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

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

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

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

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 50-69 years

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; 67:103-108

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!

Rising Incidence of Zoster Incidence up All ages 1945 -2007 Age 35-64 1993-2014 Common disease ~1,200,000 new cases/yr 1 in 3 will have zoster 1 in 2 age 85+

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!

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!

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

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

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

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

Possible New Treatment for HZO The Zoster Eye Disease Study (ZEDS) funded by NEI in 2016 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

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 Zeds.cta@nyulangone.org 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

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

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

Rationale of Zoster Eye Disease Study Herpetic Eye Disease Study (HEDS) Acyclovir Prevention Trial (APT) HEDS Study Group. N Eng J Med 1998; 339:300-306 HEDS Study Group. Arch Ophthalmol 2000;118: 1030-36. 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

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 60 years or more Time since onset HZO < 6 months vs 6 months or more Enroll 1050 study participants over 3 years

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

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

Corneal Disease Classification of HZO Recommend use same as HSV White.2014, Jul http://one.aao.org/clinical-statement/herpes-simplex-virus-keratitis-treatment-guideline Epithelial keratitis Infectious dendriform Stromal keratitis Without ulceration With ulceration (not microbial infection) Endothelial keratitis Uveitis Presentation Title Goes Here

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.

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

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)

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

Case Report Forms for Electronic Data Capture

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

PCC Activation Activation status (5/31/2019) Active PCCs 62 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 9 Brazil 3 UK 3 Need to confirm these numbers

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

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

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

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

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

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; 125:1671-4. 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: 13-17. On line announcements posted at NYULH, available for PCCs News Recruitment (IRB approved)

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

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) ZEDSSDDCCDSMCMasked03092019

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 ZEDSSDDCCDSMCMasked03092019

Accrual Over Time Since PCC Activation ZEDSSDDCCDSMCMasked03092019

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) ZEDSSDDCCDSMCMasked03092019

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 ZEDSSDDCCDSMCMasked03092019

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 ZEDSSDDCCDSMCMasked03092019

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 ZEDSSDDCCDSMCMasked03092019

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) ZEDSSDDCCDSMCMasked03092019

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 ZEDSSDDCCDSMCMasked03092019

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

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

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

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

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: 786-80 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

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

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

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.

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)

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

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

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!!