1. Herpes Zoster and the Zoster Eye Disease Study (ZEDS)
Elisabeth J Cohen, MD
Professor of Ophthalmology
New York University SoM
NYU Langone Health

2. Why Should We Care About Shingles?
Zoster/shingles is a common, serious and preventable disease!
Shingles causes
Severe acute pain for average 30 days
Severe, debilitating chronic pain unresponsive to treatment
Chronic and/or recurrent unilateral eye disease and vision loss
Unilateral hearing loss
Fatal strokes and other serious neurological diseases
Probably heart attacks and other life threatening vascular diseases
It can ruin your life or kill you

3. Two Vaccines against Herpes Zoster
First: Zostavax
New and better: Shingrix
The bottom line: Adults age 50 years and older should get Shingrix ASAP!

4. New Shingrix Vaccine Recombinant Zoster Vaccine (RZV)
Contains a viral protein in a new immunogenic solution
2 injections 2 months apart in immunocompetent adults age 50+
90-97% efficacy for all age groups
Acute local and systemic symptoms in ~15%
Efficacy persists: 85% at year 4
FDA approved Shingrix 2017 age 50+
CDC recommended 2018 for immunocompetent 50+
Presentation Title Goes Here

5. FDA Label for Shingrix Indicated for prevention HZ in adults age 50+
Not just immunocompetent adults!
Immunosuppressive treatment may reduce effectiveness
2 shots given 2 to 6 months apart
Can give at same time as flu vaccine
Only contraindication: severe allergic reaction to vaccine
Acute adverse reactions in ~ 10%
Less common age 70+ than age years

6. CDC Recommendations
Shingrix recommended for immunocompetent adults age 50 years+
Recommended if previously received Zostavax
Shingrix should be given to people with a past history of zoster
Shingrix is preferred over Zostavax
Dooling, Guo, Pater, Lee, Moore, Belongia, Harpaz. MMWR Jan 26, 2018; 67:

7. What is Herpes Zoster/Shingles?
Varicella Zoster Virus (VZV) causes
Varicella/Chicken Pox
Latent infection of nerves
Zoster/Shingles: local reactivation of latent virus
Typical unilateral, painful, usually blistering rash
We get shingles from our own chicken pox!

8. Rising Incidence of Zoster
Incidence up
All ages
Age
Common disease
~1,200,000 new cases/yr
1 in 3 will have zoster
1 in 2 age 85+

9. Age at Onset of Zoster
Rate goes up with age, but number of cases highest in 50’s
Misconceptions
Herpes Zoster is only a disease of the elderly- it affects large number of people in their prime too!
Healthy people are not at risk for zoster and its potentially disabling sequelae- we are!

10. Postherpetic Neuralgia (PHN)
PHN is pain/itch beyond 3 months after onset shingles
Most common complication of zoster
Risk factors:
Age, severity acute pain, rash, Herpes Zoster Ophthalmicus (HZO)
Not prevented by acute antiviral treatment of zoster; no good treatment
Zoster risk factor for major depression, and most common cause of suicide due to pain in people age 70+
Opinion: If you are committed to healthy aging, zoster is a disease to be avoided!

11. Anecdote
My mother worked full time to age 67…She then got very ill with Shingles…she was in severe pain. You could not even touch her hair or face. She suffered for many weeks…She was never the same….The chronic pain caused her to sleep for most of the day…The pain never really went totally away… Neither the polio, meningitis, or rheumatoid arthritis stopped my very active mother, but the shingles destroyed her life.
KC 2017

12. Zoster Risk for Stroke, Heart, Vascular Disease
Zoster long known risk factor for potentially fatal stroke
And other neurologic diseases affecting brain and spinal cord
Zoster recently reported as risk factor for heart disease
And other potentially fatal vascular diseases including Giant Cell Arteritis

13. Herpes Zoster Ophthalmicus (HZO)
HZO refers to zoster affecting forehead and eye
Can damage all parts of the eye and surrounding tissues
The Zoster Eye Disease Study (ZEDS), funded by NEI and led by NYU, aims to determine if prolonged low dose antiviral treatment can reduce these eye complications and/or chronic pain (PHN)
Presentation Title Goes Here

