AD: Clinical Monitoring Plan · Paula Miller Management iHC – –Global Project - Neuroscience...

Confidential SOP-CM-018-AD-01-01 Page 1 of 93

NoNO Inc.

A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of

Intravenous NA-1 in Subjects with Acute Ischemic Stroke Undergoing Endovascular Thrombectomy (ESCAPE-NA1 Acute Stroke Trial)

PROTOCOL NA-1-007

NA-1-007

Clinical Monitoring Plan

Version 1.0: 06FEB2017 Prepared By:

Name Title Role on study

Betsy Ann Dod Clinical Monitor Project Lead Clinical Monitoring Project Lead

Reviewed By:

Name Title Role on study Date review completed

Neel Bhatt Associate Project Director (North America)

Project Manager

Kathy Heard Director Clinical Development

NoNO Inc/Sponsor representative

Davis Chau Senior Project Leader NoNO Inc/Sponsor representative

Approved by:

Name Title Role on study Date approval received



NoNO Inc.: Protocol NA-1-007 (ESCAPE-NA-1-007) Clinical Monitoring Plan

UPC: 16NO4X001 Version 1.0 06FEB2017


Recipients: Upon finalization of the first and subsequent versions of the Clinical Monitoring Plan (CMP) a copy will be sent to the following study team members for their information.

Name Title Role on study Date sent

Dr. Michael Tymianski

NoNO Inc/Sponsor representative – President, CEO & Medical Monitor

NoNO Inc/Sponsor representative – President, CEO & Medical Monitor

06FEB2017



06FEB2017

Davis Chau Senior Project Leader NoNO Inc/Sponsor representative

06FEB2017

Cameron Harris Drug Manager NoNO Inc/ Drug Manager 06FEB2017

Karla Ryckborst University of Calgary – Coordinating Study Nurse

Coordinating Study Nurse 06FEB2017

Dr. Michael Hill University of Calgary – Coordinating Study PI and Medical Monitor

Coordinating Study PI and Medical Monitor

06FEB2017

Qiao Zhang

University of Calgary- Data Manager

Data Manager 06FEB2017

Kim Stahl iHC – Director of Project Management

iHC – Director, Program Delivery

06FEB2017

Neel Bhatt iHC – Associate Project Director, Global Project Management

iHC – Associate Project Director, Global Project Management

06FEB2017

Paula Miller

iHC – Global Project

Management - Neuroscience

iHC – Project Manager 06FEB2017

Betsy Dod iHC – Clinical Monitoring Project Lead

iHC – Clinical Monitoring Project Lead

06FEB2017

Krisztina Kovacs

iHC – Study Start-up Project Lead, Site Centricity

iHC – Study Start-Up Project Lead

06FEB2017

Roxana Costanzo iHC – Study Start-up Lead iHC – Study Start-Up

Project Lead 06FEB2017

Diana Caycedo Vankalmthout

iHC – Sr. Clinical Research Associate


06FEB2017

Jackie Jordan iHC – Sr. Clinical Research Associate


06FEB2017

Karen Rye iHC – Sr. Clinical Research Associate


06FEB2017

Yvette Herrera iHC – Sr. Clinical Research Associate


06FEB2017

Revision History

Version Date

(DDMMMYYYY) Summary of Changes

1 N/A – first version




TABLE OF CONTENTS

TABLE OF CONTENTS ............................................................................................................ 3

1. SUMMARY INFORMATION ............................................................................................... 5

2. LIST OF ACRONYMS ........................................................................................................ 9

3. INTRODUCTION ...............................................................................................................12

4. PROJECT LOGISTICS .....................................................................................................14

4.1 SOPS .............................................................................................................................................. 14 4.2 BILLCODE & TIME AND TASK LIST ...................................................................................................... 14 4.3 SCOPE OF WORK .............................................................................................................................. 14

5. STUDY ..............................................................................................................................15

5.1 SUBJECTS ........................................................................................................................................ 15 5.2 SUBJECT DEFINITIONS ....................................................................................................................... 15 5.3 PLANNED TIMELINES ......................................................................................................................... 16 5.4 VISITS .............................................................................................................................................. 16 5.5 USEFUL INFORMATION, SUBJECT ENROLLMENT, SITE FACILITIES / EQUIPMENT....................................... 18 5.6 SUBJECT ENROLLMENT ..................................................................................................................... 19 5.7 SITE FACILITIES ................................................................................................................................ 20 5.8 SITE EQUIPMENT ............................................................................................................................... 20 5.9 RETURN OF EQUIPMENT: ................................................................................................................... 21 5.10 PROJECT PLANS ............................................................................................................................... 21 5.11 STUDY DOCUMENTS ......................................................................................................................... 21 5.12 STUDY LOGS AND TEMPLATES ........................................................................................................... 21 5.13 STUDY TRACKING AND REPORTING ..................................................................................................... 23 5.14 SYSTEMS ......................................................................................................................................... 24 5.15 STUDY TEAM .................................................................................................................................... 25

6. ISSUE IDENTIFICATION AND ESCALATION .................................................................26

7. DATA PRIVACY ...............................................................................................................29

8. SAFETY REPORTING ......................................................................................................31

8.1 ADVERSE EVENTS ............................................................................................................................. 31 8.2 SERIOUS ADVERSE EVENTS ............................................................................................................... 32 8.3 PROJECT SPECIFIC ADVERSE EVENTS OF INTEREST (AEOI)................................................................. 33 8.4 PREGNANCY REPORTING ................................................................................................................... 33 8.5 EXPEDITED SAFETY REPORTS (ESRS) AND AGGREGATE SAFETY REPORTS (ASRS) .............................. 34

9. COMMUNICATION ...........................................................................................................36

9.1 COMMUNICATION WITH SITE............................................................................................................... 37 9.2 INTERNAL COMMUNICATION ............................................................................................................... 38 9.3 TEAM MEETINGS ............................................................................................................................... 39 9.4 COMMUNICATION WITH VENDORS ....................................................................................................... 39 9.5 COMMUNICATION WITH NONO INC ..................................................................................................... 39

10. VENDORS ....................................................................................................................41

10.1 IP DEPOT ......................................................................................................................................... 41 10.2 IXRS ................................................................................................................................................ 41 10.3 ELECTRONIC DATA CAPTURE (EDC) ................................................................................................. 42 10.4 CALGARY IMAGE PROCESSING AND ANALYSIS CENTRE (CIPAC) ........................................................ 43 10.5 COGNITIVE ASSESSMENT FORMS ...................................................................................................... 44 10.6 CENTRAL LABORATORY (FOR CANADIAN SITES ONLY) ........................................................................ 45




11. TRAINING .....................................................................................................................46

11.1 MONITOR/CMPL TRAINING ............................................................................................................... 46 11.2 INVESTIGATOR MEETING (IM) TRAINING ............................................................................................. 47 11.3 SITE TRAINING .................................................................................................................................. 47 11.4 COUNTRY SPECIFIC TRAINING ........................................................................................................... 49

12. INVESTIGATIONAL PRODUCT ...................................................................................50

13. CTMS ............................................................................................................................55

14. SITE INITIATION VISITS ..............................................................................................57

14.1 SIV SCHEDULING AND PREPARATION ................................................................................................ 57 14.2 SIV CONDUCT .................................................................................................................................. 58 14.3 SIV FOLLOW UP ............................................................................................................................... 59

15. ROUTINE MONITORING VISITS ..................................................................................60

15.1 RMV SCHEDULING AND PREPARATION .............................................................................................. 60 15.2 RMV CONDUCT ................................................................................................................................ 60 15.3 RMV FOLLOW UP ............................................................................................................................. 62

16. SITE MANAGEMENT ACTIVITIES ...............................................................................63

16.1 ACTIVITIES TO BE PERFORMED BETWEEN RMVS ................................................................................. 63 16.2 ACTIVITIES TO BE PERFORMED AT SPECIFIC TIME POINTS..................................................................... 63 16.3 MANAGEMENT OF CHANGES AT SITE................................................................................................... 64

17. RISK BASED MONITORING (RBM) .............................................................................65

17.1 MONITORING STRATEGY ................................................................................................................... 65 17.2 CENTRALIZED MONITORING PLAN ...................................................................................................... 66 17.3 ON SITE MONITORING PLAN .............................................................................................................. 66 17.4 MONITORING SCHEDULE ................................................................................................................... 66 17.5 SOURCE DATA VERIFICATION / SOURCE DATA REVIEW ....................................................................... 67 17.6 TRAINING ......................................................................................................................................... 68 17.7 PREPARATION FOR INTERIM ANALYSIS ............................................................................................... 68

18. CLOSE OUT VISITS .....................................................................................................69

18.1 COV SCHEDULING AND PREPARATION .............................................................................................. 69 18.2 COV CONDUCT ................................................................................................................................ 69 18.3 COV FOLLOW UP ............................................................................................................................. 70

19. ELECTRONIC MEDICAL RECORDS / ELECTRONIC HEALTH RECORDS ................71

20. PROTOCOL DEVIATIONS ...........................................................................................73

21. CASE REPORT FORM .................................................................................................77

21.1 ELECTRONIC CASE REPORT FORM (ECRF) ....................................................................................... 77

22. TRIAL MASTER FILE ...................................................................................................80

23. INVESTIGATOR SITE FILE ..........................................................................................82

24. APPENDIX 1 - LOGS AND TEMPLATES TO BE USED DURING THE STUDY ..........86

25. APPENDIX 2 -MONITORING AND DATA REVIEW PLAN ...........................................91




1. SUMMARY INFORMATION

Name of NoNO Inc: NoNO Inc.(herein, the NoNO Inc)

Title of study: A Multicentre, Randomized, Double-blinded, Placebo-controlled, Parallel Group, Single-dose Design to Determine the Efficacy and Safety of Intravenous NA-1 in Subjects with Acute Ischemic Stroke Undergoing Endovascular Thrombectomy (ESCAPE-NA1 Acute Stroke Trial)

Protocol number: NA-1-007

UPC number: 16NO4X001

Study Indication: Acute Ischemic Stroke undergoing Endovascular Thrombectomy

Phase of development: III

Type of study Interventional

Study duration: 17NOV2016 – 03OCT2019

Enrollment duration: 30 Months

Expected start and stop of enrollment period:

Start: 03 FEB2017 Finish: 01SEP2019

Number of Study Sites(s):

35 total sites globally

Total expected number of subjects enrolled globally:

1120 subjects to be enrolled globally

Total expected number of completed subjects globally:

1064 (note death prior to Day 90 is considered completing the study)

Expected number of subjects enrolled per site:

Average 30 per site, but expect range of 10-80

Monitoring strategy: The following visits/site contact will be performed (check all that apply):

Onsite Routine Monitoring Visits (RMVs)

Remote RMVs with visit report Regular, scheduled site contact with no visit report Unblinded visits

The study includes Risk-based monitoring

Onsite RMV frequency and window:

The first RMV at each site should occur where possible within 2 weeks (±2 days) of the first subject randomized, dependent on site availability, to assess adequacy of source documentation.

Onsite visits should be conducted based on site activity and follow up timelines 30 and 90 day follow up (more or less frequent based as needed). At a minimum, each site will be visited every 3 months.

Onsite visits should be conducted at the frequency determined by unverified data reports and/or triggered by safety signals or issues identified by remote review or centralized data analytics monitoring that must be resolved with an on-site visit. An average of 2 visits per subject is expected for each site that meets enrollment expectation.

Exceptions to this frequency can only be accepted upon discussion with




and approval from the Clinical Monitoring Project Lead /Project Management Operational Lead (herein referred to collectively as the Clinical Monitoring Project Lead (CMPL) and NoNO Inc. Approval of exceptions will be documented and filed in the trial master file (TMF).

Remote RMV frequency and window:

Remote visits are not being performed for this study

Regular, scheduled site contact

Sites should be contacted by telephone every week. Telephone communication with sites will be documented via telephone contact report or via follow up email to the site

% data to be SDV’d (table below)

Reduced SDV Plan For those CRF pages marked Reduced below:

The first 3 patients at each site have all questions 100% SDV’d.

If there are no issues with the first 3 patients, then the CRA will 100% SDV the remaining data for every 4

th patient.

During the ongoing monitoring if there appears to be a decline in reporting quality, then the CRA may increase the number of subject’s who have 100% SDV until the CRA is confident the site has improved. This will be documented in the MV Report.

Once the CRA has complete their SDV according to this plan and there are no outstanding queries, the CRA will mark the field as Verified in iDataFax.

Imaging will be verified against the images centrally by the U of C imaging team; CRAs are not required to verify images at the site. Items marked as NA are not part of the main protocol, and are not applicable to NA-1-007; therefore do not require review, verification or any monitoring by the CRA. eCRF SDV table is shown in Appendix 2.

Visit report templates Visit reports will be written using CTMS

Visit report completion timelines

First draft of report to be submitted within 7 business days of last day of visit. It is recommended the first review to be completed by CMPL (or designee) within 3 business days of receipt. It is recommended the second draft of report to be submitted by Monitor to the CMPL (or designee) within 2 business days of receiving comments. Report to be finalized within 15 business days of last day of visit.

Confirmation & Follow-up Letter templates

Letters will be written using CTMS

Confirmation & Follow-Up Letter timelines

Visit confirmation letters should be sent by email at minimum 2 days prior to the visit. Visit follow-up letters should be sent by email at the time of approval/finalization of the visit report

Data entry timelines

Sites are expected to enter subject visit data within 3 business days of the subject visit occurring

Query resolution timelines

Sites are expected to resolve data queries within 3 - 5 business days of the query being issued

Standard operation procedures (SOPs)

inVentiv Health staff will follow inVentiv SOPs for this study.




Location of project plans:

https://studycentral.inventivhealth.com/ NoNO Inc’s isoTracker TMF system

Location of study documents:

https://studycentral.inventivhealth.com/ NoNO Inc’s isoTracker TMF system.

University of Calgary’s Study Central

IP indication/class: NA-1 is a neuroprotectant. The potential indication is for Acute Ischemic Stroke (AIS) requiring thrombectomy.

IP storage requirements:

The IP should be stored as follows:

Temperature: 2 to 8°C at all times Comparator product: Normal Saline: Sodium Chloride Injection

Useful contacts:

iDataFax / Study Manager helpdesk email: [email protected] iDataFax / Study Manager helpdesk phone: +1 403 210-3845

(8:00 – 4:00 MTN time Monday – Friday) Davis Chau, NoNO Senior Clinical Project Leader Tel: + 1-647-680-8498 [email protected] Cameron Harris, NoNO Drug Manager and Cold Chain Tel: + 1 647 870 2353 [email protected] or [email protected] Michael D Hill, M.D., University of Calgary, Coordinating Investigator and Medical Monitor Tel: +1-403-944-8065 Email: [email protected] Karla Ryckborst, University of Calgary, Global Project Nurse Coordinator Tel: +1 403 944 2863 Email: [email protected] Betsy Dod, inVentiv Health, Clinical Monitor Project Leader Tel: + 1 860 705 6019 [email protected]

https://studycentral.inventivhealth.com/


mailto:[email protected]










Time allocation for visit preparation, conduct and follow up:

Visit Expected # visits per site

Preparation/FU/ report writing (Hours)

On-Site (Hours)

Site Initiation Visit (SIV) 1 4 8

Onsite Routine Monitoring Visit (RMV)

4 8 (CRA may request to CMPL +4 hr increments as needed to manage backlog)

Close Out Visit (COV) 1 4 8

Time allocation for site management activities: Time allocation for site management activities during the study: 1 hour per site per week.




