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Herpes Zoster and the Zoster Eye Disease Study (ZEDS)

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

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Herpes Zoster and the Zoster Eye Disease Study (ZEDS)

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  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 acutepain for average 30 days • Severe, debilitating chronic pain unresponsive to treatment • Chronic and/or recurrent unilateral eye disease and visionloss • Unilateral hearingloss • 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 VaccineRecombinant Zoster Vaccine (RZV) • Contains a viral protein in a new immunogenic solution • 2injections 2 months apart in immunocompetent adults age 50+ • 90-97% efficacyfor 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 50-69 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; 67:103-108

  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 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+

  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 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

  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: MeeLeeTom • 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

  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 PavanLangston D. Arch Ophthalmol 1995; 111:1381 Hu AY, Am J Ophthalmol 2010; 149:214 Aggarwal S. Cornea. 2014; 33(2):109 TakaseJpn 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; 339:300-306 • 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

  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 valacyclovir1000 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

  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 DiseaseClassification 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

  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.

  25. 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

  26. Other Secondary Endpoints • Development of specific disease manifestations of HZO • Primary endpoints: DEK, SK, EK, IR and SKU • Neurotrophickeratopathy 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)

  27. 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

  28. Case Report Forms for Electronic Data Capture

  29. 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

  30. PCC Activation • Activation status (5/31/2019) • Active PCCs 62PCCs 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

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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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)

  37. 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

  38. 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

  39. Masked Data Summary: Accrual • 141 Participants randomized since start of study • (52 since the last DSMC meeting) ZEDSSDDCCDSMCMasked03092019

  40. Accrual Over Time Since PCC Activation ZEDSSDDCCDSMCMasked03092019

  41. 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

  42. 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

  43. 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

  44. Endpoints • 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

  45. First Adjudication Endpoint by 12 Months ZEDSSDDCCDSMCMasked03092019

  46. Next Steps • Evaluate accrual and projections based on next 6-12 months • Consider revised timeline • Likely with no cost extensions of grant ZEDSSDDCCDSMCMasked03092019

  47. 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

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