14. Treatment of Herpes Zoster (HZ)
Oral antivirals within 72 hours of rash are approved and recommended
Valacyclovir 1000 mg three times daily for 7 days
Famciclovir 500 mg three times daily for 7 days
Acyclovir 800 mg five times daily for 7-10 days (not quite as effective)
Reduces chronic eye disease from 50% to 30%, does not reduce PHN

15. Possible New Treatment for HZO
The Zoster Eye Disease Study (ZEDS) funded by NEI in to conduct a multicenter, Randomized, placebo controlled Clinical Trial (RCT) to determine whether prolonged, suppressive valacyclovir treatment reduces complications of Herpes Zoster Ophthalmicus (HZO), including eye disease and/or postherpetic neuralgia
Presentation Title Goes Here

16. ZEDS Study Structure > 60 Participating Clinical Centers in USA
2019 adding centers in USA, Canada, Brazil and UK
Coordinating Center (CC) at NYU Langone Health
CC project manager: MeeLee Tom
Study Chair: Elisabeth Cohen, Co-Chair Bennie Jeng, U MD
Multiple PIs: Judith Hochman, Andrea Troxel CC NYUSoM, NYULH
Participating Clinical Center (PCC) at NYULH:
Principal Investigator: Ilyse Haberman
Co-investigators: Doug Lazarro, Anam Qureshi, Elizabeth Viriya. Coordinator: Tonya Robin
Medical monitor: Michael Perskin
Presentation Title Goes Here

17. Background and Rationale of ZEDS
Acute high dose oral antiviral treatment is recommended for Herpes Zoster Ophthalmicus (HZO), but there is no standard approach to antiviral treatment for ocular complications of HZO.
Rationale of the Zoster Eye Disease Study (ZEDS)
First:
Relatively recent knowledge of infectious pathogenesis of complications of Herpes Zoster and HZO
Second:
Significant benefit of suppressive antiviral treatment in reducing recurrent Herpes Simplex Virus (HSV) eye disease
HZO and HSV keratitis, caused by different herpes viruses, are analogous in many ways

18. Rationale for Zoster Eye Disease Study (ZEDS)
Active VZV infection contributes to recurrent/chronic eye disease
Dendriform epithelial keratitis PCR+ for VZV and responds to topical ganciclovir
Iritis: AC is PCR+ for VZV
Pavan Langston D. Arch Ophthalmol 1995; 111:1381
Hu AY, Am J Ophthalmol 2010; 149:214
Aggarwal S. Cornea. 2014; 33(2):109
Takase Jpn J Opthalmol 2014; 58:473

19. Rationale of Zoster Eye Disease Study
Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial (APT)
HEDS Study Group. N Eng J Med 1998; 339:
HEDS Study Group. Arch Ophthalmol 2000;118:
Long-term suppressive treatment with oral acyclovir resulted in 45% reduction in recurrent Herpes Simplex Virus disease at 1 yr
Suppressive antiviral treatment is now standard of care for HSV keratitis, and has improved outcomes
ZEDS trial analogous to the HEDS APT study for ocular disease caused by varicella zoster virus (VZV)
Valacyclovir, prodrug of acyclovir, has higher plasma concentration than acyclovir
Similar trial design: RCT of 1 yr of suppressive valacyclovir vs. placebo with follow-up every 3 months for 18 months

20. Overview of Study Design
Immunocompetent HZO patients, 18 years and older
History of typical unilateral vesicular rash in V1 distribution
Episode in medical record within the year prior to enrollment of
Dendriform epithelial keratitis
Stromal keratitis
Endothelial keratitis
Iritis
Keratitis and iritis can be called by wide variety of names: pseudodendrites, keratouveitis, disciform keratitis, uveitis…
Randomized 1:1 ratio to double masked valacyclovir 1000 mg or placebo daily for 1 yr
Randomized in 4 strata
Age of onset HZO: < 60 years vs years or more
Time since onset HZO < 6 months vs months or more
Enroll 1050 study participants over 3 years

