ZEDS: Zoster Eye Disease Study

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Herpes Zoster Ophthalmicus	Drug: Masked Placebo Drug: Masked Oral Valacyclovir	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

780 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Long-term Suppressive Valacyclovir Treatment for Herpes Zoster Ophthalmicus

Actual Study Start Date :

Aug 23, 2017

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Jul 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Encapsulated masked placebo	Drug: Masked Placebo Oral Placebo
Active Comparator: Masked Oral Valacyclovir 1000 mg daily Valacyclovir, 500 mg, oral pill, two 500mg pills daily	Drug: Masked Oral Valacyclovir Oral Valacyclovir 1000 mg/day Other Names: Valtrex

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Encapsulated masked placebo

Drug: Masked Placebo

Oral Placebo

Active Comparator: Masked Oral Valacyclovir 1000 mg daily

Valacyclovir, 500 mg, oral pill, two 500mg pills daily

Drug: Masked Oral Valacyclovir

Oral Valacyclovir 1000 mg/day

Other Names:

Valtrex

Outcome Measures

Primary Outcome Measures

Time to first occurrence of Dendriform epithelial keratitis, Stromal keratitis, Endothelial keratitis or Iritis [12 months]
The primary outcome measure is time to first occurrence of Dendriform epithelial keratitis, Stromal keratitis, Endothelial keratitis,OR Iritis, associated with pre-specified definitions of these disease manifestations and associated treatment requirements, in study participants assigned to valacyclovir compared to placebo, during one year of study treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

PARTICIPANT INCLUSION CRITERIA

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

Ability to understand, and willingness and ability to read and sign, the informed consent form.
Ability to understand and follow instructions and study procedures.
Willingness to comply with all study procedures and be available for the duration of the study.
Ability to take oral medication, and are willing to adhere to study medication regimen.
Age 18 years or older.
Diagnosed with HZO in one eye based on both of these criteria:
History of characteristic unilateral, usually vesicular, HZO rash in the dermatomal distribution of cranial nerve V1 or V2.
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.

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.

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:

History of immunocompromised status as defined by current CDC contraindications for the vaccine against zoster (44).
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.
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.
Study participants on immunosuppressive therapy including:

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.
Study participants with history of hematopoietic stem cell transplantation.