2. LIST OF ACRONYMS

Abbreviation Term

ADE Adverse Device Effect

AE Adverse Event

AEOI Adverse Event of Interest

ALCOA Attributable, Legible, Contemporaneous, Original, Accurate

AoR Acknowledgement of Receipt

AR Adverse Reaction

ASR Aggregate Safety Report

Asia-PAC Asia Pacific region

CA Competent Authority

CDA Clinical Data Analyst

CL Confirmation Letter

CM Clinical Monitoring

CMP Clinical Monitoring Plan

CMPL Clinical Monitoring Project Lead

CMT Clinical Monitoring Team

COV Close Out Visit

CRA Clinical Research Associate/Clinical Monitor (herein known as Monitor)

CRF Case Report Form

CRM Clinical Risk Manager

CSS Country Submission Specialist

CTMS Clinical Trials Management System

CTSM Clinical Trials Supply Management

DBL Data Base Lock

DC Discontinuation

DCF Data Clarification Form

DM Data Management

DSPM Data Services Project Management

ED Essential Document

EDAF Essential Document Approval Form

EDC Electronic Data Capture

EDCS Essential Document Collection and Submissions

EHR Electronic Health Record

EMEA Europe, Middle East, Africa

EMR Electronic Medical Record

ESR Expedited Safety Report

ET Early Termination

EQI Escalated Quality Issue

FDF Financial Disclosure Form

FU Follow-Up

FUL Follow-Up Letter

GCP Good Clinical Practice

GLOBAL Applicable to all regions of the world including: “The Americas (including North America and Latin America), EMEA and Asia Pacific region”




Abbreviation Term

GS&P Global Safety and Pharmacovigilance

IA Interim Analysis

IATA International Air Transport Association

ICH International Conference on Harmonization

ICF Informed Consent Form

iDF iDataFax

IMP Investigational Medicinal Product

IN/EX Inclusion/Exclusion Criteria

INT Interventional

IP Investigational Product

IRB/IEC Institutional Review Board / Independent Ethics Committee

ISF Investigator Site File

IVRS Interactive Voice Response System

IWRS Interactive Web Response System

IxRS Interactive X Response System (i.e., either Voice or Web)

Lab Laboratory

LAR Legal Authorized Representative

LM Line Manager

LS Late Stage

LSLV Last Subject Last Visit

LtAM Latin America

LTFU Lost To Follow-Up

MCL Monitoring Clarification Log

MM Medical Monitor

CMPL Monitoring Project Lead (i.e., CCMPL or PMOL)

NA North America

N/A Not applicable

N/Av Not available

NCR No Carbon Required

ND Not done

NIS Non-Interventional Study

O/C Original/Copy

OG Operating Guide

P&A Form Privacy & Authorization Form

PC Project Coordinator

PD Project Director

PDL Protocol Deviation Log

PDNF Protocol Deviation Notification Form

PI Principal Investigator

PM Project Manager

PMOL Project Management Operational Lead

POL Policy

PSV Pre-Study Visit

QAV Quality Assessment Visit

QRM Quality Risk Manager

RA Regulatory Authority

RBM Risk Based Monitoring

RM Regional Manager




Abbreviation Term

RMV Routine Monitoring Visit

SADE Serious Adverse Device Effects

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SC Study Coordinator

SD Source Data

SDA Source Data Agreement

SDR Source Data Review

SDV Source Data Verification

SDW Source Data Worksheet

SIV Site Initiation Visit

SML Study Maintenance Lead

SMS Study Maintenance Specialist

SOP Standard Operating Procedure

SoW Scope of Work

SSDRL Site Signature and Delegation of Responsibility Log

SSUPL Study Start-Up Project Lead (note that SSUPL may be replaced by Study Maintenance Lead during study maintenance activities)

Sub-I Sub-investigator

TCR Telephone Contact Report

TMF Trial Master File

ToC Table of Contents

UPC Unique Project Code




3. INTRODUCTION The purpose of the Clinical Monitoring Plan (CMP) is to describe the protocol- and NoNO Inc-specific activities required for overseeing the progress of medical research at investigator sites and for verifying that:

The rights and well-being of human subjects are protected.

The reported data are accurate, complete, and verifiable from source documents (ALCOA).

The conduct of the medical research is in compliance with the protocol, standard operating procedures, ICH GCP and the applicable regulatory requirement(s).

The CMP is a document provided to the clinical team and all clinical monitors (herein referred to as Monitors) to standardize the processes related to initiation, routine monitoring and close-out visits. This plan will define the expectations regarding the scheduling, conduct and follow-up of site initiation visits, blinded monitoring visits and close-out visits conducted by InVentiv Health as well as the site contact and source documentation review and verification requirements for the NA-1-007 study. Site selection activities, including conduct of pre-study visits are not documented in the CMP The CMP is written in accordance with InVentiv Standard Operating Procedures (SOPs), ICH Guidelines for Good Clinical Practices (E6) and all other applicable associated regulatory agency guidelines. During each monitoring visit, for the duration of the study it is expected that monitors will comply with all applicable SOPs and, in particular, as they pertain to site monitoring. The CMP will be used in addition to any InVentiv, NoNO Inc or vendor plans that may apply (e.g., SAE Plan). The CMP is applicable to all countries participating in the NA-1-007 study. The Clinical Monitoring Project Lead (CCMPL)/Project Management Operational Lead (PMOL) (herein, Monitoring Project Lead (CMPL)) is the respective member of Clinical Monitoring responsible for leading the clinical monitoring sub-team to produce all interim deliverables. The Monitor is responsible for monitoring site activities and is the primary contact person for his/her assigned Investigational Site(s). The development and finalization of the CMP will be led by the CMPL(s) assigned to the study. The CMPL may delegate completion of sections of the CMP to other study team members as deemed appropriate, but the CMPL remains accountable for the accuracy of the information contained within the plan. The initial version of the CMP will be finalized prior to the first Site Initiation Visit (SIV). At the time of initial CMP finalization it is acceptable for the close out visit information and/or drug return or destruction information to be pending further information; these sections must be developed and finalized before the first close out visit and/or the first return shipment or destruction of investigational product (IP) as appropriate. However, if the project involves a controlled substance or has IP which, after dispensation to and subsequent return by a subject, can only be retained at site for a short period of time (e.g., due to nature of IP or size of pack), the drug return and/or destruction information must be completed prior to the initial finalization of the CMP. Monitors will complete required training on the CMP prior to conducting their first SIV. Training on the COV section and/or details of drug return/destruction will be completed prior to performing these activities.




Upon finalization, the CMPL distributes the CMP to the NoNO Inc. Project Manager, Study Start-Up Project Lead (SSUPL) as a minimum, and ensures it is accessible to the Clinical Monitoring team members. The CMPL will provide training to Monitors on the initial CMP and future updates as needed. All training will be documented in inVentiv’s electronic learning management system. The CMP is a living document and should be referenced throughout the duration of the study. Therefore, when processes, procedures or study requirements are modified or added, updates to the plan are required. These updates may require the plan to be updated at that time or the update may be captured using the Clinical Monitoring Plan Addendum. Minor changes can be documented using the optional Clinical Monitoring Plan Update/Correction tracker if required and then included in the next revision of the CMP, e.g., spelling corrections, re-wording of sentences. During the course of the project, the CMP will be reviewed annually at a minimum. If changes are not deemed necessary during the review, the reviewer should document this and indicate the date of the review. The most recent approved version of the CMP, including addendums where applicable, will supersede over any other version. Each updated version will be distributed to all parties who received the initial plan as well as any new team members, as applicable. The CMPL will file all final versions of the CMP in the NoNO Inc Study Central and in Veeva Vault trial master file (TMF). Any deviation from the CMP, either planned or unplanned, should be escalated to the CMPL, PM and/or Quality Assurance and Regulatory Compliance (QARC) as applicable and appropriately documented. Deviations to the CMP may also be SOP deviations, policy deviations, serious quality issues requiring escalation, and/or study related issues and should be addressed in accordance with the applicable SOP(s).




4. PROJECT LOGISTICS

4.1 SOPs inVentiv Health employees will follow inVentiv SOPs. NoNO Inc and University of Calgary SOPs will be followed by their respective groups during the study. Current SOPs apply for the duration of the study. If/when an updated SOP becomes effective during a study and the project team wishes to continue following the previous version, approval is obtained and documented in the Study Issue and Decision Log by the CMPL/PM. The list of SOPs in use during the study can be located in the internal InVentiv website at https://inventivhealth.sumtotal.host for the iHC SOPs. Deviations from SOPs should not occur during the study. Any deviations which do occur, either with prior agreement or unintentionally, will need to be documented following the standard procedure for documenting SOP deviations. Any questions regarding the content of the iHC, SOPs should be directed to the CMPL who will escalate as necessary. All study team members will need to complete training on the iHC, SOPs as applicable to the study. Completion of SOP training will be documented within the iHCs SOP portal in iHCs Sum Total

4.2 Billcode & Time and Task List The project billcode for the NA-1-007 study is 16NO4X0001 (000000010074289) The study-specific Time and Task List is located at https://studycentral.inventivhealth.com/ Refer to the summary section of this CMP for hours allocated for visit activities. The standard task list for Clinical Monitoring activities with billable time codes is located in https://studycentral.inventivhealth.com/ Study team members should review both the Time and Task list and the standard task list for Clinical Monitoring to ensure they are:

a) Completing activities within the allocated time b) Using the correct billable time codes for activities performed

The PM is responsible for requesting billable time codes at the start of the study and if new time codes are required during study conduct.

4.3 Scope of Work The following section provides high-level details of the NA-1-007 study, including activities inVentiv personnel are contracted to perform as per the agreement with NoNO Inc. If CMPLs or monitors are asked to perform tasks they feel are outside of their responsibilities and/or not part of the contracted Scope of Work or included in this CMP, either by NoNO Inc. another study team member or site staff they should immediately escalate to the PM and CMPL respectively.

https://inventivhealth.sumtotal.host/






5. STUDY

Study phase III

Study design Interventional; Blinded; Randomized

Therapeutic area Neurology

Indication being treated

Acute Ischemic Stroke

Patient population Acute Care

5.1 Subjects

Projected # Randomized Subjects

1120 Subjects are expected to be randomized globally 32 (1.07 pts / site / month) Subjects are expected to be randomized per site

Anticipated discontinuation rate

5-10% subjects, they will not be replaced.

Anticipated # Completed Subjects

1008 Subjects are expected to complete the study globally

29 Subjects are expected to complete the study per site Subjects who die during the study will be considered completed subjects.

Type of enrollment: competitive globally

5.2 Subject definitions

Screened: A subject is considered as ‘screened’ if they have signed the ICF but then are not randomized into the study. Site staff should keep the signed ICF on site, but no data will be entered into the CRF and these patients will not be tracked or counted. Screening ID numbers will not be used and screening logs will not be kept.

Randomized:

A subject is considered as ‘randomized’, if they are randomized into Study Manager. Prior to being randomized there must be a signed ICF, met all inclusion and no exclusion criteria. As this is an Intent to Treat analysis, subjects will be followed to the end of the study even if they did not receive IP.

Completed: A subject is considered as ‘completed’ if they complete all study visits (Day 90), or if they died while still participating in the study.

Discontinued A subject is considered as discontinuation if they have been randomized but for administrative reasons or the PI determines it is in their best interest not to not complete the study

Withdrawn consent: A subject is considered to have ‘withdrawn consent’ if they no longer wish to participate in the study or if their LAR originally consented and the subject does not give regained capacity consent. This includes not returning for any further procedures/visits or an end of study visit

Lost To Follow Up (LTFU):

A subject is considered as ‘LTFU’ if they do not attend either the Day 30 or Day 90 study visits and do not respond to attempts to be contacted. Reasonable effort includes contacting the subject or documented family




member at a minimum 3 times by telephone, in person or other method. These efforts will be documented in the subject’s source notes. If the subject was lost to follow up at Day 30, site staff should re-attempt at least once at Day 90 to contact the subject or if subject is staying with a care giver.

5.3 Planned timelines

First SIV: 1 FEB 2017

Last SIV: approximately 1 JUNE 2017

First Subject First Visit (FSFV):

6 FEB 2017

Last Subject First Visit (LSFV):

100 subjects- 31 Aug 2017 600 subjects- 15 May 2018 (+20 months) 1120 subjects- 15 Aug 2019 (+ 30 months)

Last Subject Last Visit (LSFV):

15 Nov 2019 (+ 90 days)

Interim Data Analysis (IA):

IA #1 (safety) approximately 4 months after 100 randomized, 31 Dec 2017. Interim DSMB reviews will occur once 100 subjects have reached their Day 90 final study visit. IA #2 (safety and efficacy) approximately 4 months after 600 subject randomized, 15 Sept 2018 DSMB review will occur once 600 subjects complete the Day 90 follow-up)

Final Database lock (DBL):

Start: 4 to 8 weeks after LSFV

5.4 Visits

SIVs

Number planned globally:

35

Number planned per site:

1

Timeframe: SIV will occur after NoNO has confirmed, the approval of the Essential Document Package for a site is available; all essential documents, including fully executed site contract are in place; IP does not need to be on site prior to SIV

Type: On-site

Summary of details: Handover between NoNO Inc. Country Submission Specialist (CSS) and Monitor must occur prior to SIV being performed

RMVs


711: 8 hour monitoring days 488: 4 hour additional monitoring days


An average of 20 (± depending on site individual enrollment)

Timeframe: Refer to the ‘Onsite RMV frequency and window’ details in the Summary Information section

Summary of details: Adaptive monitoring is being followed for this study.




A copy of Monitoring Site Visit logs, IP Accountability, must be collected at each visit and provided to with the draft report.

Remote MVs


Remote visits are not being performed for this study

COVs


35


1

Timeframe: If a site has not randomized any subjects the COV can occur at completion of enrollment globally or earlier if there is a decision to close the site. For sites which have enrolled they will be closed within 8 weeks after database lock.

If a site has had an SIV but did not receive Investigational Product, the COV may be conducted via phone.

Type: On-site

Summary of details: After all IP at the site is confirmed and monitored by the CRA, the unused/expired IP may either be destroyed on site or returned to the Sponsor at or before the COV, but not before final drug accountability is completed by the CRA. NoNO will provide site or country specific instructions prior to the completion of enrollment.

Visit reports

Visit report templates Refer to the ‘Visit report templates’ detail in the Summary Information section of this CMP

Timeframe for report submission and finalization:

Refer to the ‘Visit report completion timeline’ detail in the Summary Information section of this CMP

Will NoNO Inc review/receive visit reports:

Yes NoNO Inc will review at least one SIV, one RMV and one COV visit report for each CRA after finalization, as applicable. If the report writing is acceptable, this is not required for further reports by that CRA (regardless of site). CMPL will send report to NoNO Inc on day 3 and Monitor will incorporate comments / CMPL will send a copy of the finalized report to the NoNO Inc within 7 days of finalization> NoNO will have access to read all reports in the TMF.

Source Data Verification

Requirements: Reduced SDV Plan For those CRF pages marked reduced noted in section 1:

o The first 3 patients at each site have all questions 100% SDV’d. o If there are no issues with the first 3 patients, then the CRA will 100%

SDV the remaining data for every 4th patient. o During the ongoing monitoring if there appears to be a decline in

reporting quality, then the CRA may increase the number of subject’s who have 100% SDV until the CRA is confident the site has improved.




This will be documented in the MV Report.



Site contact via phone, i.e., regular, scheduled phone calls


NA


NA

Timeframe: Phone calls will be performed approximately bi-weekly in between on-site RMVs Refer to the ‘Site communication frequency’ details in the Summary Information section

Summary of details: The call will occur with the PI / SC Documentation of the call is required in a telephone contact report in CTMS or with a follow up email The following will be discussed/reviewed during the calls – status of subject enrollment, SAEs, query review/resolution

Site audits

Type: NoNO Inc audit(s) to be performed by NoNO Inc / Contracted by NoNO Inc and will be performed by inVentiv / inVentiv internal audits


The global number of audits will be 6-7 planned routine audits, this number may be increased if in the event of for cause audits.

Timeframe: Starting after at least one patient has completed Day 90 visit.

Summary of details: The Monitor may be expected to be onsite during audits, but it would be preferable if the audit could be scheduled during their routine MV, however this may be outside of the routine MV also. Audit observations will be provided via telephone to the study team (NoNO, iHC and U of C) within 7 business days or within scope determined by NoNO Inc after the completion of the site audit. An audit report will be provided to the NoNO CPL and Clinical Director within 15 business days or within scope determined by NoNO Inc after the completion of the audit.

5.5 Useful information, subject enrollment, site facilities / equipment

inVentiv Project Team Shared Drive:

https://studycentral.inventivhealth.com/ To request access, contact Neel Bhatt, [email protected] or Paula Miller, and provide for iHC users: name and external user Name, Email and contact phone number.