21. Exclusion Criteria
Immunocompromise by CDC criteria for impaired cellular immunity due to disease or treatment
Refractive surgery, other than at time of cataract surgery, within 5 years, corneal transplant in eye with HZO
Renal insufficiency with eGFR) < 45
Pregnant, nursing, or do not agree to use contraception for one year
Requires valacyclovir, acyclovir, or famciclovir, for genital/eye HSV
Vaccination against zoster within 1 month of enrollment
Incarceration, unable to give informed consent, comply with protocol, or complete 18 months of follow-up

22. Primary Objective and Endpoint
To evaluate whether or not suppressive valacyclovir treatment compared with placebo will delay time to first occurrence by 12 months of new or worsening
Dendriform epithelial keratitis (DEK)
Stromal keratitis without ulceration(SK)
Endothelial keratitis (EK)
Iritis (IR) OR
Stromal keratitis with ulceration (SKU)
With pre-specified treatment requirements to be a primary endpoint

23. Corneal Disease Classification of HZO
Recommend use same as HSV
White.2014, Jul
Epithelial keratitis
Infectious dendriform
Stromal keratitis
Without ulceration
With ulceration (not microbial infection)
Endothelial keratitis
Uveitis
Presentation Title Goes Here

24. Definitions Endpoints of Stromal Keratitis With or Without Ulceration, Endothelial Keratitis, Iritis and Dendriform Epithelial Keratitis
Stromal Keratitis without ulceration: Localized or diffuse stromal infiltrates with or without keratic precipitates, corneal edema, or corneal neovascularization, and is without an epithelial defect by fluorescein staining.
Endothelial Keratitis: Disciform (localized) or diffuse corneal stromal, and usually epithelial edema, with keratic precipitates out of proportion to anterior chamber reaction (none or trace: 5 cells or less per field).
Iritis: Anterior chamber reaction graded ≥1+ (6 or more cells/field using 1x1mm slit beam) in the absence of suspected or proven microbial keratitis.
Stromal Keratitis with ulceration: Stromal infiltrates with an overlying epithelial defect by fluorescein staining due to active stromal keratitis and not neurotrophic keratopathy or suspected or proven microbial superinfection. Microbial superinfection should be ruled out by negative corneal smears and cultures and/or lack of response to intensive antibiotic treatment every hour.
Dendriform Epithelial Keratitis: Linear or elongated, often branching lesion(s) on the corneal surface that stain at least minimally with fluorescein. They are usually elevated, non-ulcerated, and without terminal bulbs.

28. Secondary Study Objectives and Endpoints
To evaluate whether or not the effect of treatment on primary endpoint persists for 6 months after treatment by comparing rates of new or worsening DEK, SK, EK, IR or SKU by 18 months follow-up in participants randomized to valacyclovir or placebo
To test hypothesis that suppressive valacyclovir treatment reduces the incidence, severity, duration of postherpetic neuralgia (PHN) compared to placebo at 12 and 18 months

29. Other Secondary Endpoints
Development of specific disease manifestations of HZO
Primary endpoints: DEK, SK, EK, IR and SKU
Neurotrophic keratopathy with and without melting, perforation, presumed or proven microbial superinfection
Episcleritis, Scleritis
Effect of past history of specific manifestations on their recurrence
Glaucoma: by IOP (22 mm Hg+ and 6 mmHg+ rise) and medical/surgical treatment required
Impact of vaccination against zoster on HZO endpoints by treatment group (valacyclovir vs. placebo)

30. Study Visits and Treatment
Prescreening review of medical records including ED and discussion with potential study participant by investigator, coordinator
Screening Study Visit 1
Consent obtained, then eGFR and pregnancy tests ordered
Enrollment/randomization Study Visit 2 (within 30 days of tests)
Study medication consisting of 3 mos supply of masked valacyclovir and placebo pills dispensed, to be taken 2 pills once daily
Valacyclovir 500 mg used because 1000 mg too big for encapsulation (and option for bid and daily dosing if side effects)
Follow up visits every 3 months for 18 months
12 month study visit: study medication discontinued
Presentation Title Goes Here

