03/28/2018

1

ZEDS Coordinators Conference Call March 28, 2018

11:00 AM-(EDT)

Participating Clinical Centers (PCC): Status Updates

Centers “Green Lighted” for Screening and Randomization N=48

Study Participants Screened (N=64)

Study Participants Randomized (N=43)

26 Centers with Patient Activity 22 Centers with No Patient Activity

2

03/28/2018

2

3

AEs and SAEs

Adverse Event (AE): any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

In ZEDS, adverse events that result in temporary or permanent discontinuation of study medication will be required to be reported to the CC.

Information about study medication discontinuation is captured on the Study Medication Form

4

03/28/2018

3

AEs and SAEs

Serious Adverse Events (SAE): any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

In ZEDS, the following events are also treated as SAEs: Acute kidney failure requiring temporary or permanent dialysis eGFR <30 Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

(TTP/HUS) Central nervous system toxic/metabolic encephalopathy (agitation,

hallucinations, confusion and delirium) Seizures

5

AEs and SAEs

Why is it important to submit SAEs in TrialMaster?

SAEs are subject to review by the ZEDS medical monitors.

Unexpected or related SAEs (SUSAR), and TTP/HUS events should be reported on the SAE form within 24 hours of knowledge of the event. SUSARs are reportable to the FDA within 15 calendar days of

knowledge of the event or with 7 days if it is a fatal or life threatening event.

All other SAEs should be reported as soon as possible. Not reportable to the FDA

6

03/28/2018

4

AEs and SAEs

Scenario 1

A study participant experienced moderate side effects to the study medication and the investigator changes to dose regimen to one tablet twice. After two weeks the study participant is still experiencing side effects and the investigator decides to discontinue the study medication.

How is this event classified?

A. Adverse Event

B. Serious Adverse Event

7

AEs and SAEs

Scenario 1

A study participant experience moderate side effects to the study medication and the investigator changes to dose regimen to one tablet twice. After two weeks the study participant is still experiencing side effects and the investigator decides to discontinue the study medication.

Is this event reportable?

Yes, the study medication discontinuation is reported on the study medication form.

8

03/28/2018

5

AEs and SAEs

Scenario 2

At Visit 3 (3-month follow-up) the study participant reports that he was taken to the emergency room complaining of severe headache and neck pain after being in a car accident. He was evaluated, diagnosed with whiplash and released.

How is this event classified?

A. Adverse Event

B. Serious Adverse Event

9

AEs and SAEs

Scenario 2

At Visit 3 (3-month follow-up) the study participant reports that he was taken to the emergency room complaining of severe headache and neck pain after being in a car accident. He was evaluated, diagnosed with whiplash and released.

Is this event reportable?

No

10

03/28/2018

6

AEs and SAEs

Scenario 3

A study participant had a baseline eGFR of 50 and was enrolled into ZEDS. Follow-up eGFR at the 3 visit was 44.

How is this event classified?

A. Adverse Event

B. Serious Adverse Event

11

AEs and SAEs

Scenario 3

A study participant had a baseline eGFR of 50 and was enrolled into ZEDS. Follow-up eGFR at the 3 visit was 44.

Yes – the eGFR is below 45 therefore study medication is discontinued.

12

03/28/2018

7

AEs and SAEs

Scenario 4

A study participant had a baseline eGFR of 50 and was enrolled into ZEDS. Follow-up eGFR at the 3 visit was 28.

How is this event classified?

A. Adverse Event

B. Serious Adverse Event

13

AEs and SAEs

Scenario 4

A study participant had a baseline eGFR of 50 and was enrolled into ZEDS. Follow-up eGFR at the 3 visit was 28.

Is this event reportable?

Yes – eGFR <30 is reported as a SAE

14

03/28/2018

8

ClinPhone ® Alerts and Warnings: Initiating a Participant After entering the Date of Birth, Sex, Onset of HZO, and Informed

Consent date, the system allows you to review the data before submitting the entry.

Verify the data entered is correct, then click SUBMIT.

If Not, click the Back arrow, make necessary changes, click NEXT, review your changes and click SUBMIT if changes are correct.

15

ClinPhone ® Alerts and Warnings: Enrolling a Participant

From the Participant Management tab, select the Participant ID Number who is to be enrolled.

16

03/28/2018

9

ClinPhone® Alerts and Warnings: Avoiding Duplicate Participants

17

ClinPhone Alerts and Warnings:

Potential patients who have been pre-screened are not submitted into ClinPhone ®

DO NOT RUSH!

Read any warning messages and alerts that pop up.

Carefully review the data before clicking on the submit button.