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.
Renal insufficiency:
Requires dialysis or has history of renal transplant or
eGFR less than 45, determined within 3 months days preceding enrollment.
Allergy or adverse reaction to valacyclovir or acyclovir.
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.
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.
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.
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.
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.
Incarceration
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Mayo Clinic - Arizona	Scottsdale	Arizona	United States	85259
3	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Scripps Clinic	La Jolla	California	United States	92037
5	Loma Linda University Eye Institute	Loma Linda	California	United States	92354
6	Jules Stein Eye Clinic - UCLA	Los Angeles	California	United States	90095
7	Byers Eye Institute at Stanford University	Palo Alto	California	United States	94303
8	UCSF- Francis I. Proctor Foundation	San Francisco	California	United States	94131
9	Pacific Eye Surgeons, Inc.	San Luis Obispo	California	United States	93401
10	University of Colorado	Aurora	Colorado	United States	80045
11	Colorado Cornea Consultants P.C.	Littleton	Colorado	United States	80120
12	Medstar Georgetown University Hospital	Washington	District of Columbia	United States	20007
13	Delray Eye Associates, PA	Delray Beach	Florida	United States	33484
14	University of Florida	Gainesville	Florida	United States	32610
15	Florida Eye Specialists	Jacksonville	Florida	United States	33204
16	University of Miami - Bascom Palmer Eye Institute	Miami	Florida	United States	33136
17	Eye Consultants of Atlanta, PC	Atlanta	Georgia	United States	30339
18	University of Illinois	Chicago	Illinois	United States	60612
19	NorthShore University Health System	Glenview	Illinois	United States	60026
20	Case Western Reserve University	Cleveland	Indiana	United States	44106
21	Indiana University - Glick Eye Institute	Indianapolis	Indiana	United States	46202
22	University of Kansas Medical Center	Prairie Village	Kansas	United States	66208
23	University of Kentucky	Lexington	Kentucky	United States	40509
24	LSU Health Science Center	New Orleans	Louisiana	United States	70112
25	Shreveport Eye Clinic	Shreveport	Louisiana	United States	71106
26	University of Maryland	Baltimore	Maryland	United States	21201
27	The Krieger Eye Institute	Baltimore	Maryland	United States	21215
28	Wilmer Eye Institute John Hopkins	Bethesda	Maryland	United States	20817
29	Crossroads Eye Physician	Owings Mills	Maryland	United States	21117
30	Tufts Medical Center	Boston	Massachusetts	United States	02111
31	Massachusetts Eye and Ear Infirmary	Boston	Massachusetts	United States	02114
32	Boston Medical Center	Boston	Massachusetts	United States	02118
33	Lahey Medical Center	Peabody	Massachusetts	United States	01960
34	Eye Health Services	Weymouth	Massachusetts	United States	02189
35	University of Michigan	Ann Arbor	Michigan	United States	48105
36	Verdier Eye Center	Grand Rapids	Michigan	United States	49546
37	Northwest Eye Clinic	Golden Valley	Minnesota	United States	55427
38	Jennifer Burdick	Minnetonka	Minnesota	United States	55305
39	Mayo Clinic	Rochester	Minnesota	United States	55905
40	Washington University Opthalmology	Saint Louis	Missouri	United States	63110
41	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
42	EyeCare MD of NJ	Morristown	New Jersey	United States	07960
43	Albany Stratton VA Medical Center	Albany	New York	United States	12208
44	Finger Lakes Ophthalmology /The Eye Care Center	Canandaigua	New York	United States	14424
45	Stony Brook Ophthalmology	East Setauket	New York	United States	11733
46	Northwell Health	Great Neck	New York	United States	11021
47	New York Eye and Ear Infirmary	New York	New York	United States	10003
48	NYU Langone Health	New York	New York	United States	10016
49	Weill Cornell Ophthalmology	New York	New York	United States	10021
50	Duke University	Durham	North Carolina	United States	27710
51	Cincinnati Eye Institute	Cincinnati	Ohio	United States	45242
52	Case Western Reserve University	Cleveland	Ohio	United States	44106
53	Devers Eye Institute	Portland	Oregon	United States	97210
54	Casey Eye Institute - Oregon Health and Science University	Portland	Oregon	United States	97239
55	Vantage Eye Care Center, LLC	Bala-Cynwyd	Pennsylvania	United States	19004
56	Geisinger Eye Clinic	Danville	Pennsylvania	United States	17822
57	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
58	Corneal Associates at Wills Eye Hospital	Philadelphia	Pennsylvania	United States	19107
59	University of Tennessee - Hamilton Eye Institute	Memphis	Tennessee	United States	38163
60	Cornea and Cataract Consultants of Nashville	Nashville	Tennessee	United States	37203
61	Vanderbilt Eye Institute	Nashville	Tennessee	United States	37232
62	Cornea Associates of Texas	Dallas	Texas	United States	75231
63	University of Texas Southwestern	Dallas	Texas	United States	75390
64	Cornea Consultants of Texas	Fort Worth	Texas	United States	76107
65	Alkek Eye Center - Baylor College of Medicine	Houston	Texas	United States	77030
66	R and R Eye Research, LLC	San Antonio	Texas	United States	78229
67	University of Utah - Moran Eye Center	Salt Lake City	Utah	United States	84132
68	Virginia Eye Institute	Richmond	Virginia	United States	23226
69	Virginia Mason Medical Center	Seattle	Washington	United States	98101
70	NY Eye Surgeons	Seattle	Washington	United States	98133
71	University of Wisconsin - Madison	Madison	Wisconsin	United States	53705
72	Royal Alexandra Hospital	Edmonton	Alberta	Canada	T5H 3V9
73	University of British Columbia/Vancouver General Hospital Eye Care Centre	Vancouver	British Columbia	Canada	V5Z 3N0
74	Kingston Health Sciences Centre-HDH Site and Queen's University	Kingston	Ontario	Canada	K7L 5G2
75	Prism Eye Institute	Oakville	Ontario	Canada	L6H 0J8
76	Centre Hospitalier de l'Université de Montréal (CHUM)	Montréal	Quebec	Canada	H2X 3E4
77	The Research Institute of the McGill University Health Centre/McGill Academic Eye Centre	Montréal	Quebec	Canada	H3A 4S5
78	Clinique Axe Visuel	Sherbrooke	Quebec	Canada	J1H4C7