31. Case Report Forms for Electronic Data Capture

32. Clinical Operations Status Report Data Safety Monitoring Committee (DSMC) 5.8.19
Addition Participating Clinical Centers (PCCs)
USA
Canada
Brazil UK
Recruitment of study participants
Challenges re enrollment
PCC meetings, training and webinars
Revision of Case Report Forms (CRFs)
Trial quality assurance through monitoring
Primary endpoint adjudication
Publications
Successes

33. PCC Activation Activation status (5/31/2019)
Active PCCs PCCs with enrolled/randomized study participants 49
Number of enrolled study participants 156
PCCs pending training/certification, IRB, contracts and/or activation
USA 7
Canada
Brazil 3 UK
Need to confirm these numbers

34. Actual Screening and Enrollment (5/31/2019) vs. Plan

35. Challenge of Lower than Expected Enrollment
Continued increased contact with underperforming PCCs
Discussions with Executive/Steering Co on enrollment
Additional payments to PCCs to support pre-screening effort, coordinator professional development, for study participants
Adding PCCs in USA, Canada, Brazil, and UK
Adding satellite locations with study medication at PCCs
Talks by study chair, co-chair, PIs at national conferences and grand rounds to promote enthusiasm for support of ZEDS
Added the bullet about screening support

36. Enrollment Barriers
~50% of ZEDS investigators use suppressive antiviral treatment for HZO despite lack of high quality evidence
Contributes to enrollment below expectations
Suppressive antiviral treatment is only allowed in ZEDS after enrollment/randomization when diagnosis occurs of new/worsening DEK, SK, EK, IR, or SKU
Study medication stopped only while on open label oral antiviral treatment
Study participant continues in study
Much easier to enroll recent onset than chronic HZO study participants
Plan survey of investigators regarding barriers to enrollment and approaches to overcome them

37. Changes in Case Report Forms
Case Report Forms (CRFs) have been revised and implemented to capture information on
Vaccinations against zoster pre and post enrollment after aim added to evaluate impact of vaccination against zoster on HZO and study outcomes
Suppressive antiviral treatment pre enrollment
Steroids use – a new CRF starting at enrollment
New Verification Form of Possible Primary Endpoint to send to CC
Verifying investigator review of data to be submitted related to possible primary endpoint diagnoses
Investigator is responsible for accuracy of data, coordinator for submission into TrialMaster

38. Primary Endpoint Adjudication
As of 5/31/2019: 53 diagnoses of new/worsening possible endpoints (SK, EK, IR, SKU or DEK)
43 possible primary endpoints adjudicated by 2 members and chair of Clinical Event Review Committee (CERC)
20 confirmed primary endpoints,
23 not primary endpoints
Expected in order not to miss endpoints and for secondary/exploratory endpoints
10 additional possible primary endpoints pending adjudication

39. Publications Monthly newsletters for investigators, coordinators
FAQs section addresses questions re protocol
Available on Website
Editorial
Jeng BH. Herpes Zoster Eye Disease: New ways to combat an old foe. Ophthalmology. 2018; 125:
Survey of ZEDS investigators’ baseline HZO practices and opinions
Lo, DM; Jeng, BH; Gillespie, C; Wu, M; Cohen, EJ. Current Practice Patterns and Opinions in the Management of Recent Onset or Chronic Herpes Zoster Ophthalmicus of Zoster Eye Disease Study Investigators. Cornea 2019; 38:
On line announcements posted at NYULH, available for PCCs
News
Recruitment (IRB approved)

40. Successes
62 active PCCs, including 49 with study participants enrolled
Adding PCCs in US, Canada, Brazil and UK
Additional payments
Adding satellite locations to make study more accessible
Obtained study medication with longer expiration date
Reduce need for additional drug campaigns
Allows for satellite locations with study med at PCCs

