10/13/2019

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ZEDS Investigator/Coordinator Meeting at AAO, Oct. 13, 2019

Elisabeth Cohen, MD

Bennie Jeng, MD

ZEDS Investigator/Coordinator Meeting Agenda

Enrollment Update and need to improve

New Verification of Primary Endpoint Form and revised Manual ofOperations and Procedures (MOP) Revised MOP addresses changes in Case Report Forms

Reminders

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PCC Activation (9/30/2019)

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Activation status Activated PCCs 71

Canada 2 With study participants 59 With enrolled and randomized study participants 50

Without participants 7 Inactivated 5

PCCs pending training/certification, IRB, contracts and/or activation USA 7 Canada 6 Brazil 2 UK 2

Recruitment and Enrollment of Study Participants (9/30/2019)

Screened and consented (Study Visit 1) 239 Screen failures: 42

Enrolled and randomized (Study Visit 2) 182

Study participants completed 12 months (Visit 6) 92 Study participants completed 18 months (Visit 8) 43

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Actual Screening and Enrollment (9/30/2019) v. Plan

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0

100

200

300

400

500

600

700

Number of Participan

ts

October‐17

November‐17

December‐17

January‐18

February‐18

March‐18

April‐18

May‐18

June‐18

July‐18

August‐18

September‐18

October‐18

November‐18

December‐18

January‐19

February‐19

March‐19

April‐19

May‐19

June‐19

July‐19

August‐19

September‐19

Proposed Total (2‐Arms) 4 16 28 40 52 64 80 96 118 142 172 212 248 284 320 356 392 428 464 500 536 572 608 644

Actual Randomized Total 2 11 14 24 37 47 64 68 74 79 89 93 100 115 125 131 137 143 151 156 165 172 174 182

Actual Number Screened Total 3 19 29 43 58 68 85 94 103 113 119 125 144 158 165 172 179 187 196 208 211 219 230 239

Challenge of Enrollment Below Expectations

Discussions with Executive/Steering Co

Additional payments to PCCs for pre-screening effort, studyparticipants, coordinator professional development awards

Adding PCCs in USA, Canada, Brazil, UK Welcome your suggestions

Addition of option for satellite locations at PCCs

Talks at national conferences, grand rounds, and locally topromote enthusiasm for support of ZEDS Encourage you to do this, material available on ZEDS web-site

and happy to provide you more

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Congratulations!

Coordinator professional development award recipients 2019

Hamad Gul, Mayo Clinic – Rochester

Munira Hussain, University of Michigan

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Enrollment Survey of Investigators

Purpose: to gather thoughts, experiences, and suggestions ofinvestigators re barriers to enrollment and ways to overcome them

Anonymous IRB approved internet survey 7/9-9/6/2019 Components

Study protocol implementation issues Patient population of potential study participants Barriers for patients to become study participants Barriers for investigators to enroll study participants Effectiveness of things implemented Effectiveness of possible things that could be implemented Open ended question about reasons for low enrollment Experience with other clinical trials and ZEDS Open ended request for suggestions

Response rate: 54% (79/145)

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Preliminary Enrollment Survey Results

Questions about study protocol It is easy to enroll study participants 71% disagree Study coordinators don’t have enough time 71% agree It is easy to dispense study med and use CRFs >80% agree

Questions about patient barriers HZO patients want to be treated with antiviral pills 69% agree HZO patients on antivirals do not want to enroll 69% agree The study drug is too big 73% disagree

Personal barriers I believe antivirals are effective 91% agree The questions ZEDS is designed to answer are important 100% agree

Effectiveness in helping enrollment Protocol so can use antivirals after new/worse HZO 70% helpful

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Enrollment Survey Comments

Lack of coordinators at potential satellites Request for script for potential study participants

Available on website (IRB approved) Revision submitted to IRB

Add FAQ section on public website (submitted to IRB) Why should I be part of this study? Will I need more appointments? Why join study if can be treated with antivirals anyway? Welcome your suggestions!

More compensation for coordinators and study participants Advertising to patients, ophthalmologists, primary care MDs,

optometrists etc Social media options explored and too expensive

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Survey Comments and Clarifications

Lengthening time frame for chronic HZO to 2-3 years since initialepisode would help. Onset of HZO rash can be anytime in past, but need episode of

active epithelial or stromal keratitis or iritis within year prior toenrollment

Would improve enrollment if allowed antivirals for worsening HZO Open label antiviral treatment is allowed in new/worsening DEK,

SK, EK, IR or SKU is diagnosed Most recent onset HZO patients want vaccination instead of oral

treatment Study participants can be vaccinated after enrollment and

continue study med. Since episode of HZ stimulates VZVimmunity for at least 1 year, usually delay vaccination until then

For recent onset HZO, once inflammation controlled and on stabletreatment, try to enroll in ZEDS Enroll recent onset ASAP! Do not need to be stable, just off

antivirals

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Enrollment Challenges

~50% of ZEDS investigators at start of enrollment used suppressiveantiviral treatment for HZO despite lack of high quality evidence Contributes to enrollment below expectations

Suppressive antiviral treatment is allowed in ZEDS only afterenrollment/randomization when diagnosis occurs of new/worseningDEK, SK, EK, IR, or SKU Study medication stopped only while on open label oral antiviral

treatment and resumed afterwards Study participant continues in study

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Development of AAO Preferred Practice Patterns

Quality of studiesI: Meta-analyses, Randomized Controlled Trials (RCTs)II: Case-control or cohort studiesIII: Case reports, case series

Quality of recommendationsGood: further research unlikely to change estimate of effectModerate: further research likely to impact estimate of effectInsufficient: estimate of effect is very uncertain

Key recommendationsStrong: benefits clearly outweigh risks or do notDiscretionary: when trade-offs less certai

Based on evidence without mention of expert opinion!