Study Webpage www.escapena1.org



http://www.escapena1.org/




login: ESCAPENA1 (all capitals) password: Stroke44

Study Manager (Records Management and Randomization – to be updated in next version)

iDataFax Download Application download available at Mac: iDatafax 2014.1.2 Mac Windows: iDataFax 2014.1.2 Windows

iDataFax/ Data Management Help Desk

[email protected]

mRS and NIHSS Scale Assessment Training Link

http://ESCAPENA1.TrainingCampus.net

GCP Training Link

http://www.inventivhealthclinical.com/investigators-login.htm User name: inventivhealthclinical Password: iHCGCP

Courier accounts: Details of courier accounts for specific activities The following account can be used for other activities, e.g., shipping original documents: Courier name: FedEx Account number: being procured, to be updated in next version of this document To request pick up: https://www.fedex.com/

5.6 Subject enrollment

Subject Randomization Number Allocation:

Subject randomization numbers will be assigned automatically by Study Manager (IXRS) in sequential order by site at the time of subject randomization. Numbers will be in the following format: a 5-digit string leading with a 2-digit site number followed by a 3-digit subject number. example 01-001

Subject Identifier Information:

Subjects will only have one number- as described above in “Subject Randomization Number Allocation.”

Subject recruitment

Recruitment expectations:

It is expected that sites will randomize an average of 1-2 subjects every month.

Poor recruitment: A site is considered to not be meeting their enrollment expectation if they have not enrolled a subject within one month of the SIV. After one month, the site will be reviewed by the Study Team (NoNO Inc. University of Calgary and iHC). Site without enrollment after 3 month discussions on continuation to occur, if the site will continue then refresher training will occur. After 1 month with no enrollment:

After the Study Team has discussed the lack of enrollment, the Coordinating Investigator will likely be the first contact with the site PI to discuss recruitment strategies.

The Coordinating PI will send a follow up email to be sent to PI and SC, copying the Study Team (including NoNO CPL and CMPLs. The CMPL will forward this email to the relevant CRA and LM where appropriate.

https://www.dropbox.com/s/h9jpwdq0wkbpqdk/iDataFax2014.1.2.pkg?dl=0

https://www.dropbox.com/s/445eu0na3wtjah0/idatafax_2014_1_2.msi?dl=0


http://www.inventivhealthclinical.com/investigators-login.htm

https://www.fedex.com/




The CRA will follow up with any action plan described in the email

After 3 months with no enrollment:

After the Study Team has discussed the lack of enrollment, the CMPL will confirm to the CRA the action plan.

If the Study Team decides to close the site, the CRA will perform a COV

Monitors should ensure CMPLs are informed of the progress, or lack thereof, for poorly enrolling sites.

Fast recruitment: A site is considered to be a fast enrolling site if the randomization rate is greater than an average 2 subjects every month. For these sites, an increased monitoring frequency will be considered.

Over recruitment: In this study there are no maximum numbers per site. However, as quality is key; on a monthly basis the CPL and the Study Team will review the overall recruitment rate as well as the monthly recruitment rate at a site. At any time if the CRA or other member of the study team is concerned about the quality of the data and subject follow up at a site, this should be escalated to the CMPL. The CMPL will alert the Study Team to any concerns. The NoNO CPL will be responsible to observe the overall country recruitment numbers with regard to the country specific insurance coverage and drug availability.

5.7 Site facilities

Facility requirements Most facilities used as part of the protocol are per standard of care (i.e., CT suite, Angio suite, ICU) and the CRA is not responsible to check on these facilities. Monitor should only confirm that the IP storage (pharmacy and local fridge) and the study document storage facilities continue to be acceptable.

5.8 Site equipment

The site is expected to have access to or provide the following equipment: (refer to Vendor section for information of equipment which will be provided to all sites by NoNO Inc)

Equipment Calibration/Maintenance requirements

Comments

Pharmacy Refrigerator for IP storage

Maintenance records are required for pharmacy refrigerators. Calibration records for the temperature logger is required

Fridge (CT or Angio Suite) for IP storage

Maintenance records are required for CT refrigerators. Calibration records for the

Site staff should be checking temperatures on all working days.




Equipment Calibration/Maintenance requirements

Comments

temperature logger is required

Freezer for specimen storage (-20degC or colder)- (as required for Canadian Sites only)

Maintenance records are required for freezers. Calibration records for the temperature logger is required

Required only for sites in Canada participating in PK/Immunogenity. Site staff should be checking temperatures on all working days.

Centrifuge (as required for Canadian Sites only)

Annual maintenance check to be performed and appropriate documentation provided

Required only for sites in Canada participating in PK/Immunogenity

Computed Tomography (CT) Scanner

Annual maintenance documentation provided

Magnetic Resonance Imaging (MRI) Scanner (if used)

Annual maintenance documentation provided

If used for the study.

5.9 Return of equipment:

All equipment provided or loaned to site for use during the study will be returned to NoNO Inc at the end of the study unless otherwise agreed.

5.10 Project Plans Details of all project plans in use for this study are located in the Project Index at https://studycentral.inventivhealth.com/ Refer to the Project Index for details of all project plans in use for this study. All final versions of all project plans, including this CMP are filed in the TMF.

5.11 Study Documents Final versions of all study documents are filed in the TMF. Final versions of all study documents may also be filed in study central located at https://studycentral.inventivhealth.com/ / University of Calgary’s www.escapena1.org / and NoNO Inc’s isoTracker TMF system. To ensure the most current, approved versions of study documents are in use, study documents should not be saved to personal drives or folders, but should be accessed via Veeva Vault eTMF / study central https://studycentral.inventivhealth.com/ / University of Calgary’s www.escapena1.org / and NoNO Inc’s isoTracker TMF system The Essential Document Collection and Submissions (EDCS) team is responsible for collecting all study documentation from sites during the submission phase of the study. After the initial handover meeting from EDCS to Clinical Monitoring, Clinical Monitoring is responsible for collecting updates to documents as indicated in the ISF section of the CMP.

5.12 Study logs and templates Various study logs, templates, forms and checklists (collectively known as ‘logs and templates’) will be used during the study, both by site staff and inVentiv study team members. Details of specific logs and templates in use for this study, including responsibility for development are listed in appendix 1, ‘Logs and Templates to be used during the study’. All final, completed logs









and templates will be filed in the TMF. Study-specific versions of logs and templates (i.e., blank templates) will also be uploaded to the study central located at https://studycentral.inventivhealth.com/ / University of Calgary’s www.escapena1.org Development of the logs and templates:

Study- and/or site-specific logs, templates, forms and checklists (logs and templates) will be developed according to the applicable SOPs, using approved controlled document templates as applicable. Details of who is responsible for developing the logs and templates is indicated in appendix 1

Revision or update of current versions of logs and templates:

Changes to study and/or site logs and templates may be required if: o an update to the controlled document template is released o changes to NoNO Inc templates are made by NoNO Inc o study and/or site-specific updates are required

Changes should be implemented in the study- and/or site-specific log or template within the timeframe indicated in the table in appendix 1

If it is deemed that a newly effective controlled document template will not be implemented at the study and/or site level, this decision should be documented in the study issue and decision tracking log

The role responsible for making the log or template study and/or site-specific will be responsible for making the revisions at the study and/or site level

CMPLs will inform Monitors of revised/updated versions of logs and templates along with instructions how to implement and where necessary, transfer information to the updated version.

Introduction of new study logs and templates during study conduct:

Add new logs and templates requiring implementation during the study to the list of ‘Logs and Templates to be used during the study’

If new documents are to be used at site the CCMPL is responsible for updating the study-specific ISF Table of Contents (ToC) with the new document. The CCMPL will provide the updated ToC to Monitors who will email to sites along with the new document for filing in the ISF.

Site provided logs and templates:

It is not acceptable for sites to use their own logs and templates e.g., IP accountability log, subject ID log

Use of worksheets/templates to record subject source data:

The Coordinating Site (U of C) will provide templates/worksheets (e.g., source data worksheets) to the other study sites via the escapena1.org website. These can be used / adapted by individual sites as they require.

In addition to the source data worksheets, Subject medical records will be used as the location to document source data for subjects during their participation in this study.

Standard assessment tools (i.e., mRS, NIHSS, SNAP etc.) will be provided in compliance with copyright laws to the sites via the escapena1.org website. These will be used for the collection of cognitive assessments and patient reported outcomes.

iHC employees are not permitted to create or provide source data worksheets, either at the request of the site or the NoNO Inc.






If, against recommendation, a site develops their own source data worksheet or similar template, the site is responsible for ensuring that it contains all needed information to allow the Monitor to perform source data verification to confirm subject eligibility, subject safety and that all data collected in the CRF is accurate and complete. The Monitor is not permitted to review the SDW template for accuracy.

o If the SDW is not the source of the data, the monitor will use the original entry/source to complete SDV

If the NoNO Inc or a vendor providing services for this study creates a SDW or similar document for use in this study the PM and/or CMPL is responsible to highlight the risks associated with use of SDWs to the NoNO Inc and/or vendor. The risks of using SDWs could include, but are not limited to:

o Potential to miss key data which should be captured during the subject’s participation in the study

o Potential limitation of data documented due to only data listed on the SDW being entered by site staff

o Inconsistency between the SDW and subject medical record, resulting in increased time on-site by monitors in order to verify both sources of data

o Over-reliance on the SDW instead of the entire subject medical record during monitoring, potentially missing key or other information pertaining to the subject’s participation in the study

o Exclusion of exam/tests/results obtained during the subject’s participation in the study from the subject’s medical records which may be necessary for future patient care, as SDWs are often archived with the study files/ISF.

If the NoNO Inc and/or vendor insists on using SDWs, the PM/CMPL will confirm in writing to the NoNO Inc and/or vendor that the NoNO Inc/vendor is solely responsible for the content, review and approval of such tools. This notification will be filed in the TMF.

o The NoNO Inc should provide the SDWs in local languages as required.

Use of any site/NoNO Inc/vendor developed SDW will be captured in the Source Data Agreement.

5.13 Study tracking and reporting

Details of vendor systems are included in the vendor section of this CMP. Details of tracking and reporting of specific activities, e.g., deviations, are included in the relevant section of this CMP.

Excel spreadsheet

CRU iDataFax (iDF)

inVentiv Health Veeva Vault / and NoNO Inc’s isoTracker TMF system

inVentiv Health CTMS (report / confirmation/follow up letters)

CRU Study Manager report (IxRS report)

Report System / tracker

Who enters data

Reviewed by

Frequency of update

Access

Country / site status

iHC CTMS/ iDataFax / Study Manager

Monitors CMPL / PM

As data / status changes occur. Minimum monthly review/update

IHC ShareWeb or UoC ShareWeb

Enrollment status

Study Manager

Sites Monitor / CMPL /

As data / status changes occur.

IHC ShareWeb or UoC




Report System / tracker

Who enters data

Reviewed by

Frequency of update

Access

PM Minimum monthly review/update

ShareWeb

Site visit tracker

CTMS Monitors CMPL At each site visit IHC ShareWeb

Data entry status

EDC system report

Automatic data transfer from EDC

Monitor / CMPL / PM

Weekly To be confirmed on next version of the CMP

Data review status

EDC system report


Monitor / CMPL / PM


Data cleaning status

EDC system report


Monitor / CMPL / PM


Data query status

Export of EDC system report


Monitor / CMPL / PM


Aggregate Safety Reports

NoNO system

NoNO Inc Monitor / CMPL / PM

6 monthly minimum

email

5.14 Systems

The table below details the systems in use for the ESCAPE-NA-1 study. Where applicable, relevant details for training pre-requisites, system access, et.c. are included in the relevant section of this CMP.

System System Name/Vendor/ location

Roles and level of access

eTMF Veeva Vault https://login.veevavault.com/auth/login

PM – contributor, editor CMPL – contributor Monitor – contributor PC/CTA – contributor (may have edit rights)

CTMS iMedidata <Vendor, if applicable> https://login.imedidata.com/login

PM – owner CMPL – owner and Monitor access Monitor – Monitor access PC/CTA – owner

EDC iDataFax University of Calgary, Clinical Research Unit (CRU) http://www.datafax.com/client-login/

PM – read only CMPL – read only Monitor – Monitor access PC/CTA – read only Site – read / write PI – read / write / approve

IxRS Study Manager University of Calgary, Clinical Research Unit (CRU)

PM – Reports CMPL –Reports Monitor – Reports

https://login.veevavault.com/auth/login

https://login.veevavault.com/auth/login

https://login.imedidata.com/login

https://login.imedidata.com/login

http://www.datafax.com/client-login/

http://www.datafax.com/client-login/




System System Name/Vendor/ location

Roles and level of access

Central Laboratory

Charles River Quebec, Canada

NA Note: testing only done at the end of the study

Central reader / imaging

ESCAPE-NA-1 Imaging Core Lab, CIPAC Foothills Medical Centre, Stroke Research www.escapena1.org.

N/A

NoNO Inc owned SUSAR reporting/ tracking

iDataFax for collection NoNO internal tracker

N/A

5.15 Study team

Details of past and current inVentiv study team members, NoNO Inc study team members, University of Calgary Coordination Team, vendors and/or study committees are included on the project team contact list located at https://studycentral.inventivhealth.com/






6. ISSUE IDENTIFICATION AND ESCALATION ALL issues are to be identified, discussed, documented, escalated and resolved as appropriate. Depending on the seriousness of the issue, this may involve escalating as a quality issue or documentation in the monitoring visit report/follow up e-mail will be sufficient. It is essential that all issues, regardless of severity, are documented through to resolution in order to demonstrate that due diligence has been performed and ensure an appropriate audit trail is available. Serious quality issues or concerns will be managed according to the current inVentiv process for managing quality issues. Refer to this process for definitions of quality issues which require escalation to Quality Assurance and Regulatory Compliance (QARC) as well as the study team. A site issue is one which either in its current state or if allowed to continue, could impact one or more of, but not limited to, the following:

Patient safety (i.e., a subject given the wrong dose of medication; IP non-compliance; use of expired lab kits; subject not given enough time to review the ICF and therefore not provided informed consent and does not fully understand the study process)

Data integrity (i.e., inadequate or unavailable source data, yet data in CRF; completion of data (CRF/source) by those not delegated or trained to perform the activity; subjects not understanding the requirements to complete diaries/electronic devices and thus not having the necessary data for the study)

Compliance of study conduct according to the protocol, ICH GCP /or applicable regulatory requirements

Study timelines or milestones

Quality of any aspect of the study, including investigational product quality

NoNO Inc confidentiality Or could involve:

Fraud

Misconduct

Lack of investigator oversight

Unblinding of study drug Monitors are the owners of site issues and are responsible for following the issue through to resolution; ensuring adequate communication and documentation are maintained throughout the process. Issue Identification: Issues may be identified through many sources including, but not limited to:

On-site visits or monitoring activities – ICF review; S/AE review; SDV; IMP accountability; ISF review; meeting with site staff; general patient or study status review

Preparation for onsite monitoring visits

Planned, scheduled phone contact with site staff

Unplanned, ad-hoc contact with site staff

Site contacting Monitor directly with issue or questions

Email communication with site staff

Conduct of follow up activities post-visit or post-communication with site staff The CMPL is responsible for documenting issues on the study-specific Issue and Decision Tracking Log as appropriate.




