Clinical trial NCT03134196: Zoster Eye Disease Study
Official title: Long-term Suppressive Valacyclovir Treatment for Herpes Zoster Ophthalmicus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Herpes Zoster Ophthalmicus
Keywords: Herpes Zoster Ophthalmicus
Zoster Eye Disease Study
Varicella Zoster Virus
Zoster
Shingles
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: National Institutes of Health (NIH)
First posted: 2017-04-28
Enrollment: 527
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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.

Primary outcomes:
measure: 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)
timeFrame: Month 12
Secondary outcomes:
measure: Number of Participants With Persistent Treatment Benefit at 18 Months, 6 Months After Cessation of Treatment
timeFrame: Month 18 (6 months post treatment)
measure: Number of Postherpetic Neuralgia (PHN) Episodes
timeFrame: Month 12
measure: Number of Postherpetic Neuralgia (PHN) Episodes
timeFrame: Month 18 (6 months post treatment)
measure: Average Duration of Postherpetic Neuralgia (PHN) Pain
timeFrame: Month 24 (12 months post-treatment)
measure: Average Duration of Postherpetic Neuralgia (PHN) Pain
timeFrame: Month 30 (18 months post treatment)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Eye Institute
state: California
city: Los Angeles
country: United States
facility: Jules Stein Eye Clinic - UCLA
state: California
city: Palo Alto
country: United States
facility: Byers Eye Institute at Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF- Francis I. Proctor Foundation
state: California
city: San Luis Obispo
country: United States
facility: Pacific Eye Surgeons, Inc.
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Littleton
country: United States
facility: Colorado Cornea Consultants P.C.
state: Colorado
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Delray Beach
country: United States
facility: Delray Eye Associates, PA
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Florida Eye Specialists
state: Florida
city: Miami
country: United States
facility: University of Miami - Bascom Palmer Eye Institute
state: Florida
city: Atlanta
country: United States
facility: Eye Consultants of Atlanta, PC
state: Georgia
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Glenview
country: United States
facility: NorthShore University Health System
state: Illinois
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University - Glick Eye Institute
state: Indiana
city: Prairie Village
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: LSU Health Science Center
state: Louisiana
city: Shreveport
country: United States
facility: Shreveport Eye Clinic
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: The Krieger Eye Institute
state: Maryland
city: Bethesda
country: United States
facility: Wilmer Eye Institute John Hopkins
state: Maryland
city: Owings Mills
country: United States
facility: Crossroads Eye Physician
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Peabody
country: United States
facility: Lahey Medical Center
state: Massachusetts
city: Weymouth
country: United States
facility: Eye Health Services
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Verdier Eye Center
state: Michigan
city: Golden Valley
country: United States
facility: Northwest Eye Clinic
state: Minnesota
city: Minnetonka
country: United States
facility: Jennifer Burdick
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University Opthalmology
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Morristown
country: United States
facility: EyeCare MD of NJ
state: New Jersey
city: Albany
country: United States
facility: Albany Stratton VA Medical Center
state: New York
city: Canandaigua
country: United States
facility: Finger Lakes Ophthalmology /The Eye Care Center
state: New York
city: East Setauket
country: United States
facility: Stony Brook Ophthalmology
state: New York
city: Great Neck
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: New York Eye and Ear Infirmary
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Weill Cornell Ophthalmology
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Eye Institute
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Portland
country: United States
facility: Devers Eye Institute
state: Oregon
city: Portland
country: United States
facility: Casey Eye Institute - Oregon Health and Science University
state: Oregon
city: Bala-Cynwyd
country: United States
facility: Vantage Eye Care Center, LLC
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Eye Clinic
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Corneal Associates at Wills Eye Hospital
state: Pennsylvania
city: Memphis
country: United States
facility: University of Tennessee - Hamilton Eye Institute
state: Tennessee
city: Nashville
country: United States
facility: Cornea and Cataract Consultants of Nashville
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Eye Institute
state: Tennessee
city: Dallas
country: United States
facility: Cornea Associates of Texas
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Fort Worth
country: United States
facility: Cornea Consultants of Texas
state: Texas
city: Houston
country: United States
facility: Alkek Eye Center - Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: R and R Eye Research, LLC
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Moran Eye Center
state: Utah
city: Richmond
country: United States
facility: Virginia Eye Institute
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: NY Eye Surgeons
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia/Vancouver General Hospital Eye Care Centre
state: British Columbia
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre-HDH Site and Queen's University
state: Ontario
city: Oakville
country: Canada
facility: Prism Eye Institute
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montréal
country: Canada
facility: The Research Institute of the McGill University Health Centre/McGill Academic Eye Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: Clinique Axe Visuel
state: Quebec
Study officials:
affiliation: NYU Langone Health
name: Elisabeth Cohen, MD
role: STUDY_CHAIR
References:
citation: 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.