41. DSMC Statistical Considerations: Primary Objective - Assumptions and Sample Size
12-month cumulative failure rate for primary endpoint in placebo group: estimated at 30%
Detect 30% relative risk reduction compared to placebo
Equivalent to 12-month cumulative failure rate of 21.3% for valacyclovir patients
Equivalent to detectable hazard ratio for failure on valacyclovir relative to placebo of 0.67 (based on logrank test)
α = 0.05 (2-sided); power = 90%
3 year accrual period
Projected accrual:
start up phase: 6% randomized in first 6 months
20% in first 12 months
40% per year in years 2 and 3
Sample size: 1050 (525 per arm)
ZEDSSDDCCDSMCMasked

42. Masked Data Summary: Accrual
141 Participants randomized since start of study
(52 since the last DSMC meeting)
Strata
Accrual to Date
(March 19, 2019)
Number of
Randomized Participants
Percent of Participants
All Strata
141
100
< 60y, Recent 29 21
< 60y, Chronic 42 30
≥ 60y, Recent 37 26
≥ 60y, Chronic 33 23
ZEDSSDDCCDSMCMasked

43. Accrual Over Time Since PCC Activation
ZEDSSDDCCDSMCMasked

44. Endpoints and Follow-up by Study Visit
Median time from randomization to first endpoint (n=11): 2.9 months (range: 0.9 – 6.2 months)
Median time on study for all participants
(n=141): 6.3 months (range: 0 – 16 months)
ZEDSSDDCCDSMCMasked

45. Baseline Characteristics (March 19, 2019)
57% of randomized participants are female
Both genders represented in each of the 4 strata
85% of participants are White
3 participants (2%) are Hispanic or Latino
Median age at randomization: 60 (Q1-Q3: 51-71)
82% of participants did not receive zoster vaccine prior to enrollment
1 (1%) received RZV
24 (17%) received ZVL
ZEDSSDDCCDSMCMasked

46. Serious Adverse Events
8 SAEs reported in 6 participants not deemed by masked medical monitor to be related to study med
Death
Stroke
Heart attack
Acute kidney injury due to urinary retention
Crohn’s aggravated (2)
Bacteremia
Migraine requiring hospitalization
No Acute Renal Failure SAEs have been reported
ZEDSSDDCCDSMCMasked

47. Adjudicated endpoints 28 suspected endpoints
14 confirmed (in 11 study participants)
Median time from randomization to endpoint
2.9 months
range: 0.9 – 6.2 months
Adjudicator agreement: 43%
DSMC recommended obtain data on reasons for disagreement, adjudication CRF revised to do so, adjudicator endpoint training addressed
ZEDSSDDCCDSMCMasked

48. First Adjudication Endpoint by 12 Months
First Endpoint Type N
Dendriform Epithelial Keratitis (DEK) 1
Stromal Keratitis (SK) 9
Endothelial Keratitis (EK) 3
Iritis (IR)
Stromal Keratitis with Ulceration (SKU)
ZEDSSDDCCDSMCMasked

49. Evaluate accrual and projections based on next 6-12 months
Next Steps
Evaluate accrual and projections based on next 6-12 months
Consider revised timeline
Likely with no cost extensions of grant
ZEDSSDDCCDSMCMasked

50. Lessons I Have Learned on What it Takes to Get a Grant
Expertise: Leads to meaningful clinical question to study
Passion: Study is important to you and for public health
Team: It takes a very committed academic medical center to be successful.
Hard work!!!
Grit: When I wanted to give up, the team wanted to try again
Luck: Beyond challenging to get a fair review from NIH

51. Compelling Hypothesis
Prolonged suppressive antiviral treatment will reduce complications of Herpes Zoster Ophthalmicus (Shingles of the eye)
Recent knowledge that zoster is followed by chronic active VZV infection contributing to serious complications, including eye disease, pain, stroke…
Suppressive antiviral treatment significantly reduces recurrent Herpes Simplex Virus (HSV) eye disease, which has similarities to herpes zoster eye disease

52. Before the Grant 2008 developed Herpes Zoster Ophthalmicus (HZO)
2009 stopped operating due to loss of vision in right eye
I thought zoster ended my career
But the truth is it re-energized my career in new directions