Issue Escalation: Routine issues which, in their current state, are not a quality issue or can be easily resolved do not require escalation therefore, documentation in the visit report or via email/contact report log is sufficient. Many issues will be resolved with no requirement to escalate. All quality issues which require escalation should be escalated to, or through, the CMPL for resolution. Persistent protocol or GCP non-compliance should be escalated to CMPL urgently. Notify the Principal Investigator (PI) of any identified issues in a timely manner appropriate to the seriousness of the finding. If an issue is discovered during a site visit, the PI should be notified during/at the end of the visit wherever possible or discussed in the follow up phone call if the PI was unable to attend the visit. Corrective action should be commenced during the site visit as applicable. If there is the potential of fraud or misconduct, the study CMPL and Monitor’s Line Manager (LM) should be notified prior to discussion with the PI. The initial and subsequent communication with the PI must be documented and filed in the Trial Master File and Investigator Site File as applicable. For significant issues the Monitor should contact the CMPL directly as soon as possible after identifying the issue, preferably by phone and a follow up e-mail sent to the CMPL after the initial phone contact. The issue will still be captured in the visit report and follow-up letter; however, it is not sufficient to use submission of the visit report containing details of the issue as a method of issue notification/escalation. Even though a site issue may have been escalated, the Monitor remains the owner of the issue unless otherwise agreed and clearly documented. The Monitor is responsible for follow up activities to ensure resolution of the issue is progressing, even when corrective and/or preventive actions are assigned to other people. If progress is not being made the Monitor should escalate according to the escalation pathway below. If there is any uncertainty whether an issue should be escalated, Monitors should contact the CMPL and the CMPLs should contact the Project Manager to discuss and decide the appropriate next steps. Line Managers should also be contacted to discuss issues and provide support as needed. Escalation pathway:

Monitor (Issue owner)

CMPL LM*

PM LM*

Project Director

Senior Director/NoNO Inc & U of C

* As necessary Consult with QARC at any time point during the escalation process. Issue Resolution: The Monitor is the owner of an issue and is responsible to ensure resolution is achieved in a timely manner, unless it has been agreed and documented that ownership has been transferred to another, more appropriate team member.




Issues should be resolved promptly, and preferably within two site visit cycles, including finalization of the visit report or within 90 calendar days, whichever is sooner. The Monitor should communicate regularly with involved parties both at site and internally to ensure action items are progressing. If no response or progress is noted after two contacts, escalate to the study CMPL and Line Manager or further along the escalation pathway as necessary. The Monitor is responsible for keeping the PI informed about site level issues which have been escalated. If an issue or action item has not been resolved at the end of the second monitoring visit or within 90 calendar days after the issue was identified, whether or not identified at a site visit, the issue, where required, including steps taken to resolve the issue should be escalated to the study CMPL via phone and/or email. The CMPL will then support the Monitor to move the issue towards resolution and determine whether site contact from the CMPL is required. If there is any uncertainty how to resolve an issue, the next role in the escalation pathway should be contacted to discuss and decide the appropriate next steps. Line Managers should also be contacted to discuss issues and provide support as needed. Resolution of issues should be clearly documented, including the date of resolution.




7. DATA PRIVACY The Clinical Operations team must adhere to current procedures in relation to maintaining data privacy during the collection and processing of personal data and ensure that all e-mails to investigative sites that contain personal data are encrypted as appropriate. If encryption is not possible documents should be sent as password protected pdf files. Privacy and Authorization Form (P&A Form) Personal data is any information relating to an identified or identifiable natural person. The Privacy and Authorization Form (P&A Form) is the form used to document the consent of clinical study site staff to the processing of their personal data within inVentiv. The P&A Form is collected for all site staff globally except in the United States. From the time of SIV until site closure the Monitor will be responsible to ensure P&A Forms for any new site staff are collected:

Confirm all site staff listed on SSDRL have P&A Form on eShare

Collect P&A Form for any site staff who have not yet provided one

If no form is on file and personal data has been collected/received escalate to [email protected]

If P&A Form is 5 years old at COV, Monitor is responsible for collecting new form and filing

P&A Form filing:

Copies of P&A Forms should be provided to inVentiv and the original should remain at the investigative site

The Monitor will upload the signed P&A Form to eShare and the copy received should be confidentially destroyed or email with scanned copy permanently deleted, unless retention is required as per local regulations

The P&A Form will be named as ‘Country-Last Name-First Name – Year.pdf (city or town name can be inserted after country if a P&A Form with the same name already exists)

The P&A Forms do not get filed in the TMF unless a NoNO Inc specific template is being used. If NoNO Inc P&A Form or equivalent is signed it will be filed in TMF

It is acceptable for either original or copies of P&A Forms to be filed in the ISF

Link to eShare: https://eshare.inventivhealth.com/sites/i3Dppi/default.aspx The inVentiv P&A Form needs to be collected, and filed at section 05.02.11 in the site management section of Veeva Vault. If any site staff refuse to sign the P&A Form, that individual’s personal data i.e., CV, financial disclosure information, should not be collected or disclosed. Their personal data should only be filed in the ISF. A note to file should be filed in the TMF to confirm the CV was not collected because P&A Form was not signed and to confirm that the particular staff member is qualified by education/training to fulfill the delegated tasks. The PI should sign the note to file to confirm this. If the PI refuses to sign the P&A Form the person collecting the P&A Form will escalate to the CMPL, SSUPL, PM and where required, NoNO Inc as soon as possible to consider possible PI replacement.


https://eshare.inventivhealth.com/sites/i3Dppi/default.aspx




If the staff member refusing to sign the P&A Form is a sub-investigator or any other clinical study site staff, for which data is a part of the essential document package (as described in the Study start up plan), then the person collecting the P&A Form escalates to the CMPL, SSUPL and PM, in order to consider possible solutions such as staff removal from the team list. Difficult cases and/or questions may be referred to the Director of Data Protection ([email protected]) for further guidance. Curriculum Vitae (CV) From the time of SIV until site closure the Monitor will be responsible to collect a CV for any new site staff or when a CV is updated for ongoing site staff. The Monitor will QC the CV, file in the TMF and track as appropriate. Information contained within CVs should be restricted to only that data required for the clinical study and exclude personal data such as date of birth, home address, hobbies, etc. If a site submits a CV containing personal data the Monitor should request the site staff member removes the personal information and provides an updated version. A standard CV template which can be used to replace CVs containing personal data where necessary is available from the inVentiv repository. The Monitor can extract the required professional information and insert into a standard CV template and return to site staff to verify accuracy and date. The detailed CV may be filed in the ISF but the detailed version received by inVentiv should be confidentially destroyed and only the CV without personal data will be filed in the TMF. CVs will be filed in the ISF and TMF and should be updated and dated every 2 years or as per local requirements. CRAs will not be collecting CVs with signatures as required by the iHC SOP as NoNO has indicated otherwise.





8. SAFETY REPORTING The study-specific Safety Monitoring Plan (SMP) is located at: Study Central https://studycentral.inventivhealth.com/ . All Clinical Monitoring team members are required to complete training on the safety monitoring plan. Medical Monitoring activities for this study are provided by NoNO Inc and the Coordinating Investigator at University of Calgary. The CMPL or Monitor can contact the Medical Monitor with any safety/medical related questions.

8.1 Adverse events

AE/AR reporting period:

Start: from time subject signs ICF End: AE collection will continue until Day 30, and SAE to Day 90 or the final contact.

Reporting process and timelines:

Enter all Adverse Events (AE)/Adverse Reactions (AR) in the AE page of the CRF. Data entry timelines as per standard data entry timelines for this study. If an AE/AR meets the Serious Adverse Event (SAE)/ Serious Adverse Reaction (SAR) criteria or worsens so that it meets the criteria, it must be reported as an SAE/SAR (see SAE/SAR reporting section)

Study specific reporting requirements:

All AE/ARs (to Day 30) and all SAE/SARs (to Day 90) will be collected.

Out of range lab parameters:

Laboratory parameters which are deemed to be clinically significant by the PI or authorized delegate will be documented as an AE/AR. Clinical Significate lab results prior to randomization are considered medical history.

Ongoing AEs/ARs: AEs/ARs which are continuing at the time of the subject’s Day 30 visit (or at the time of their last contact if before Day 30) will be captured as ongoing in the CRF.

Source Document Requirements:

AEs/ARs should be reviewed, assessed for seriousness, severity, relationship to study drug and followed up by Principal Investigator (PI) or authorized delegate and documented adequately in the medical records

Monitor review requirements:

The Monitor will review source data at every onsite visit to ascertain whether any AEs/ARs have occurred and if so, that the AEs/ARs have been documented appropriately in the source. The Monitor will review all AEs/ARs until resolution or, if event is ongoing, AE collection will continue until Day 30, and SAE to Day 90 or the final contact to ensure that all details of the event, including resolution/ongoing status, are adequately documented in the medical record.

Inadequate AE/AR Reporting

Inadequate reporting should be escalated to the CMPL / PM / NoNO Inc (or all three). Retraining on AE/AR reporting and/or corrective action provided to the PI and site staff is required and training is to be documented in the monitoring report and the site staff training log.





8.2 Serious adverse events

Seriousness criteria: Death

Life-threatening

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above

SAE/SAR reporting period:

Start: from time the subject is randomized into the study End: Day 90 or the final contact.

Reporting process and timelines:

PI or authorized delegate has to report the SAE/SAR or follow-up information to Pharmacovigilance, NoNO Inc. within 24 hours of becoming aware of the event. Reporting will be via eCRF As a back up reporting can be done via fax or email Fax Number: +1-416-603-5505 Email address: [email protected] eCRF: complete SAE report form in iDataFax Paper CRFs: if iDataFax is offline SAEs should be reported to Competent Authorities and/or IRBs/IECs as per local country requirements.

Minimum required information:

Study number

Subject number

Gender

Year and month of birth

PI’s name and Site number

Details of SAE

Criteria for classification as “serious”

Study drug code and treatment date

Date of SAE onset and time if within 24 hours of study drug

Causality assessment

Study specific reporting requirements:

All SAEs/SARs will be documented.

Ongoing SAEs/SARs: SARs which are continuing at Day 90 should be followed to conclusion if possible. Unrelated SAEs ongoing at Day 90 do not require follow up to conclusion.

Location of forms/guidelines:

SAE/SAR report forms are found in iDataFax or in the Operating Guideline SAE/SAR completion guidelines are available in iDataFax iDataFax link to be added in next version


SAE/SAR should be reviewed, assessed for seriousness criteria, relationship to study drug and followed up by Principal Investigator (PI) or authorized delegate and documented adequately in the medical records. The PI or authorized delegate is obligated to pursue and provide information as requested by NoNO Inc in addition to that requested on the SAE form. Information must include a description of the AE in sufficient detail to allow for a complete medical assessment of the




case and independent determination of causality by the Medical Monitor (MM). Supporting documentation such as anonymized hospital discharge summaries or laboratory reports may be requested by NoNO Inc. If the SAE/SAR results in death NoNO Inc may request an English summary of the death certificate and autopsy findings (if available and if required)

Monitor review requirements:

The Monitor will review source data at every onsite visit to ascertain whether any SAEs/SARs have occurred and if so, that the SAEs/SARs have been documented appropriately in the source and applicable SAE/SAR report. The Monitor will review ongoing SAEs/SARs until resolution or if event is ongoing until Day 90 or the final contact and to ensure that all details of the event, including resolution/ongoing status are adequately documented in the medical record. The Monitor will ensure any event follow up information is provided to NoNO Inc and IRB/IEC (if applicable) as soon as it becomes available.

Inadequate SAE/SAR Reporting

Inadequate reporting should be escalated to the CMPL / PM / NoNO Inc (or all three). Retraining on SAE reporting and/or corrective action provided to the PI and site staff is required and training is to be documented in the monitoring report and the site staff training log.

Listing of SAE/SAR Reports

A list of SAE/SAR reports occurring at their site will be provided to Monitors every month but can also be requested from the NoNO CPL if required more frequently. Six Month Line Listings will be provided by the NoNO CPL for submission to IRB/EC (if required).

8.3 Project specific adverse events of interest (AEOI)

There are no Project specific AEs of interest for this study.

8.4 Pregnancy reporting

If a female subject becomes pregnant during the study they do not require to be withdrawn from the study. The subject and pregnancy will be followed as indicated below.

Pregnancy reporting requirement:

Start: from time subject is randomized into the study End: at subject’s completion of study/Day 90 All pregnancies will be followed until birth, spontaneous abortion or termination of the pregnancy. The Investigator must fill out a Pregnancy Reporting Form and inform the Sponsor within one month of identifying a pregnancy case. Study staff must then maintain contact with the subject to obtain information about the outcome—i.e., details about the delivery and the newborn, or about pregnancy termination—and must update the Pregnancy Reporting Form. Note that some countries may require a Pregnancy Reporting ICF to be signed.

Reporting Process and timelines:

PI or authorized delegate has to report the pregnancy to inform NoNO Inc within one month of identifying a pregnancy case. A follow up reporting form will used to document the outcome of the pregnancy.




Reporting will be via email to [email protected] Pregnancies will not be recorded in the eCRF. Complications during pregnancy may be reported as AEs if they meet the AE reporting criteria. Pregnancies should be reported to Competent Authorities and/or IRBs/IECs as per local country requirements.

Location of forms/guidelines:

Pregnancy notification forms: Available in the Operating Guideline Pregnancy form completion guidelines: Available in the Operating Guideline.


Pregnancies will be reviewed and followed up by Principal Investigator (PI) or authorized delegate and documented adequately in the medical records.

Monitor review requirements

The Monitor will review source data at every visit to ascertain whether any pregnancies have occurred and if so, that the pregnancies have been documented appropriately in the source. The Monitor will review pregnancies until the completion of the study at the site and to ensure that all details of the event, including status, are adequately documented in the medical record. NoNO will follow up with the PI for the outcome of any reported pregnancies. The Monitor will ensure any event follow up information is provided to NoNO Inc and IRB/IEC (if applicable) as soon as it becomes available.

Inadequate Pregnancy Reporting

Inadequate reporting should be escalated to the CMPL / PM / NoNO Inc (or all three). Retraining on pregnancy reporting and/or corrective action provided to the PI and site staff is required and training is to be documented in the monitoring report and the site staff training log.

8.5 Expedited safety reports (ESRs) and aggregate safety reports (ASRs)

Responsibility for Expedited Safety Reports (ESRs) and Aggregate Safety Reports (ASRs):

Details can be found in the Safety Management Plan (SMP). If there is a conflict between this document and the SMP, the SMP is the correct document. ESRs: Canada and US - NoNO Inc is responsible for distribution of ESRs to PIs, REB/IRB, CA and IHC. ROW- IHC is responsible for distribution of ESRs to PI, IEC/IRB and CA. ASRs: Canada and US- NoNO is responsible for distribution of ASRs to the PIs IRB/REB, and CA and IHC. ROW- iHC is responsible for distribution of ASRs to sites, IRB/IEC and CA a according to the Safety Monitoring Plan (SMP) and local requirements. Sites and IRB/IEC will only receive blinded information. CAs may





receive unblinded information as per the local agreement with the CA.

Location of ESRs: A list of ESRs/ASRs issued for the study will be maintained by NoNO Inc and is will be provided to the Study Central. The list should be reviewed against the ESRs filed in the site’s ISF to ensure all ESRs have been received as per local requirements. Individual ESRs are filed in Study Central to ensure that inVentiv Monitors can retrieve any ESR that is missing at site as applicable.

Filing of ESRs and ASRs in ISF:

All ESRs and ASRs will be submitted to sites as described above. ESRs / ASRs should be filed in the site’s ISF following receipt / review

Verification of completeness of ESRs/ASRs:

See the Safety Management Plan




9. COMMUNICATION The study-specific communication plan is located at: https://studycentral.inventivhealth.com/ . All Clinical Monitoring team members are required to complete training on the communication plan. The study-specific Frequently Asked Questions (FAQ) Log is located at: https://studycentral.inventivhealth.com/ . There will be two FAQ logs, one specifically for U of C, NoNO and IHC. A second FAQ Log will be focused on site FAQs and this FAQ log located on www.escapena1.org. The study-specific Telephone Contact Report template is located in the Operating Guideline Email Communication / Policy Due to the number of countries (regions, multiple time zones), the majority of communication will be conducted via e-mail. This will ensure that all team members are informed about all project issues and the project is carried out consistently in all countries. The following guidelines should be followed with respect to email use and good email communication practices: Subject Header

All e-mails should have an appropriate Subject Header applied to give a clear indication of the subject matter.

The project identification should be placed first in the subject line.ie, Protocol identifier (i.e., number/Name/UPC), country, site #, PI name, subject#, topic (remove country, site #, PI name, subject # as appropriate)

The nature of the email should be included in the subject line and should follow the project protocol number.

Running emails (e-mail strings) should use a specific subject header.

When replying to a running email, avoid forwarding out-of-date, irrelevant and confidential information.

Use of the “To”, “Cc”, “Bcc” lines

Direct the email to the individual from whom a response is required. One email per task is helpful; always specify who executes the task and within what timeline. This individual should be present in the “To” line.

Copy the proper team members in the “cc” line. Individuals in the “cc” line should only respond to the e-mail in order to correct a mistake or to suggest an improvement, otherwise the e-mail intends to only inform them of the subject.