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Suppressive Antiviral Treatment for HZO

Current evidence is very limited:No RCTs, case-control or cohort studiesOne level III case report series

Miserocchi E Cornea. 2014; 33(6):565

Retrospective study of > 200 herpes simplex virus (HSV) andHZO patients at Italian Ocular Immunology and Uveitis Center

Suppressive valacyclovir 500 mg daily or acyclovir 400 mg bidSuppressive antiviral treatment decreased recurrent episodes of

inflammation by35% in HZO patients39% in HSV patients(Calculated by EJC from results!)

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Reasons to Support Enrollment in ZEDS

ZEDS is unique opportunity to do a RCT to develop high qualityevidence-based recommendations regarding the role of suppressiveantiviral treatment in the management of HZO and a new standardof care.

It is necessary to determine if suppressive valacyclovirtreatment is effective in reducing complications of HZO andimproving outcomes

Enroll your eligible HZO patients with active dendriform keratitis,stromal keratitis, or iritis as soon as possible, aware that if newor worsening DEK, SK, EK, IR, or SKU occurs, then open labelantiviral treatment is allowed within the study.

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Verification Form of Possible Primary Endpoints

Whenever new/worsening DEK, SK, EK, IR and/or SKU occurs onEXAM, it is the responsibility of the investigator to review theseCRFs for accuracy prior to submission in TrialMaster by coordinator: Ophthalmic Exam diagnosis HZO treatment Steroids Endpoint form(s)

Investigators should refer to the definitions and flow charts fordiagnoses, and determination of substantial increase and reductionin treatment so completed in accordance with ZEDS protocol

New Verification Form of Possible Primary Endpoint sent to CC Verifying investigator reviewed data related to possible primary

endpoint diagnoses Investigator is responsible for accuracy of data, coordinator for

submission into TrialMaster

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* Full Strength and Weaker Steroids for EndpointDefinition

Full strength steroids: Weaker Steroids:

Prednisolone Acetate 1% (strongly recommended)

Comparable for endpoint definition:

• Difluprednate 0.05%,• Dexamethasone 0.1%,• Prednisolone phosphate

1%

Loteprednol 0.5% (strongly recommended)

Comparable for endpoint definition:

• Rimexolone 1%• Prednisolone acetate

0.12%• Fluoromethalone 0.1% or

0.25%• Fluoromethalone acetate• Loteprednol 0.2%

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Steroids Form to Track All Usage and Changes

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Primary Endpoint Adjudication (9/30/2019)

• 73 diagnoses of new/worsening SK, EK, IR, SKU or DEK

• 31 confirmed primary endpoints by Clinical Event Review Co

• 30 not confirmed as primary endpoints

– Expected in order not to miss primary endpoints or forsecondary/exploratory endpoints

• 12 additional possible primary endpoints with CERCadjudication pending

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Confirmed Endpoints (9/30/2019)

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3

21

4 30

31

0

5

10

15

20

25

30

35

DEK SK EK IR SKU Total

Nu

mb

er

Reminder!

Be careful about whether recent vs chronic onset HZO! Recent onset: Enrollment Randomization Study Visit 2 less

than 6 months after onset of HZO Chronic onset: Enrollment Randomization Study Visit 2 is 6 or

more months after onset of HZO Onset of HZO is date of onset of typical rash Not date of most recent episode of active HZO

Recent vs Chronic determined at Enrollment RandomizationStudy Visit 2 not Screening Study Visit 1! Can change and become chronic onset after Screening Visit

and by time of Enrollment visit, especially if visit 2 delayed Why important?

Requirements for eligibility: chronic onset needs to be on stabletreatment and off all antivirals 30+ days at Enrollment vs recentonset who only need to be off antivirals by Enrollment

Error results in incorrect stratification and is a protocol deviation

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Reminders!

It is very important for the coordinators to attend the conference callsthe last Wednesday of the month 11am-12 (eastern) Investigators, please make it possible for them to do so!

Please submit the monthly pre-screening logs required for centerpayments

Please read our monthly newsletter, which is also on the ZEDSwebsite, and includes important announcements and >100 FAQS

Please do not hesitate to contact us. We are here to help in any waywe can! ZEDS.CTA@nyulangone.org; ZEDS.monitor@nyulangone.org Elisabeth.cohen@nyulangone.org; bjeng@som.umaryland.edu

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Thank you

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