53. The Idea
In 2010 I had the idea for the Zoster Eye Disease Study of suppressive antiviral treatment to reduce complications of Herpes Zoster Ophthalmicus

54. First Steps
Suggested idea to lead center of Herpetic Eye Disease Study (HEDS)
They conducted 2010 survey of Cornea Society listserv (N=100)
~85% or cornea specialists treat chronic or recurrent HZO
~50% thought prolonged antiviral treatment reduced recurrences
Did nothing else
Sy A Cornea 2012;31:
Second survey in 2013 of listserv and cornea leaders by NYU to determine preferred suppressive antiviral regimen and identify potential study centers (N >150 respondents)
Valacyclovir 500 mg bid or 1000 daily preferred by ~60%
>60% interested in participating in a clinical trial
Sackel D Eye Contact Lens 2014; 40:200-6
Third survey in 2013 by NYU of potential centers and ex-cornea fellows at 4 major programs to identify centers and number of HZO cases
60 centers completed participating center applications for first grant
18 centers treated >100 HZO cases in 2012

55. The NYU Team That Made It Happen
Dafna Bar-Sagi:
Make the public health significance clear!!!
Judy Hochman’s tremendous clinical trial experience continuously invaluable in countless ways
Asks questions and makes suggestions that would not occur to me
Expertise and patience to navigate NIH
Experience running Coordinating Center of large multicenter RCTs
Statistical and data management expertise from the outset

56. The NYU Team Jacqui Arciniega: Senior Project Director
From draft one in January 2013 has walked me through every step of the way through grant preparation
Was encouraging, although she knew much better than I suspected
the long road ahead
Carefully understood grant application options and requirements
and made sure entire team got all pieces of the project done
NYU MDs : Michael Perskin, Laura Balcer
Important contributions to protocol

57. What It Takes: Strike One 2013
2012: First draft
Contacted NEI, referred to project officer who told me he did not know that zoster affected the eye until our conversation!
2013:
Drafts widely distributed at NYU and to cornea leaders in USA
All comments incorporated into countless drafts (>>30) over 9 mos.
Conducted surveys
Submitted 9/25/2013
October 1, 2013 government shut down, project officer left.

58. What It Takes: Strike Two 2014
Spring 2014: Summary statement with scores of 46, 40 (CC)
Spoke with new project officer at NEI
May to September 2014: Worked to address all comments of summary statement, widespread review of numerous drafts, and continuous rewriting
(I had 3 eye operations related to complications of HZO)

59. What It Takes: To Quit or Not to Quit 2015
Spring 2015: Summary statement score 36
Comments beyond frustrating: did not read the grant, misquoted papers I was co-author of, same very negative reviewer
Contacted NEI
Spoke to #2 in clinical trials: told me that 30% of NEI budget goes to “our disease”, when in fact 30% went to Herpes Simplex Virus eye disease, and ZERO to Herpes Zoster
I was done: What part of NO don’t you understand!
Had 4th, most serious, eye operation
NYU leaders determined to try again!!!
Added Bennie Jeng, Chair Ophthalmology, U MD new study Co-Chair
June-Sept many, many drafts
Contacted NEI to request informed reviewers, suggested reviewers again

60. 2016: Amazing Success! April 2016: Summary Statement Score 23!!!
Conversation with NEI very positive we would be funded
Team began work to be ready for centers to begin enrollment
Notice of Grant Award 9/30/2016
NEI named of Data Safety Monitoring Co (DSMC)
Met 12/16, approved protocol 1/17
2017: Start-up complicated: IRB approvals, case report forms, contracts with clinical centers and vendors for study drug, encapsulation and placebo, randomization, electronic data capture, training and certification of investigators and coordinators
First study participant in October, 2017
Everything slower than expected

61. You Can Get a Big Grant IF!
You have the expertise to ask an important question and know how to get the answer
You need passion to get through the long and winding NIH process
NYULH has the team to provide all the necessary support to make it happen
You need to be willing to work very hard and be persistent in overcoming unexpected and unreasonable obstacles
It helps to have some good luck too!
Getting a grant is just the beginning!
After you get it, still need passion, team work, hard work and grit!!