Do not use “reply to all” on e-mails as standard – ask CMPL if unsure who to copy. General

Include details of the author’s role and contact information via the “signature” option.

Capitalized text should be avoided as it may be read as SHOUTING.

The word “URGENT” or the (!) symbol should only be used if a response is really required within 24 hours. Voicemail should be used in addition to e-mail in case of urgent issues.

Email security and encryption inVentiv requires emails containing patient or personal data to be encrypted. Encryption protects the information in an email from being viewed by anyone other than its intended recipients.






inVentiv does not have a secure email link with NoNO Inc; hence emails sent to NoNO Inc do require encryption. Any message sent through regular email containing the following information will be encrypted:

Sites lists, data trackers which include Investigator/site staff personal data

CVs or resumes from investigators, site staff or inVentiv employees

Bank account / tax details

Patient health information

Key-coded research subject information including patient listings, CRF copies, CIOMs reports, SAE forms, etc.

In order for inVentiv staff to encrypt an email, the word ENCRYPT should be written as the very first word in the subject line. The first time inVentiv sends an encrypted email to a recipient, there will be instructions for “decrypting” the message into a readable form by registering with the inVentiv encryption system. If encryption is not possible documents should be sent as password protected pdf files.

9.1 Communication with site The Monitor is the main point of communication with the investigator and site staff after site activation. If an issue or question raised is outside of the Monitor’s competency area, then the Monitor will inform the CMPL who will direct the question to the most appropriate individual. The Monitor will be copied in the communication where appropriate.

General All relevant site communication via phone or email must be filed in the TMF/ISF / documented in CTMS All investigators will be provided with the contact information of their primary point of contact as well as contact details of the Project Core Team during the SIV.

Communication via email

Sites should be contacted by email approximately bi-weekly. Escalate to CMPL if this frequency cannot be met.

Email communication should have a clear and concise title in the subject line, i.e., NA-1-007 site #, PI name, subject#, topic (remove subject # as appropriate)

E-mail communication with sites should always be formal, similar to writing a letter

Email communication which is required to be filed in the TMF should be in English

Communication via telephone

The PI will be contacted approximately bi-weekly by phone, unless the frequency is determined to decrease by request of the PI or as discussed with the CMPL

The Study coordinator will be contacted approximately bi-weekly by phone or email , unless the frequency is determined to decrease by request of the PI or as discussed with the CMPL

All phone calls with site staff will be documented in a Telephone Contact Report/ in CTMS or by follow-up email.

Escalate to CMPL if this frequency cannot be met.

Communication via email

Visit confirmation and follow up letters will be in email format whenever possible

All types of letter can be emailed to site if allowed per country regulations

All letters will be filed in the TMF and ISF




Newsletters The University of Calgary will be responsible for distributing any newsletters to PI, sub-I, study coordinators at each site as needed. These will be posted on the escapena1 website.

Information will include details of project status, enrollment, administrative or process clarifications and Frequently Asked Questions (FAQ).

Investigator questions Investigators’ questions will be addressed as a matter of urgency and if the answer is not immediately known, the Monitor will inform the PI that a response will be provided within a timely manner, and will provide the expected timeframe, preferably within 48 hours maximum. If the timeframe is expected to be longer, the Monitor will keep the site informed of the status. Additional details may be found in Section 6 of the Operations Guide.

Communication filing requirements

All relevant site communication will be filed in the TMF and ISF as applicable

Refer to TMF and ISF sections of this CMP for details

Escalation If the PI is persistently unavailable for scheduled and/or ad hoc calls or in replying to emails the Monitor should escalate to the CMPL for guidance If the PI persistently does not respond to emails or voicemail the Monitor should escalate to the CMPL for guidance

9.2 Internal Communication

Clear, concise and timely communication between the internal study team is essential for the successful completion of the study. CMPLs and Monitors will communicate with many functional areas throughout the duration of the study, including but not limited to:

Project Management o Project Manager o Project Coordinator /Clinical Trial Associate (CTA)

Essential Document Collection and Submissions o Study Start Up Project Lead or Study Maintenance Lead o Country Submission Specialist or Study Maintenance Specialist

Site Contracts o Site Contracts Lead

Risk Based Management o Clinical Risk Manager

Site Intelligence – Patient recruitment and retention (as applicable)

Clinical Trials Supply Management (as applicable)

Document Management

Data Management

Data Services Project Management

Medical Monitoring

Global Safety and Pharmacovigilance The internal meetings relevant to CMPLs/Monitors are detailed in the communication plan. Handover from EDCS to Clinical Monitoring




Prior to each site’s SIV, an initial handover meeting from EDCS to Clinical Monitoring will be completed and documented following the current standard procedure for handovers between EDCS and CM. Handovers from EDCS to CM will also occur for subsequent submission/approval or notifications performed by EDCS to IRBs/IECs and/or RAs/CAs e.g., protocol amendments, ICF changes following the current standard procedure for handovers between EDCS and CM.

9.3 Team meetings Refer to the communication plan for details of team meetings applicable to CMPL and Monitors.

9.4 Communication with vendors The NoNO Inc will be the primary point of contact with the contracted vendors. The CMPL can contact the CRU Data Manager without prior permission of the CPL. The CMPL should not contact any other vendors without prior permission from NoNO. Monitors should not be in direct contact with vendors unless it is to assist with query resolution where appropriate, . If the Monitor is in contact with the CRU, the CMPL should be copied on the communication. The CMPL will escalate any issues to the PM in a timely manner.

9.5 Communication with NoNO Inc The inVentiv Project Manager is the primary point of contact for the NoNO Inc and is responsible for communicating directly with the NoNO Inc study team with respect to the management and operation of the study and project-related matters throughout the study. The CMPL will communicate with the NoNO Inc CPL regarding status updates, issues and questions relating to Clinical Monitoring activities. Before highlighting newly identified issues to NoNO Inc the CMPL will discuss the issue with the PM and/or LM and consider the severity/impact, required actions and the most appropriate method of notifying the NoNO Inc (e.g., at next teleconference/meeting, direct phone call, via email). NoNO Inc meetings CMPL(s) are expected to attend are detailed in the communication plan. The PM is not required to be copied on email communication between the CMPL and the NoNO Inc unless it relates to a serious issue or risk of not meeting a milestone/timeline. Monitors will not be expected to communicate with the NoNO Inc study team members unless contacted directly by NoNO Inc or agreed with the CMPL/PM.

Team Teleconferences – CMPL will provide status updates, overview of enrollment, issues, etc.

Team Meeting Minutes – CMPL will provide copy of meeting minutes from Monitor calls and file them in the TMF.

Project Status Reports – CMPL will send to PM / NoNO Inc the following status reports:

Status report Report format Frequency to provide report

Provide report to

Enrollment Study Manager output - excel

Weekly PM / insert NoNO Inc role




Completed subject visits

To be confirmed on next version of CMP

Visit report tracker Excel spreadsheet - CTMS

Weekly PM / NoNO Inc




10. VENDORS NoNO will manage the vendors and IHC is not responsible for these activities. The following vendors are involved in the ESCAPE-NA-1 study:

Investigational Product depot: University of Iowa and TBD Refer to IP section of this CMP for details relating to IP supply

IxRS: Study Manager: CRU

EDC iDataFax: CRU

Imaging Calgary Image Processing and Analysis Centre (CIPAC)

Cognitive assessment forms

Copywrite access will be purchased by U of C from the various vendors

Core document translations Transperfect

10.1 IP Depot

Name: University of Iowa and TBD

Responsibilities Overview:

The NoNO Drug Manager will be the contact with the depots for shipment of IP to study sites.

Study Materials/ Reference documents:

Operating Guideline

Address: TBC

Support Contact details:

Helpdesk email: [email protected]

Vendor Systems: Study Manager (IxRS) will be used for the tracking and management of IP.

Vendor Data Management:

Will be managed by the NoNO Drug Manager

Equipment Supplied: None

Equipment required at site:

NoNO is responsible to provide study sites with CT fridges if required.

Equipment Ordering: CT fridges NoNO will work with sites to ensure CT fridges are provided if required. Timeframe for receipt of fridges: CT fridges must be on site prior to the SIV.

Shipping Process and Courier/s:

Will be managed ad hoc by the NoNO Drug Manager.

10.2 IxRS

Name: Study Manager


The CRU is responsible to ensure the randomization and study drug system is available to the completion of randomization


See the Study Manager User Guide.

Address: University of Calgary





Helpdesk email: [email protected] Helpdesk phone for study team: Monitors to contact CMPL. The CMPL can contact the Global Coordinating Nurse- Karla Ryckborst, if there are issues with Study Manager

Vendor Systems: Location: Link to be added on next version of the CMP System accessible to: NoNO, inVentiv study team, Study Sites Training required to obtain access: None- Study Manager Manual for troubleshooting Role responsible for requesting and cancelling access for inVentiv study team: CMPL Role responsible for requesting and cancelling access for site: Monitor will update CMPL with the details regarding the site information and why if prior to COV. Summary of information accessible in system to Monitors: <subject enrollment details, treatment allocation, randomization number, etc.> Summary of information accessible in system to sites: <subject enrollment details, treatment allocation, randomization number, etc.>

Data corrections: Monitor to alert CMPL, who will inform Karla Ryckborst if any corrections to the data entered in to Study Manager, is required.

10.3 Electronic Data Capture (EDC)

Name: iDataFax


iDataFax is an online data management software system commonly referred to as Electronic Data Capture or EDC. iDataFax (iDF) is a standalone software client/application which is downloaded and can be run on your local PC.


iDataFax User Guide (found under: Help- Topics of the iDataFax application or posted on the ESCAPE-NA-1 Study Webpage: www.escapena1.org

Address: University of Calgary


Helpdesk email: CRU user support at: [email protected] Helpdesk phone for site staff and study team: Monday to Friday, 10-4 EST

Vendor Systems:

Location: iDataFax software can be downloaded from the following links: Dropbox links: - For Mac: iDatafax 2014.1.2 Mac - For Windows: iDataFax 2014.1.2 Windows Sync links (if Dropbox does not work): - For Mac: iDataFax 2014.1.2 Mac - For Windows: iDataFax 2014.1.2 Windows

After you have successfully installed iDataFax, you will need to enter the Server Name: datafax.cru.ucalgary.ca You will be emailed your user ID and Password. System accessible to: In order to access iDataFax for the upcoming review phase of the ESCAPE NA-1 trial you will need to download the newest version (iDataFax 2014.1.2)






https://ln.sync.com/dl/ce296a300#8pzdkigk-6ti29vm3-iamqm936-funz6pmd

https://ln.sync.com/dl/f71f25350#32eaphf6-cpgvsg9f-m8y773q2-cg6sasfr




Training required to obtain access: https://drive.google.com/file/d/0B5CjjU_YK1CZakdtRnh0OG5abnc/edit?usp=sharing Role responsible for requesting and cancelling access for inVentiv study team: CMPL Role responsible for requesting and cancelling access for site: Monitor will update CMPL with the details regarding the site information and why if prior to COV. Summary of information accessible in system to Monitors: eCRFs Summary of information accessible in system to sites: eCRFs

Data corrections:

eCRF Queries (including eSAE queries) will be generated electronically through the EDC system. The Investigator/delegate is responsible for resolving SAE-related queries within 48 hours and for resolving other queries within 5 working days. Nearing database locking queries may be requested more quickly.

Additional Information:

Instructions for completing the ESCAPE NA-1 data collection worksheets can be found on the ESCAPE NA-1 website and in the Help icon within iDataFax.

10.4 Calgary Image Processing and Analysis Centre (CIPAC)

Name: Calgary Image Processing and Analysis Centre (CIPAC)


The Calgary Image Processing and Analysis Centre (CIPAC) will act as the core lab for the duration of the project.


ESCAPE-NA-1 Study Webpage: www.escapena1.org Imaging Charter

Address: Foothills Medical Centre, Stroke Research, Room C1241B Attention: ESCAPE NA-1 Imaging Core Lab 1403 - 29th St. NW, Calgary, AB Canada T2N 2T9 Tel: 403-944-2863


Helpdesk email: [email protected] Helpdesk phone for study team: +1 403-944-2863 Helpdesk phone for site staff: +1 403-944-2863

Vendor Systems:

Location: the File Transfer Protocol (FTP) instructions are located in the Imaging Charter. File Transfer Protocol Link is accessible to the study site Training required to obtain access: Training is not required, the site can follow the instructions in the manual. If the site has never completed an image transfer with CIPAC before, the CIPAC manager will contact the site to complete a practice transfer. Role responsible for requesting and cancelling access for inVentiv study team: not applicable Role responsible for requesting and cancelling access for site: not applicable Summary of information accessible in system to Monitors: none, however there is an Image Transmittal page in the eCRF that can be accessed by the Monitors Summary of information accessible in system to sites: None, this is a file transfer process only, access by sites to the images is not available

Vendor Data Management

Provision of image: image will be sent to CIPAC by the preferred method of transfer to the core lab (CIPAC) is through electronic upload to a pre-determined secure file transfer protocol (sFTP) server. There are no significant technological requirements for end users to use the sFTP application. Access to the server can be performed from a regular computer workstation with an internet connection and an FTP client (e.g., Filezilla), or

https://drive.google.com/file/d/0B5CjjU_YK1CZakdtRnh0OG5abnc/edit?usp=sharing






through an Internet browser (Chrome, FireFox, Internet Explorer, Safari etc.). Some clarification on browser and Java version employed may be required at initial site set up. If the recommended electronic transfer is not possible, a CD with anonymized imaging may be mailed to the address provided above. Frequency of image provision: Baseline and 24 hour images should be sent to Calgary Image Processing and Analysis Centre (CIPAC) within 7 days of Randomization. All imaging should be compiled in a compressed file, labeled with the Research ID, and located on the local computer workstation of the data manager. This will ensure a efficient and reliable upload process. System requirements for provision of image: no significant technological requirements only an internet connection is required. Data query process: If an image was not loaded properly or is missing, the CIPAC manager will contact the site directly for resolution.

Equipment Supplied:

N/A


Access to computer and de-identified images.

Additional Information

In the event that site staff absolutely cannot use an FTP to transfer the images, then the site will mail by CD. The CIPAC Manager will work directly with the site to obtain the images. CIPAC has adopted the CIHR and IHE’s definition of de-identification as the processes that reduce the probability of an individual being associated with that individual’s data. CIPAC will accept, store and release only de-identified imaging data. The extent of de- identification of imaging data and a listing of which demographics (i.e., direct or indirect identifiers) is to be preserved for each study are detailed in the protocol and must have corresponding Research Ethics Board approval. All users from external sites are responsible for obtaining de-identified imaging data from their imaging departments before uploading it to the sFTP server. It is essential that each external site removes all subject identifiable information according to the ESCAPE NA-1 protocol, and replaces these identifiers with correctly formatted Research Identifiers. For the purposes of the ESCAPE NA-1 study, these formats have been detailed in the study manual. If the external site is unable to provide de-identified imaging data, the external site data manager shall contact the core lab manager to determine the best course of action.

10.5 Cognitive Assessment Forms

Name: mRS, NIHSS, SNAP, MOCA, Barthel Index, Boston Naming and EQ-5D forms from various vendors.


The University of Calgary Coordinating Centre will obtain the copy write and provide the forms in the validated local languages.


Blank forms will be available at www.escapena1.org


Contact Karla Ryckborst if additional copies are required and not available on the webpage. Email: [email protected]





10.6 Central laboratory (For Canadian Sites Only)

Name: Charles River


Charles River is responsible to provide all lab kits for Immunogenicity and PK Samples and for the storage and testing of these samples. All sites in Canada will collect immunogenicity samples for up to 250 subjects Three or four sites in Canada will collect PK samples up to 100 subjects. NoNO will contact you regarding the site selected for the PK sub-study.


The Laboratory Manual will be available in Study Central.

Address: Quebec, Canada


Helpdesk email: <Email address> Helpdesk phone for site staff: <Insert global phone number, including country code or provide location of country-specific phone number list>

Vendor Systems: Will not be used for this study.

Vendor Data Management:

PK and Immunogenicity results will be reported directly to NoNO Inc prior to DB lock and will not be provided to the PI or iHC for review.