Potential patients who have been pre-screened are not submitted into ClinPhone ®

A record of these patients should be kept in your screening logs

18

03/28/2018

10

Non-Study Visit Forms

Non-study visits include all routine care visits for eye exams between study visits. They occur for a variety of reasons including:

o new complaints due to HZOo scheduled follow-up for HZOo to pick up study medication if bottle is lost or damagedo problems in the non-study eyeo pre and post eye surgery

Study participants should be instructed to inform the coordinator and/or study investigator if they are going to be seen, or have been seen, by an ophthalmologist outside of the PCC to ensure that a copy of the outside office record is sent to the study investigator and/or coordinator as soon as possible.

19

Non-Study Visit Forms

Non-study visits in TrialMaster® are affiliated with a follow-up visit. On the study visit form, question 1a asks for the number of visits to an

ophthalmologist related to the study eye since the last protocol visit. Once a number is entered, the non-study visit forms become available in TrialMaster®.

At the time on the non-study visit, the applicable paper case report forms should be completed and place in the study participant’s records.

At the time of the next study follow-up visit, the non-study visit forms can be entered into TrialMaster®.

20

03/28/2018

11

Timeline for Bloodwork and Randomization

A serum creatinine blood test for eGFR determination will be prescribed at the screening visit to be performed within 30 days prior to the enrollment visit. The 30 day window refers to the date of collection of the blood sample,

not the date of analysis of the blood sample. If an eGFR has already been completed within 30 days of the

enrollment visit and the results are available, it is not necessary to have a repeat test.

If it is determined that the enrollment visit will occur > 30 days after the screening visit, the blood test should be delayed. Ex: Study participants who have chronic onset HZO and have a “flare-

up” of the disease should be advised to wait until close to the end of the treatment period to have the blood test.

Ex: Study participant who are eligible to be rescreened with 3 months Zoster vaccination Participation in another interventional clinical trial

21

Documentation of Informed Consent

22

03/28/2018

12

Central IRB Continuing Renewal

Current IRB approval expires on May 23, 2018

Submission goal: 2nd week of April

Upon approval, the approval letter and new ICF will be available to you on the Exchange Begin using the new ICF immediately Discard any extra copies of the expired ICF

New CIRB liaison: Jessica James (jessica.james@vanderbilt.edu)

23

Protocol Amendment 2.0 – Highlights of Changes

Inclusion Criteria 6. Diagnosed with HZO in one eye based on both of these criteria:

a. History of characteristic unilateral, vesicular, rash in the dermatomal distribution of cranial nerve V1.

6. Diagnosed with HZO in one eye based on both of these criteria:

a. History of characteristic unilateral, usually vesicular, rash in the dermatomal distribution of cranial nerve V1.

Exclusion Criteria 5. History of vaccination against zoster within one month prior to enrollment. Study participants who meet this exclusion criterion may be rescreened.

5. History of vaccination against zoster within one month prior to enrollment. Study participants who meet this exclusion criterion may be rescreened. 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.

24

03/28/2018

13

Protocol Amendment 2.0 – Highlights of Changes

Exclusion Criteria 5. Keratoplasty or keratorefractive surgery of the involved eye with zoster.

5. 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.

Temporary Discontinuation due to Vaccination Against Zoster

If the study participant decides to get the zoster vaccine live against zoster, the study medication will be discontinued one day before and resumed one month after vaccination.

If the study participant decides to get the Zoster Vaccine Live (ZVL, Zostavaxmanufactured by Merck) against zoster, the study medication will be discontinued one day before and resumed one month after vaccination. If the study participant gets the Recombinant Zoster Vaccine (RZV), also referred to as the herpes zoster subunit vaccine (Shingrix, manufactured by Glaxo Smith Kline), the study medication is to be continued.

25

Protocol Amendment 2.0 – Highlights of Changes

Temporary or Permanent Discontinuation due to Use of Open Label Oral Valacyclovir, Acyclovir or Famciclovir Treatment for Other Conditions

Temporary or Permanent Discontinuation due to Use of Open Label Oral Valacyclovir, Acyclovir or Famciclovir Treatment for Other Conditions If study participant develops any

other medical condition that necessitates long-term treatment with valacyclovir, acyclovir, or famciclovir, study drug will be permanently discontinued.

Temporary or Permanent Discontinuation due to Use of Open Label Oral Valacyclovir, Acyclovir or Famciclovir Treatment for Other Conditions If study participant develops any

other medical condition that necessitates treatment with valacyclovir, acyclovir, or famciclovir, study drug will be discontinued while on open label treatment and resumed afterwards. The open label treatment period should not usually exceed two weeks.

26

03/28/2018

14

Protocol Amendment 2.0 – What’s Next?

02/28/18 – Approved by NYU Langone Health IRB

03/21/18 – Approved by Central IRB at Vanderbilt University PCCs received a notification that the amendment has been approved Log into the Exchange and download the approval letter and copy of

the protocol

PCCs under local IRB oversight – sent a “redlined” and “clean” version of the protocol, and a table of changes for submission to the IRB. Upon approval send us a copy of the approval letter.

DSMC approval pending

Some of the changes will require changes in the CRFs and TrialMaster®

27