Herpes Zoster Ophthalmicus
Conditions
Keywords
Herpes Zoster Ophthalmicus, Zoster Eye Disease Study, Varicella Zoster Virus, Zoster, Shingles
Brief summary
This is a multi-center, randomized, double-masked, placebo-controlled clinical trial of suppressive valacyclovir for one year in immunocompetent study participants with an episode of dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, and/or iritis due to Herpes Zoster Ophthalmicus (HZO) in the year prior to enrollment.
Detailed description
The objective of the Zoster Eye Disease Study (ZEDS) is to determine whether prolonged suppressive oral antiviral treatment with valacyclovir reduces complications of Herpes Zoster Ophthalmicus (HZO), thereby improving clinical outcomes in this common and potentially vision- and life-threatening disease. There are 1,000,000 new cases of Herpes Zoster (HZ) per year in the USA, with 10-20% being HZO. Specific Aims Primary Aim: The primary aim of this double-masked, placebo controlled multicenter randomized clinical trial will test the hypothesis that suppressive antiviral treatment for 12 months with oral valacyclovir 1000 mg daily reduces the rate of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis or iritis compared to placebo, at 12 months as the primary endpoint, and at 18 months including 6 months of follow-up after treatment, as a secondary endpoint, in patients with HZO who have had an episode of one of these disease manifestations during the year prior to enrollment. Secondary Aim: The second aim is to test the hypothesis that suppressive treatment for 12 months with oral valacyclovir 1000 mg daily reduces the severity and duration of postherpetic neuralgia (PHN), compared to placebo, at 12 months and at 18 months as secondary endpoints, in similar patients with HZO. PHN is a debilitating chronic pain syndrome that negatively impacts quality of life, especially in elderly patients. The study will enroll immunocompetent patients age 18 years and older who have HZO diagnosed at variable times in the past, with these types of active anterior segment ocular segment disease within the past year. Eligible patients will be randomized in a 1:1 ratio to long-term suppressive treatment with oral valacyclovir 1000 mg daily or placebo for 12 months, plus usual ophthalmic care, and followed every 3 months for a total of 18 months, to determine outcomes of new or worsening dendriform epithelial keratitis, stromal keratitis, endothelial keratitis or iritis and/or severity and duration of PHN during 12 months of treatment and for 6 months following treatment discontinuation. The results with regard to PHN may be applicable to HZ in other locations. If suppressive valacyclovir treatment is determined to be effective, the potentially devastating disease burden of HZO and HZ may be reduced for patients, as well as the annual costs to society, estimated in the USA to be one billion dollars.
Interventions
DRUGMasked Placebo
Oral Placebo
DRUGMasked Oral Valacyclovir
Oral Valacyclovir 1000 mg/day
Sponsors
National Eye Institute (NEI)
National Institutes of Health (NIH)
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Encapsulated masked placebo
Masked Placebo: Oral Placebo | 261 |
| Masked Oral Valacyclovir 1000 mg Daily Valacyclovir, 500 mg, oral pill, two 500mg pills daily
Masked Oral Valacyclovir: Oral Valacyclovir 1000 mg/day | 266 |
| Total | 527 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 13 | 15 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Scheduling Conflict | 1 | 0 |
| Overall Study | Site Closed Scheduling Conflict | 1 | 0 |
| Overall Study | Site Unable to Contact Participant | 2 | 0 |
| Overall Study | Withdrawal by Subject | 19 | 12 |
Baseline characteristics
| Characteristic | Masked Oral Valacyclovir 1000 mg Daily | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 26 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 255 Participants | 501 Participants | 246 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 27 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 22 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 16 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 235 Participants | 457 Participants | 222 Participants |
| Region of Enrollment Canada | 34 participants | 63 participants | 29 participants |
| Region of Enrollment New Zealand | 6 participants | 14 participants | 8 participants |
| Region of Enrollment United States | 226 participants | 450 participants | 224 participants |
| Sex: Female, Male Female | 131 Participants | 266 Participants | 135 Participants |
| Sex: Female, Male Male | 135 Participants | 261 Participants | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 261 | 1 / 266 |
| other Total, other adverse events | 0 / 261 | 0 / 266 |
| serious Total, serious adverse events | 18 / 261 | 19 / 266 |
Outcome results
Primary
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
Population: Data were analyzed by intention-to-treat. Treatment requirements for endpoints were revised on January 6, 2020 to allow a recent reduction in steroids for SK, EK, IR, and SKU as the estimated endpoint rate assumed this, and applied retroactively to all endpoints without any knowledge of study outcome data by treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 Participants |
| 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) | 75 Participants |
95% CI: [0.5, 1.06]
Secondary
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)
Population: Data were analyzed by intention-to-treat.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Average Duration of Postherpetic Neuralgia (PHN) Pain | 14.3 Months |
| Masked Oral Valacyclovir 1000 mg Daily | Average Duration of Postherpetic Neuralgia (PHN) Pain | 13.6 Months |
Secondary
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)
Population: Data were analyzed by intention-to-treat.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Average Duration of Postherpetic Neuralgia (PHN) Pain | 18.7 Months |
| Masked Oral Valacyclovir 1000 mg Daily | Average Duration of Postherpetic Neuralgia (PHN) Pain | 13.6 Months |
Secondary
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)
Population: Data were analyzed by intention-to-treat. Treatment requirements for endpoints were revised on January 6, 2020 to allow a recent reduction in steroids for SK, EK, IR, and SKU as the estimated endpoint rate assumed this, and applied retroactively to all endpoints without any knowledge of study outcome data by treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment | 104 Participants |
| Masked Oral Valacyclovir 1000 mg Daily | Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment | 87 Participants |
95% CI: [0.56, 0.99]
Secondary
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
Population: Data were analyzed by intention-to-treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Postherpetic Neuralgia (PHN) Episodes | 24 Number of PHN episodes |
| Masked Oral Valacyclovir 1000 mg Daily | Number of Postherpetic Neuralgia (PHN) Episodes | 25 Number of PHN episodes |
Secondary
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)
Population: Data were analyzed by intention-to-treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Postherpetic Neuralgia (PHN) Episodes | 20 Number of PHN episodes |
| Masked Oral Valacyclovir 1000 mg Daily | Number of Postherpetic Neuralgia (PHN) Episodes | 16 Number of PHN episodes |