Equipment Supplied: Laboratory kits to be supplied by Charles River


Centrifuges and freezers will be required at site and will be supplied by the site staff. Shipment details will be provided in the Study Sample Manual.

Equipment Ordering: Initial lab supplies: Initial supplies will be will be provided to site automatically shipped prior to SIV; ordered by the CPLReplacement lab supplies: Replacement supplies will be shipped upon completion of request form by site to the NoNO CPL Monitors can place orders on behalf of sites. Timeframe for receipt of lab supplies: Supplies generally arrive 7 days after ordering.

Shipping Process and Courier/s:

Courier: FedEx Contact details to request sample collection: www.fedex.com Collection times: Sample collections will be made on Monday, Tuesday or Wednesdays. Refer to central lab manual for details of collection times. Packaging materials: Will be provided by Charles River Sample handing requirements: At least one site staff personnel will need to have received IATA certification. Dry ice: Dry ice is not required for this study. Samples may be shipped with ice packs or dry ice if provided by site. Dry ice cannot be delivered when collecting the samples.




11. TRAINING

11.1 Monitor/CMPL Training Training for the Clinical Monitoring team members will be assigned, completed and documented according to the current standard procedure for completion and documentation of project-specific training. Assigned trainings may be conducted during team meetings, investigator and Monitor meetings, via individual documented self-review, remote training and workshops i.e., WebEx meeting (live or recorded) throughout the course of the study. The study-specific training matrix is located at https://studycentral.inventivhealth.com/ in iHC Study Central. Refer to this matrix for details of study-specific training which must be completed in relation to this study. Study specific training materials are located in the inVentiv Study Central at https://studycentral.inventivhealth.com/ . Study specific training will be assigned via the inVentiv electronic learning management system / manually by CMPL/ presentations in Calgary / links provided in Study Manager. Completion of study-specific training will be captured via the inVentiv electronic learning management system / manual excel tracker. inVentiv staff must have completed the necessary inVentiv, NoNO Inc and study-specific training related to the required activity before that study activity is performed. The following table provides details of some of the study-specific training required – note that this table is not fully comprehensive and the study-specific training matrix should be reviewed for additional information. Generally the PM, MM and other functional leads will provide training to the CMPL and the CMPL will provide training to Monitors. Other functional leads and the Medical Monitor will provide training to CMPLs and Monitors as applicable.

Training item Method of training

Who provides training Provided at IM

Protocol Self-read Self-read N/A

Protocol overview F2F, WebEx or team meetings

NoNO Medical Monitor / CMPL

N/A

Protocol amendments Self-read Self-read N/A

Protocol amendments overview

F2F or WebEx Medical Monitor / NoNO Inc / CMPL

N/A

Therapeutic area training F2F / WebEx / Online video

Medical Monitor / NoNO Inc / CMPL / Sum Total

N/A

IB/study drug F2F or WebEx Medical Monitor / NoNO Inc / CMPL

N/A

Clinical Monitoring Plan Self-read Self-read N/A

Clinical Monitoring Plan overview

F2F or WebEx CMPL N/A

Clinical Monitoring Plan amendments

Self-read Self-read N/A

RBM overview training F2F or WebEx CMPL/CRM N/A

Clinical Monitoring Plan Amendment overview (if required)

F2F or WebEx CMPL N/A

EDC training F2F / WebEx / CRU / CMPL N/A




Training item Method of training

Who provides training Provided at IM

Online video

eCRF Completion Guidelines Self-read Self-read N/A

Central lab training (Canada Only)


IRT training Self-read CRU / CMPL N/A

Country-specific training Self-read Self-read N/A

Calgary Image Processing and Analysis Centre (CIPAC)


Transition of team members: Role to role transition of team members, i.e. Monitor replacing a Monitor will be completed as per the current process for project team member transitions. Generally, during Monitor transitions the CMPL will complete the study overview handover activities and the outgoing Monitor will complete the site-specific handover activities. The appropriate transition checklist will be completed with the CMPL and Monitor completing the information relevant to their portion of the handover. The completed transition checklist will be filed in the TMF.

11.2 Investigator Meeting (IM) Training There will not be an IM for this study.

11.3 Site Training The following table provides details of the required site training before, during and after the SIV. The training can be delivered as, but is not limited to, face-to-face meeting, read and understand, or WebEx meeting. Monitors should ensure all site staff listed on the Site Delegation Responsibility Log (SSDRL) have completed the appropriate training prior to the site staff performing any study related activities. All training provided to site staff team members will be documented on the Site staff training log and each entry signed by the trainer and trainee. Training provided by the PI to his study staff will also be documented on the Site staff training log with appropriate signatures. The Site staff training log and any applicable training certificates will be filed in the ISF and TMF (copy of Site staff training log to be collected at COV for TMF filing). Prior to SIV: (so that site will be able to proceed with subject recruitment immediately post-SIV/greenlight)

Training item Details Site staff requiring training Person providing training

ICH GCP certification

Certificate to be dated within 2 years prior to SIV. Training from Transcellerate, Health Canada Div 5 or inventive Health GCP training is acceptable Update training required every 2 years

PI, primary SC, and staff listed on the 1572.

Training to be completed for other site staff as required per local regulations

Web training/Self-training





IRT: Study Manager Single training PI, primary SC, and staff responsible per the SSDRL

Web Training

EDC: iDataFax Single training PI, primary SC, and staff responsible per the SSDRL

Web Training

Assessments: mRS

NIHSS

Certificate PI, and staff with the responsibilities per the SSDRL

Web Training

Assessments: Barthel Index

EQ-5D-5L

MoCA

BNT 15 SNAP

CRA or self training

During SIV: (Note that an IM was not completed for the study)


SIV standard requirements

As per SIV section of this CMP and/or SIV agenda

As per SIV section of this CMP and/or SIV agenda

Monitor

Post-SIV / ongoing*: (see note below regarding Post-SIV training requirements)


Re-training If the site has not consented any subjects and at least one month has elapsed since training via the SIV, where agreed with NoNO and the CMPL, the site staff should be re-trained on protocol-specific requirements prior to recruitment or screening of the first subject. This training should be documented and filed in the ISF and TMF.

Monitor

Any training for new site staff team member

As appropriate to training item

New site staff team member PI, Monitor may assist as necessary

Refresher training As appropriate to training item

As needed PI, Monitor may assist as necessary

Protocol amendments/ ICF amendments/new safety information


As needed Monitor

Study/process updates or new


As needed Monitor




information

Calgary Image Processing and Analysis Centre (CIPAC)

Single training Staff responsible per the SSDRL

CIPAC Self training

* Post-SIV or ongoing training may be conducted as a formal session at the next monitoring visit or an informal face-to-face or phone discussion covering the (re-)training and/or issues as appropriate. Post-SIV or ongoing training conducted at a monitoring visit should be documented on the site staff training log; in the supplementary comments section in the monitoring visit report and in the follow-up letter or in a follow-up email to the PI. Post-SIV or ongoing training conducted via telephone or informally face-to-face should be documented in a follow-up email/letter to the PI as well as documented on the site staff training log.

11.4 Country Specific Training The following country level training specific to the ESCAPE-NA-1 study is required.

Training item Country Details Training required by

Person providing training

Tarius (Regulatory database regulatory training) for the country which will be visited

As required Review country-specific regulatory requirements

Monitor performing monitoring and/or site management activities outside of their country of residence

Self-training

PK Canada Single Training

Primary SC, and staff responsible per the SSDRL

Monitor Lab manual/self training

Immunogenity Canada Single training Primary SC, and staff responsible per the SSDRL

Monitor Lab manual/self training

Hazardous materials/dangerous goods training requirements (i.e. IATA) as applicable

Canada I.e., IATA training certificate or equivalent required

At least one site staff personnel handling subject samples will require this

Self-training




12. INVESTIGATIONAL PRODUCT This section of the CMP contains information regarding the Investigational Product (IP), including supply of IP, storage requirements and information/instructions for how IP is monitored, tracked and accounted for at all clinical study sites.

Clinical Trials Supply Plan / IP Manual

See the Operating Guideline

Is unblinded monitoring required:

Yes No

Will site/ pharmacy staff preparing/ dispensing IP be blinded or unblinded>

Blinded Unblinded

Investigational Product

IP type: Medicinal product Device

IP name: NA-1

IP indication/class: Neuroprotectant- planned indication for Acute Ischemic Stroke with endovascular therapy

IP dosing: NA-1 2.6 mg/kg will be administered as a single 10 ± 1 minute intravenous infusion in the upper or lower extremity using an infusion pump starting within 30 minutes of randomization.

Is IP a controlled substance:

Yes No

IP formulation: infusion

IP primary packaging: IP will be packaged in vials with 2.6 mg/kg per vial and 6/vials per

shrink wrapped brick boxes contain 12 doses 6 of NA-1 and 6

placebos.

The approximate size of a box is 3x6x8 inches and 1, 2 or 3 boxes will be sent in the initial shipment, depending on your expected monthly enrollment.

Comparator Product

Comparator type: Medicinal product Device

Comparator provided by:

Site NoNO Inc

Comparator name: Normal Saline: Sodium Chloride Injection

Comparator indication/class:

sterile, nonpyrogenic solution

Comparator dosing: 2.6 mg/kg normal saline (placebo volume) will be administered as a single 10 ± 1 minute intravenous infusion in the upper or lower extremity using an infusion pump starting after eligibility for endovascular recanalization therapy is confirmed by a CT scan.

Is Comparator a controlled substance:

Yes No (only by prescription)




Comparator formulation:

infusion

Comparator primary packaging:

Comparator/placebo will be packaged in vials with 2.6 mg/kg per vial and 6/vials per transparent shrink wrapped brick boxes contain 12 doses 6 of NA-1 and 6 placebos. Comparator will be included in the box with the IP. There is no visual difference in the vials. Each vial will be labelled with a unique 5 digit vial number.

Comparator secondary packaging:

There is no secondary packaging.

General

Supplies to be shipped with IP:

No additional supplies will be shipped with IP

Supplies site required to supply themselves to prepare/administer IP:

50 or 100 mL mini drip bags (saline solution), infusion pump, antiseptic wipes, needle and syringe

IP Storage: The IP should be stored as follows:

Temperature: 2 to 8°C at all times Exposure to light: no specific requirements Security: secure/locked area with access to appropriate staff only

IP Storage in the Pharmacy and local Fridge

Satellite sites are not used in this study. IP will be stored for long term storage in the pharmacy. IP ready for allocation will be transferred to a fridge located closer to the CT or angio suite. Transfer of doses from the pharmacy to the fridge must be done in less than 1 hour; NoNO is not providing specific details on the exact transfer process, allowing the site some flexibility.

Ask the site to describe their process for transporting IP between locations and assess adequacy

Temperature excursions occurring during shipment:

TempTale devices with download instructions will be included in the shipment. If the TempTale shows a temperature excursion has occurred the site should place the entire shipment in quarantine and contact [email protected] immediately and provide temperature out of range report or kit numbers, temperature reached copy of data download. Suitability for use and further instructions will be confirmed by the NoNO Inc. Drug Manager and provided to the site. The confirmation that the IP is suitable for use must be filed in the ISF and TMF.

Temperature monitoring at site

Temperature monitoring devices should permit continuous, 24 hours a day / 7 days a week recordings of the temperature. Any periods of more than 1 hour of non-recording where the storage temperature cannot be proven will be documented as a temperature excursion. In addition, site staff should be visually checking the temperature logger and recording the temperature at least once per working day in order to discover if there have been any temperature excursions. This manual temperature step is not necessary if the site has a fully alarmed system that provides alerts that are responded to.





Temperature excursions occurring during storage at site:

If a temperature excursion of more than 1 hour occurs the site should quarantine all IP affected – the quarantine area must provide the same storage requirements as for non-quarantined material in case the IP is deemed suitable for use. The site will contact the NoNO Inc [email protected] as soon as the excursion is noted and provide temperature out of range report, kit numbers, temperature reached, and duration of excursion. Suitability for use and further instructions will be confirmed by the NoNO Inc Drug Manager and provided to the site by the NoNO Inc Drug Manager. The confirmation that the IP is suitable for use must be filed in the ISF and TMF. Updates to the IP inventory may also require updating as requested by the NoNO Inc Drug Manager. Note: due to time zone coverage, it may take the Drug Manager a full working day to respond to temperature excursions.

IP vendor: NoNO Inc Krembil Research Institute 8KD406, 60 Leonard Avenue Toronto Ontario M5T 2S8 Canada [email protected] +1 416 603-5481

Importation documentation:

Import licenses and required documentation will be managed by NoNO Inc

Initial supply of IP to site:

Approval of shipment of initial IP supply to individual sites will follow the current standard procedure for authorization of IP release. Upon approval of IP shipment by NoNO Inc.an automatic order will be initiated by Study Manager. The number of boxes/cartons sent to sites in their first shipment will depend on the number of subjects they expect to enroll

Re-supply of IP to site Replacement supplies will be shipped automatically by depot when low supply threshold vials is reached. The number of boxes/cartons sent to sites in their re-supply shipments will depend on the number of subjects they expect to enroll and can be adjusted by the CPL or Drug Manager if necessary.

Randomization codes/unblinding:

Randomization details are maintained by IxRS. Unblinding can only be requested by PI who will need to contact the Medical Monitor. If the decision to unblind is agreed to, the Medical Monitor will contact the unblinded data management Clinical Research Unit (CRU) staff. This unblinded person will email the PI directly with the unblinded subject treatment information. NoNO will be informed that an unblinding has occurred, but not the unblinding allocation.

IP Preparation: A syringe for each individual subject dosing will be prepared by calculating the volume to draw from the vial as follows: (2.6 mg/kg x subject weight in kg)/(20 mg/ml). This will determine the number of mL to pull up into the syringe. For subject weighing 100-120 kg the full volume of the vial (13.5mL) will be used. Weight will be collected in IxRS and the dose calculation will be included with the randomization alert.

IP Dispensing: Dose timing shall start at the time of drip onset. Study drug should be






administered within 60 minutes of the NCCT and within 30 minutes of randomization. The syringe containing study drug will be injected into the intravenous port of a 50 or 100 mL drip bag of 0.9% normal saline that has been labeled with the randomization number. The bag will be mixed by squeezing and inverting the bag several times. After dilution into the drip bag, the drug is stable for up to 5 hours, however it should be infused into the subject as soon as practical with a target randomization to treatment time of 30 minutes or less. The infusion is 10 minutes (+/- 1 minute).

IP returns:

NoNO will confirm with each site/country in writing if the IP will be returned or if it can be destroyed on site. IP will be destroyed at the end of study, unless NoNO provides site/country specific instructions for its return.

Monitors must have completed 100% drug accountability for the affected IP before it is returned. This should be documented on the Study Drug- End of Study form.

IP destruction: NoNO will confirm with each site/country in writing if the IP will be destroyed on site

Monitors must have completed 100% drug accountability for the affected IP before it is destroyed. This should be documented on the Study Drug- End of Study form.

IP will be destroyed at the end of study, unless NoNO provides site/country specific instructions for its return.

Unused, or expired IP can be destroyed on site only if allowed by local regulations and the site has appropriate facilities to do so and an appropriate, documented procedure in place.

IP will be destroyed at the end of study as requested by NoNO Inc., unless NoNO Inc. otherwise specified by NoNO Inc

IP which has been accounted for should be destroyed as per site’s standard procedure and destruction documented on the On Site Investigational Materials Destruction Record

Dispensed vials (empty vials) should be stored by the study site until the Monitor has completed study drug accountability. It is not necessary to keep empty vials between 2-8C, but should be stored securely.

IP documentation: The site staff will maintain the following documents:

Study Drug Dispensing Log

Study Drug-End of Study Form

On Site Study Drug Destruction Record or Study Drug Return

Temperature log

From Study Manager, a Drug Inventory list can be exported

IP Expiration Dates: Changes to IP expiration date will require re-labelling according to written procedures and will be managed by NoNO.

IP Accountability: 100% drug accountability of all vials is required. Drug accountability should occur at every RMV.

Site to Site Transfer: Transfer of IP will only be considered in extenuating circumstances and appropriate authorization must be obtained from a Qualified




Person or another suitably qualified professional who has been trained in the principles of Good Manufacturing Practice (GMP). Refer to the current standard procedure for site to site transfer of IP.

