlled clinical trial of suppressive valacyclovir for one year in immunocompetent study participants with an episode of dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to Herpes Zoster Ophthalmicus (HZO) in the year prior to enrollment.
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.
180 studies on the registry are indexed under Chickenpox; 28 are open to participants now.
This study's enrollment of 527 is above the median of 475 across 149 interventional studies indexed under Chickenpox.
Browse Chickenpox studies →NYU Langone Health is the lead sponsor of 1,430 studies on the registry; 258 are open to participants now.
Of its 235 completed or terminated interventional studies of FDA-regulated products, 197 (84%) have results posted.
Counted across the registry records on this site, refreshed daily.
PARTICIPANT INCLUSION CRITERIA
To be eligible for study participation, an individual must meet all of the following criteria:
Diagnosed with HZO in one eye based on both of these criteria:
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 , and only need to be off oral and topical antivirals by the enrollment visit.
PARTICIPANT EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this study:
History of status as defined by current CDC for the vaccine against zoster (44).
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.
Renal insufficiency:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Reproductive potential
Able to have children. For women this usually means from the first period until menopause, unless permanently unable to through surgery; for men, unless permanently sterile. Read who the line is about — participants, women, men, or their partners.
Criteria about it usually ask for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CD4 count
The number of CD4 cells, a type of white blood cell, in a given amount of blood. It is used to follow how well the immune system is doing in HIV.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Encapsulated masked placebo
Drug: Masked Placebo
Valacyclovir, 500 mg, oral pill, two 500mg pills daily
Drug: Masked Oral Valacyclovir
Oral Placebo
Oral Valacyclovir 1000 mg/day
Also known as: Valtrex
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)
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.
Time frame: Month 12
Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of 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.
Time frame: Month 18 (6 months post treatment)
Number of Postherpetic Neuralgia (PHN) Episodes
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).
Time frame: Month 12
Number of Postherpetic Neuralgia (PHN) Episodes
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
Time frame: Month 18 (6 months post treatment)
Average Duration of Postherpetic Neuralgia (PHN) Pain
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.
Time frame: Month 24 (12 months post-treatment)
Average Duration of Postherpetic Neuralgia (PHN) Pain
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.
Time frame: Month 30 (18 months post treatment)
| Milestone | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Started | 261 | 266 |
| Completed | 223 | 237 |
| Not completed | 38 | 29 |
| Withdrew: Death | 2 | 1 |
| Withdrew: Lost to follow-up | 13 | 15 |
| Withdrew: Physician decision | 0 | 1 |
| Withdrew: Withdrawal by subject | 19 | 12 |
| Withdrew: Site unable to contact participant | 2 | 0 |
| Withdrew: Site closed scheduling conflict | 1 | 0 |
| Withdrew: Scheduling conflict | 1 | 0 |
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.
| Participants | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| 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) | 86 | 75 |
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.
| Participants | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment | 104 | 87 |
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 PHN episodes | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Number of Postherpetic Neuralgia (PHN) Episodes | 24 | 25 |
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
| Number of PHN episodes | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Number of Postherpetic Neuralgia (PHN) Episodes | 20 | 16 |
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.
| Months | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Average Duration of Postherpetic Neuralgia (PHN) Pain | 14.3 (10.8 to 17.8) | 13.6 (10.7 to 16.4) |
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.
| Months | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Average Duration of Postherpetic Neuralgia (PHN) Pain | 18.7 (13.6 to 23.7) | 13.6 (11.6 to 15.6) |
Collected over 18 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 2/261 (0.8%) | 18/261 (6.9%) | 0/261 (0%) |
| Masked Oral Valacyclovir 1000 mg Daily | 1/266 (0.4%) | 19/266 (7.1%) | 0/266 (0%) |
| Event | Placebo | Masked Oral Valacyclovir 1000 mg Daily |
|---|---|---|
| Chest PainGeneral disorders | 2/261 | 0/266 |
| Breast CancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/261 | 0/266 |
| Crohn's FlareGastrointestinal disorders | 0/261 | 2/266 |
| COVID-19 InfectionRespiratory, thoracic and mediastinal disorders | 0/261 | 2/266 |
| Tachy-brady SyndromeCardiac disorders | 1/261 | 0/266 |
| Myocardial InfarctionCardiac disorders | 1/261 | 0/266 |
| Left Main Coronary Artery DiseaseCardiac disorders | 1/261 | 0/266 |
| Sepsis with multi-organ failureGeneral disorders | 1/261 | 0/266 |
| COVID-19 InfectionInfections and infestations | 1/261 | 1/266 |
| SepsisInfections and infestations | 1/261 | 0/266 |
All randomized participants were included in the data analysis, not just participants who completed the study. Data were analyzed by intention-to-treat.
| Age, Continuous(years) | Placebo | Masked Oral Valacyclovir 1000 mg Daily | Total |
|---|---|---|---|
| Median | 58 (49 to 68) | 58 (49 to 66) | 58 (50 to 68) |
| Sex: Female, Male(Participants) | Placebo | Masked Oral Valacyclovir 1000 mg Daily | Total |
|---|---|---|---|
| Female | 135 | 131 | 266 |
| Male | 126 | 135 | 261 |
| Ethnicity (NIH/OMB)(Participants) | Placebo | Masked Oral Valacyclovir 1000 mg Daily | Total |
|---|---|---|---|
| Hispanic or Latino | 15 | 11 | 26 |
| Not Hispanic or Latino | 246 | 255 | 501 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Placebo | Masked Oral Valacyclovir 1000 mg Daily | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 4 | 4 |
| Asian | 13 | 14 | 27 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 1 |
| Black or African American | 15 | 7 | 22 |
| White | 222 | 235 | 457 |
| More than one race | 10 | 6 | 16 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Placebo | Masked Oral Valacyclovir 1000 mg Daily | Total |
|---|---|---|---|
| Canada | 29 | 34 | 63 |
| United States | 224 | 226 | 450 |
| New Zealand | 8 | 6 | 14 |
PDFs hosted by the registry, ClinicalTrials.gov.
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Studies of the drug tested here: Valacyclovir