IP Compliance: Follow current standard procedure for IP compliance handling

IP Monitoring at SIV The IP section of the SIV will be performed by the monitor. Refer to the Requirements for Conduct of SIVs and the SIV section of the CMP.

IP Monitoring during RMV

The IP monitoring activities of RMVs will be performed by the monitor.

Refer to the Requirements for Conduct of RMVs and the RMV section of the CMP

IP Monitoring at COV The IP monitoring activities at the COV will be performed by the monitor.

Refer to the Requirements for Conduct of COVs and the COV section of the CMP

As the final dose of IP will be administered 90 days prior to the last subject visit, final drug accountability maybe completed prior to the COV.




13. CTMS

CTMS system: inVentiv Health iMedidata

Link to CTMS: https://login.imedidata.com

Access: Pre-requisite training must be completed before access will be granted Access is granted as per standard CTMS processes

Responsibilities for data entry/update:

See table below

Data sources/transfers:

N/A

Reports: The following reports can be exported from CTMS: Study Management Report

Visit Schedule Report

Action Item Aging Report

Standard Activities Report

Site Report

Documents Report

Telephone Contact Report

Filing requirements: Documents and reports produced in CTMS will require filing in the TMF if applicable The following documents will automatically be filed in the TMF upon document finalization: visit reports, visit confirmation and follow up letters

Support: Questions and issues regarding the study-specific data and reports in CTMS should be directed to the CMPL if the information is not available in the FAQ section of CTMS Technical questions and issues should be directed to the IT helpdesk

CTMS activity Role responsible

Frequency of update

Naming convention

Comments

Set up site – address/contacts

CMPL / PM to request PC / CTA to set up sites

At time of site selection for participation

N/A PC/CTA to request via IT helpdesk

Assign site number

NoNO Inc At time of site selection for participation

2 digit numbers NoNO Inc will provide

Amend site details

CMPL prior to SIV Monitor after SIV

As needed N/A Request via IT helpdesk

Enter country level data/ updates

CMPL Within 2 weeks of data availability

N/A

Enter site level data/ updates

Monitor Within 2 weeks of data availability and/or at or post site visit

N/A Request via IT helpdesk

Enter subject Monitor Within 2 weeks of N/A

https://login.imedidata.com/




CTMS activity Role responsible

Frequency of update

Naming convention

Comments

level data/ updates

data availability and/or at or post site visit

Protocol deviations / ICF status / Action items

Monitor Within 2 weeks of data availability and/or at or post site visit

N/A PDs will be provided by CRU and attached to RMVs/COV as required. ICF will be provided as CTMS - Process to be confirmed on the next CMP

Visit reports Monitor to write CMPL to review

As per report timelines

This will be determined by CTMS to allow for automatic eTMF filing

Visit confirmation letter

Monitor Prior to visit This will be determined by CTMS to allow for automatic eTMF filing

Visit follow up letter

Monitor to write CMPL to review

CMPL at the time of letter/visit report approval/finalization

This will be determined by CTMS to allow for automatic eTMF filing

CRAs to attach PD listing.

Site communication

Monitor As needed Refer to communication section of CMP

Telephone contact reports will be entered in CTMS

Safety documentation

Monitor As needed N/A

Regulatory/ start up documentation

Monitor As needed N/A

It is important to use the correct naming of the documents in CTMS, so that the document migrates correctly to the eTMF




14. SITE INITIATION VISITS Site Initiation Visits (SIV) should be conducted as soon as possible after the Essential Document (ED) package is approved by NoNO Inc. The CMPL will notify the Monitor when the SIV can proceed. The following conditions must be met for the SIV to proceed: • Fully completed, approved and signed Essential Document (ED) package • IP on site is not mandatory • CT Suite Refrigerator equipment on site • PI / SC to have completed training for:

- Protocol - Investigator Brochure - Operations Guide - Safety Plan - iDataFax (EDC) online training &EDC Guidelines - Study Manager (IxRS) - ICH GCP Training - IATA Training (Canadian sites as required)

• Assessment Training:

- Modified Rankin Scale (mRS): certification required by PI and Investigators as required by the Study Task Delegation Log

- National Institutes of Health Stroke Scale (NIHSS) - Barthel Index - EQ-5D-5L - Montreal Cognitive Assessment (MoCA) - Boston Naming Test 15 - Sunnybrook Neglect Assessment Procedure (SNAP)

SIVs are to be conducted at an onsite visit.

14.1 SIV Scheduling and Preparation The standard activities for SIV scheduling and preparation as detailed in the Requirements for Visit Preparation Activities will be followed. The CMPL will communicate with the SSUPL to obtain details of planned SIV timelines. The CMPL will provide these timelines to the relevant Monitors to assist will workload planning. The following table provides details of the study-specific SIV activities the Monitor is expected to perform prior to the SIV being completed. • The order in which they have been listed is not necessarily the order in which they must be

completed • The table can be printed and used as a checklist if helpful, but this is not mandatory

SIV Preparation Activity Details Check

Review study and site documentation

The documents in addition to Essential Documents noted in section 13.2 are required prior to sites randomizing their first subject and hence must be collected before or at the SIV or prior to the site staff participation in the study.

SIV Agenda https://studycentral.inventivhealth.com/





SIV Presentation https://studycentral.inventivhealth.com/

14.2 SIV Conduct

The standard activities for SIV conduct as detailed in the Requirements for Conduct of SIVs will be followed. The following study-specific documents should be completed, signed and/or collected during the SIV:

Document Completed by Signed by

Monitor Auditor Visit Log Monitor(s) Site Staff

Study Drug Accountability Form Pharmacist or designee / reviewed by Monitor

Pharmacist and/or PI

Current CV Each Site Staff Member on the 1572

Dated: (signature not required unless this is mandatory per local regulation)

GCP Training Certification Each Site Staff Member on the 1572

NA

Current Medical License Each Site Staff Member on the 1572

NA

mRS certification Staff assigned to complete assessments

NA

NIHSS certification Staff assigned to complete assessments

NA

Financial Disclosure Form Each Site Staff Member on the 1572

The staff member who is completing the FDF

iDataFax Training PI and Site Staff assigned to enter eCRF

Equipment calibration/certification documentation

NA

Source Data Agreement PI / Site Staff PI Study Task Delegation Log PI / Site Staff PI

CT Refrigerator Temperature Log Study Coordinator or designee

IATA Certification (Canada only) Person responsible for shipping PK or Immunogenicity samples

Same

The following table provides details of the study-specific SIV activities the Monitor is expected to perform during the SIV. • The order in which they have been listed is not necessarily the order in which they must be


SIV Activity Details Check

Investigational Product IP will be shipped to sites prior to the SIV. In some cases IP will be shipped following the SIV based on the storage conditions. Training on IP handling and completion of IP logs. of the PI and pharmacist, where applicable is required, this can be





done during the SIV The IP section of the SIV will be performed by the monitor. The Monitor should confirm the CT fridge is set up and ready for study drug and inform NoNO if this is not the case.

Monitoring expectations Expected duration of SIV is 6 hours

Status reporting requirements

CT Fridge temperature logs sent at the end of the month. If there are any unreported temperature excursions, the Monitor should escalate to the CMPL immediately,

14.3 SIV Follow Up

The standard activities for SIV follow up as detailed in the Requirements for Visit Follow-up Activities will be followed. The following table provides details of the study-specific SIV activities the Monitor is expected to perform after the SIV has been completed. • The order in which they have been listed is not necessarily the order in which they must be


Post SIV Activity Details Check

Subject enrollment authorization – written confirmation

Written confirmation of authorization to begin enrolling subjects will be sent to the PI by the Monitor once all documents and requirements are in place and the CMPL has confirmed site can be activated.

IxRS will be activated at this time by the Coordinating Center

If all documents and requirements for the site to be activated are NOT in place at the end of the SIV the Monitor will inform the PI of outstanding actions.




15. ROUTINE MONITORING VISITS The first RMV at each site should occur where possible within 2 weeks (±2 days) of the first subject randomized. Subsequent RMVs should be conducted with sufficient frequency to assess the following: Subject randomization, compliance with protocol procedures, the completeness and accuracy of data entered into the e-CRFs, verification of e-CRF data against original source documents, and occurrence of AEs. Visits should be scheduled based on site activity and follow up timelines 30 and 90 day follow up (more or less frequent based as needed). At a minimum each site will be visited every 3 months. This frequency is adaptable based on site enrollment rate, site status, outstanding data entry/data queries, quality issues/concerns, etc. If the Monitor anticipates a deviation to the standard frequency for a particular RMV they will contact the CMPL to discuss the timeframe for the next RMV. Exceptions to the standard frequency can only be accepted upon discussion with and approval from the CMPL and NoNO Inc. Approval of exceptions will be documented and filed in the TMF. Requests for additional, extended or co-monitoring visits to support high enrolling and/or poor performing sites should be directed to the CMPL who will evaluate the need. CMPL can give approval for additional, extended or co-monitoring visits as appropriate / will request approval for co-monitoring visits from NoNO Inc and the PM.

15.1 RMV Scheduling and Preparation The standard activities for RMV scheduling and preparation as detailed in the Requirements for Visit Preparation Activities will be followed. The following table provides details of the study-specific RMV activities the Monitor is expected to perform prior to the RMV being completed. • The order in which they have been listed is not necessarily the order in which they must be


RMV Preparation Activity Details Check

Remote review of CRF and subject data

Remote review of CRF and subject data prior to the RMV is expected. Review should include: Enrollment metrics for number of enrolled, randomized,

completed, early terminated, lost to follow-up subjects

CRF completion status including missing data, missing pages, and missing visits

Data queries/responses including number of queries, query responses, and query aging

Protocol deviations

AEs/SAEs/ Pregnancies

PI is signing CRF in a timely manner

15.2 RMV Conduct

The standard activities for RMV conduct as detailed in the Requirements for Conduct of RMVs will be followed.




The following study-specific documents should be completed, signed and/or collected during the RMV:

Document Completed by Signed by

Monitor Auditor Visit Log Monitor(s) Site Staff

Study Drug Accountability Form Pharmacist or designee / reviewed by Monitor

Pharmacist and/or PI

Any document that is outstanding or needs a revision at the time of the RMV

The following table provides details of the study-specific RMV activities the Monitor is expected to perform during the RMV.

The order in which they have been listed is not necessarily the order in which they must be completed.

The table can be printed and used as a checklist if helpful, but this is not mandatory.

RMV Activity Details Check

Informed consent The time when written informed consent was obtained for a subject/LAR should be documented in the source documents along with the date of informed consent

Subject eligibility review Data for randomized, not enrolled, do not require review.

Source data verification: Monitor will cross check data entered in CRF against data in source documents for: For those CRF pages marked reduced in section 1:

o The first 3 patients at each site have all questions 100% SDV’d.

o If there are no issues with the first 3 patients, then the CRA will 100% SDV the remaining data for every 4th patient.

o During the ongoing monitoring if there appears to be a decline in reporting quality, then the CRA may increase the number of subject’s who have 100% SDV until the CRA is confident the site has improved. This will be documented in the MV Report.



Data queries do require SDV

Data queries issued in the run-up to data base lock require





SDV; however SDV can be performed remotely. Only de-identified source documents will be provided for remote SDV and all subject identifying information must be redacted and subject identifier added to each page of source data. After completion of SDV the redacted source data must be confidentially destroyed.

Completed CRFs The PI or sub-Investigator, if appropriately delegated will sign completed CRFs

IP review and accountability

IP review and accountability will be performed by a monitor.

15.3 RMV Follow Up

The standard activities for RMV follow up as detailed in the Requirements for Visit Follow-up Activities will be followed. The following table provides details of the study-specific RMV activities the Monitor is expected to perform after the RMV has been completed. • The order in which they have been listed is not necessarily the order in which they must be



Visit report Multi-day visits occurring on sequential days (excluding weekends) will be written up in one report

If a multi-day visit or two separate visits with greater than 5> days in the middle (excluding weekends) are performed, they will be considered as separate visits and will be written up as two separate reports




16. SITE MANAGEMENT ACTIVITIES

16.1 Activities to be performed between RMVs The following activities should be completed during the period between scheduled on-site RMVs:

Motivational visits Motivational visits will be performed as needed. It is anticipated a motivational visit will be conducted if the site has not randomized a subject within 4 weeks of the SIV. The monitor will obtain approval from the CMPL for each motivational visit before visit is scheduled.

Source Data Verification (SDV)

Remote SDV cannot be completed in between monitoring visits.

Review of IxRS data To be completed every week ± 2 days to include: randomized subjects

Details of the review do not need to be documented

Contact with PI The PI should be contacted by phone or email 2 week ± 2 days to discuss the following: Global and country-level study status

Enrollment status and recruitment strategies

Patient safety concerns

Protocol deviations

Status of patient data entry

Query resolution

Provide training/re-training as required

Outstanding issues or actions

To ensure appropriate PI oversight

Answer any outstanding or new questions

A summary of the conversation will be documented in a FU email to the PI or in a telephone contact report within CTMS.

Contact with SC The SC should be contacted by phone or email every 2 weeks ± 2 days to discuss the following: Global and country-level study status

Enrollment status and recruitment strategies

Patient safety concerns

Protocol deviations

Status of patient data entry

Query resolution

Provide training/re-training as required

Status of study supplies

Shipment of lab samples / imaging uploads

PK & Immunogenity samples, as required in Canadian sites ONLY

Outstanding issues or actions

Answer any outstanding or new questions

A summary of the conversation will be documented in a FU email to the PI or in a telephone contact report within CTMS.

16.2 Activities to be performed at specific time points

Annual progress report to EC/IRB




The Country Submission Specialist (CSS) is responsible for submitting the annual progress report to ECs/IRBs. Prior to the 12 month post-approval date the CSS will contact the Monitor to request details of study progress at the site. CSS will compile the information and submit to the EC/IRB. The annual progress report will be filed in the ISF and TMF.

16.3 Management of changes at site Transfer of subject to a different investigational site Subject transfers will be discussed on an ad hoc basis, but are not expected routinely in this study. Change in Principal Investigator The key requirements for managing a change in PI, either temporarily (e.g., >4 weeks) or permanently are documented in the Site Management Change Form, which will be completed for each change in PI. EDCS (CSS/SSUPL) must be notified of potential change in PI to ensure appropriate submissions or notifications are made to the IRB/IEC and RA/CA where applicable. If there is a situation where the change in PI needs to occur prior to required submissions/notifications being made or approved (i.e., sudden, unexpected replacement of PI) the impact for the site will need to be reviewed and where necessary, site enrolment may need to be temporarily halted. Change in other site staff In accordance with local regulations and requirements, IRB/IEC or RA/CA may be notified of change in site staff. Where applicable, discuss requirements with SSUPL. Relocation of site The key requirements for managing permanent site relocation, are documented in the Site Management Change Form. To meet subject needs (i.e., unable to move from re-hab facility), it is possible that the Day 30 and Day 90 visits will be done remotely. This is not considered a relocation of site and will be permitted with no additional documentation. Relocation of site’s facility (e.g., imaging, local laboratory) It is possible that imaging may be done at a secondary location in the hospital, if this occurs, discuss with CMPL to determine the impact to the site. Ensure any maintenance records are completed. Discuss IRB/IEC and/or RA/CA notifications which may be required with the CSS. Site no longer wishes to participate in study / PI leaves site and no replacement PI available The monitor will discuss the situation with the CMPL who will escalate to PM/NoNO Inc as appropriate and determine whether a replacement site will be opened. Management of ongoing subjects will be reviewed and an appropriate plan of action determined and documented. The timeframe for conduct of a Close Out Visit will be determined. Other site management situations Monitor will discuss on a case-by-case basis with the CMPL and where necessary the SSUPL. If required, document the change or situation using the Site Management Change Form.




17. RISK BASED MONITORING (RBM)

17.1 Monitoring Strategy Risk-based monitoring (RBM) is a comprehensive monitoring method that aims to control risks that may affect patient safety, data quality or compliance with the protocol or regulations. This is achieved utilizing strategies to target the most intense monitoring effort to the data and sites with the highest level of risk. The level of risk is an ongoing process that requires initial and ongoing risk assessment and real-time analysis of the data using data collected in the CRF on iDataFax.

The RBM strategy is comprised of components which include targeted and triggered on-site monitoring, and centralized data analytics monitoring to supplement monitoring oversight. Each CRF page (plate) will go through 7 levels of review, briefly described in the table below

Quality Level in iDF

Responsible Description Comment

Level 0 Site CRF page empty

Level 1 Site Data entry completed

Level where site PI signs

Level 2 Various Data query exists If a query is created the plate will be moved to level 2 by the person creating the queries.

Queries can be generated at Level 3, 4, 5, 6.

Level 3 Central QC Data QC completed

Level 4 CRA or Central SDV Data verified CRA opens the Task list and starts monitoring pages ready for them.

After monitoring the page the CRAs will click on “Final” and this will automatically move the plate to level 5.

If the CRA generates a query, they need to manually move the plate to Level 2.

Level 5 Central Study Coordinator

Data cleaned Once plate is at level 5 sites cannot enter/change data

Level 6 Central Stats Reviewed for outliers

Level 7 Central Coordinating PI approves plate

Data Locked




17.2 Centralized Monitoring Plan

On a daily basis the QC staff from the U of C Coordinating team will review all daily data entered by the study sites (Levels 2-3 described above).

As per the SDV Plan in Appendix x, there are a number of CRF plates that will not be verified at the site by the CRA, but verified centrally. The CRA will not be required to look at, review these pages at all the plates will be view only.

As per Section 6.7 of the protocol, these additional KRIs will be monitored by the coordination team. The Coordinating PI will follow up with site PIs that are routinely outside of these parameters and the site CRA will be informed of this communication and the corrective action plan.

Time from randomization to start of study drug administration (<30 min)

Time of Drug infusion start to drug infusion completion (10 ± 1 minutes)

Time of stroke onset to time of study drug infusion start

Time of stroke onset to reperfusion

Time of start of study drug administration to reperfusion

NCCT to Randomization (<30 min)

NCCT-to-study drug initiation time (<60 min)

NCCT-to-groin puncture time (“picture-to-puncture”) (<60 min)

NCCT-to-recanalization time (“picture-to-reperfusion”) (<90 min)

Rate of aspiration pneumonia

Rate of use of general anesthesia

Rate of symptomatic deep venous thrombosis/pulmonary embolism

Proportion of subject with any SAE per site

Fidelity of primary thrombectomy device intended for use versus primary thrombectomy

device actually used

17.3 On Site Monitoring Plan

A joint effort between CRU staff, NoNO CPL and IHCs monitoring platform will review of the study data using key risk indicators (KRIs). Potential issues are identified by comparing the individual site metrics for a KRI to the overall average for all sites or to an established threshold. This will be an ongoing process for the first 3 to 6 months of the study, and the Study Team (IHC, U of C, NoNO) will continue to provide more direction and clarity on this process.

17.4 Monitoring Schedule

The first on-site monitoring visit will be conducted within 2 (±2 days) weeks after randomization of the initial subject at the site. Routine visits will be conducted by the assigned Monitors as per the relevant sections of this CMP. Subsequent on-site visits will be determined based on the workload at the site and may also be triggered by safety signals or issues identified by remote review or centralized review monitoring that must be resolved with an on-site visit. The frequency of onsite routine monitoring visit will range between 5 and 90 days. Key Risk Indicators that should be reviewed by the CRA in order to plan the next visit will include:




o New subject enrollment o Number of CRF pages on the Task List, it is expected that a complete CRF for

one subject is on average 60 pages, and a complete CRF review will take 2-3 hours. These metrics can be reviewed after the first 3 months of the study to determine if they are accurate.

o Number of answered queries o High number of Protocol Violation (major)

Inclusion/Exclusion criteria not met, Improper consent procedure, Incorrect vial administered, No or partial dose administered, Incomplete Day 90 assessment (mRS, NIHSS and Barthel Index)

o Related AE rate by site, low percentage of AEs reported o Subject Discontinuation rate by site o Number of missed visits (Day 30) o Compliance with study specific protocol requirements

Post dose Vital signs not collected Imaging not transferred in a timely manner high number of temperature excursions eCRFs not completed in a timely manner partial/incomplete visits (i.e., missing BNT15, MoCA etc) low or no enrolment after 90 days Change in PI or key Coordinator

17.5 Source Data Verification / Source Data Review

Monitors will perform 100% of SDV and SDR for the first 3 subjects enrolled at each site as noted in eCRF SDV table is shown in Appendix 2. Once the CRA has complete their SDV according to this plan and there are no outstanding queries, the CRA will mark the field as “Final” in iDataFax, which will automatically move the plate to level 4. Imaging will be verified against the images centrally by the CIPAC; CRAs are not required to verify images at the site. Items marked as NA are not part of the main protocol, and are not applicable to NA-1-007; therefore do not require review, verification or any monitoring by the CRA.

If the Monitor is satisfied with the site performance of all requirements for those first 3 subjects, then subsequent subjects will be reviewed at the reduced SDV and SDR noted in section 1. If at this time, or any time subsequent to first 3 subjects reviewed, the Monitor identifies critical issues with the site performance or understanding of the process, the Monitor should reeducate the site appropriately and the Monitor may choose to increase the next subject review of SDV/SDR to ensure understanding and implementation of change. This decision and the reason for it must be documented in the monitoring report. Critical findings should be discussed with the CMPL. The minimum amount of reduced SDV/SDR for all study subjects shall include:

100% of all critical data and supporting processes described in the critical data/critical process table

100% of all informed consents

100% inclusion/exclusion requirements (subject eligibility)

100% of all SAEs

100% Investigational Product compliance




# CRITICAL DATA and critical Processes

Review Process

1 See Appendix 2 for list of CRF plates that require 100% or reduced SDV

SDV the data entered

For CRF plates that are on a reduced plan at a minimum the CRA will confirm the plate is completed as per the CRF Completion Guidelines

2 Informed Consent Forms and regained capacity ICFs

3 IP Temperature Monitoring

17.6 Training

The CRA will complete the general training for iDataFax. Once this training completed as study specific monitoring focused WebEx will be provided by the CRU. The recording will be made available for use later.

17.7 Preparation for Interim Analysis

As per the protocol an interim analysis on the first 600 subjects will be conducted by the IDMC. The decision from this analysis will determine if the study will end early for futility, safety concerns or overwelming efficacy, or the study will continue to 1120 subjects. Therefore, it is important that the following data points be at Level 5 prior to the data cut for this evaluation:

o Day 90 mRS

o All SAEs

o All plates from baseline to Day 30

As soon as the 600th subject is randomized, NoNO will create a list identifying these subjects. They should be prioritized for QC and SDV reviews. The completion of the subject’s Day 90 visit may trigger an additional monitoring visit.




18. CLOSE OUT VISITS – This section will be completed on the next version Close Out Visits (COVs) should be conducted last subject globally has completed the study and NoNO Inc has provide the approval or if no subjects have been randomized at the site and it has been agreed the site will be closed. The CMPL will notify the Monitor when the COV can proceed. COVs are to be conducted at an onsite visit.

18.1 COV Scheduling and Preparation The standard activities for COV scheduling and preparation as detailed in the Requirements for Visit Preparation Activities will be followed. The following table provides details of the study-specific COV activities the Monitor is expected to perform prior to the COV being completed. • The order in which they have been listed is not necessarily the order in which they must be


COV Preparation Activity Details Chec

k

COV scheduling As well as the PI, it is expected that <Insert details of other required attendees> will also attend the COV

18.2 COV Conduct The standard activities for COV conduct as detailed in the Requirements for Conduct of COVs will be followed. The following study-specific documents should be completed, signed and/or collected during the COV:

Document Completed by Signed by Collect (original or copy)

Study Task Delegation Log

Site Visit Log

End of study Financial Disclosure

Study Drug- end of study accountability

The following table provides details of the study-specific activities the Monitor is expected to perform during the COV.

The order in which they have been listed is not necessarily the order in which they must be completed.

The table can be printed and used as a checklist if helpful, but this is not mandatory.

COV Activity Details Check

IP The IP monitoring activities at the COV will be performed by




the monitor. As the last dose will be administered 90 days prior to the last subject visit, this may be done at an earlier RMV

18.3 COV Follow Up

The standard activities for COV follow up as detailed in the Requirements for Visit Follow-up Activities will be followed.

The following table provides details of the study-specific COV activities the Monitor is expected to perform after the COV has been completed. The order in which they have been listed is not necessarily the order in which they must be completed • The table can be printed and used as a checklist if helpful, but this is not mandatory

COV FU Activity Details Check




19. ELECTRONIC MEDICAL RECORDS / ELECTRONIC HEALTH RECORDS Electronic Medical Record (EMR): An electronic record of health-related information on an individual that can be created, gathered, managed, and consulted by authorized clinicians and staff within one healthcare organization. Electronic Health Record (EHR): An electronic record of health-related information on an individual that can be created, managed, and consulted by authorized clinicians and staff across more than one healthcare organization. Electronic Medical Records (EMR) / Electronic Health Records (EHR) (collectively known as EMR/EHR) only qualify as original source documents if the electronic system is the first place that the data is recorded. If an alternate method is used to collect the data (e.g., paper study work sheet or medical notebook) and it is then transcribed or this data is scanned and/or uploaded into the system, the EMRs/EHRs are not the source documents though the EMRs/EHRs should still be reviewed to ensure there are no data transcription or data import errors. The monitor is responsible for identifying when a clinical study site is utilizing an EMR/EHR system. For sites utilizing an EMR/EHR system, the monitor is responsible for:

Ensuring appropriate access to electronic records are available to monitors, auditors, and regulatory inspectors

Identifying when EMR/EHRs will be the source records

Discussing requirements for EMR/EHR systems with the study site personnel

Informing study site personnel of record retention requirements for electronic records Details of the requirements Monitors need to confirm are contained within the associated documents for the specific visit type and must be reviewed at each site visit. Use of a non-compliant EMR/EHR system may cause risk of potential harm to subjects, breach of subject privacy rights, and lack of data integrity and has regulatory implications. If the Monitor identifies that the EMR/EHR system does not meet requirements or contain adequate controls they will escalate to the CMPL for discussion with Quality Assurance and Regulatory Compliance (QARC) and NoNO Inc. where necessary. If a site introduces the use of EMR/EHR part way through the study the requirements of the EMR/EHR system should be discussed at the next scheduled visit. Certified copies of EHR The preference is always for Monitors to have access to the EMR/EHR. If a site will not permit EMR/EHR access to the Monitor, the level of access is not secure/appropriate or the system does not meet the required standards, the Monitor will escalate to the CMPL for discussion regarding the site’s suitability to participate/continue in the study and whether use of EMR/EHR as source data has the potential to harm subjects, their privacy rights or the data integrity of the study. If agreed with the CMPL, it is allowable for the site to provide certified copies of records throughout the course of the study which will be used to perform SDV. The below expectations of the certification process will be reviewed with the PI and site staff and will be monitored




throughout the study. The Monitor will review 10-20% of EMR/EHR with site staff to confirm that printed records are an accurate representation. When a site is providing certified copies for monitoring purposes the following should occur:

Print records from EMR/EHR o Ensure the versions are kept complete by secure binding, i.e., staple or have the

version number or PI initials and date on each page

Include a certification statement* that notes: o Date range of the records o Subject ID the records pertain to o Statement that the records are a true and accurate representation of EMR/EHR o Name and date of person certifying (i.e., PI or delegate. If delegated, confirm name

and approval for certification is included on SSDRL) * Note that it is acceptable for the certification statement to be a handwritten note on the first page of the printout. If the records are updated in any way, they need to be re-printed and re-certified. Each time a record is printed for each subject it should be individually certified with a certification statement. All versions of certified copies should be retained for the full duration of the record retention period as per local requirements. At every RMV the Monitor should:

Review the certification statement

Confirm that all date ranges are covered

Confirm re-certifications are completed as appropriate o Complete a 10-20% review of EMR/EHR with site staff to ensure the printed records

are accurate and document this in the visit report. Any discrepancies will be documented in the visit report and discussed with the PI

o Additional sample reviews will be performed until the monitor identifies certified copies are complete, current and accurate when compared to the EMR/EHR system.




20. PROTOCOL DEVIATIONS Deviations may be identified from various sources and clinical study activities that include, but are not limited to:

Programmed edit checks in the eCRF

Communications with the site

Data review by the monitor (e.g., source data verification, review of informed consent documentation)

Data management (DM)/Medical Monitor (MM) data review in eCRF and reconciliation of data from different sources (imaging and IxRS)

Investigator and/or study staff activities (e.g., performing study procedures/assessments)

Remote eCRF review

Site audit or Quality Assessment Visit (QAV)

Safety management activities (e.g., safety reporting)

Review of suspected Escalated Quality Issues (EQIs)

Review of other clinical study related documents Prospective protocol waivers for any aspect of a study protocol will not be approved as per inVentiv processes. The study-specific Protocol Deviation Plan is located in the Operations Guideline (section 6.4) and should be referenced as required Definitions

Protocol deviation: A protocol deviation is any change, divergence or departure from the study design or procedures defined in the protocol.

Important/major protocol deviation: An important or major protocol deviation (herein termed major deviation) is any change, divergence or departure from the study design or procedures defined in the protocol that might significantly affect a subject’s rights, safety or welfare or the completeness, accuracy and/or reliability of the study data.

Examples of major and minor classification: Major

Inclusion/Exclusion criteria not met

Improper consent procedure, Subject or Legal Authorized Representative (LAR) did not provide informed consent prior to completion of any study procedures or in compliance with ICH GCP

Incorrect vial administered

No or partial dose administered

Incomplete Day 90 assessment (mRS, NIHSS and Barthel Index)

Baseline ASPECTs not assessed correctly

Post dose Vital signs not collected

Imaging not transferred in a timely manner Subjects who have been allocated study treatment without meeting the inclusion/exclusion criteria must be immediately escalated to the MM and NoNO Inc via the CMPL.




Minor (persistence, recurrence or other specific issues may change these from minor major deviations)

Imaging performed outside of 24-hour time window

Missed visit

Window deviations of visits

Start of study drug greater than 30 minutes from randomization

Study drug infusion duration more or less than 10 min (+/- 1 min)

IP temperature deviation outside the range specified

Failure to attempt to collect responses from a self-reported questionnaire (if subject is not able to give response, this is not a deviation)

Major or Minor Deviations that could be major or minor include:

Untrained rater performed scale administration (class of deviation determined by magnitude of trend of deviations per subject/site).

Missed assessment/procedure (class of deviation depends on which procedure was missed)

Did not re-consent subject or caregiver at first study visit following IRB/EC approval of updated ICF

SAE or Pregnancy not reported to NoNO Inc within timelines

Safety events not reported to IRB/EC according to local requirements

Reporting and documentation of deviations Deviations which occur during this study will be entered into the Protocol Deviation eCRF page via iDataFax used to capture PDs. All deviations which have been source data verified and/or confirmed with the site staff, regardless of how the deviation was identified will be included in the eCRF page and communicated to the PI as appropriate. Deviations should be reported to IRBs/IECs and/or Competent Authorities according to the local country and/or site’s requirements or IRB/IEC reporting criteria. Study-specific requirements for managing PDs (including Regulatory and Competent Authority (CA) submission requirements as warranted by local country regulations) are outlined in the Project Plan (PP) and the Operations Guide. The Monitor is responsible for:

Identifying deviations from protocol, ICH GCP and/or regulatory requirements during routine monitoring visits (RMV) or during other communications with the site and /or during data listing review

Where required, prior to attending the RMV the monitor should print out a list of protocol deviations and these should be reviewed with the site staff during the RMV and document any re-training on a training form and note in the RMV report

Performing source document review of all deviations that occur at the site

Discussion of deviations identified at the RMV or which have occurred since the previous RMV with PI and site staff, including implementation of corrective and preventive actions

Ensuring correct documentation of deviations in MVR and FUL, including corrective/preventive actions as required




Where required, ensuring appropriate filing of the deviations in the ISF and other deviation related documentation (i.e., IRB/IEC or competent authority notification/ acknowledgement of receipt) in the ISF and TMF.

Ensuring correct reporting of all deviations that occur at the site and that deviations are reported to IRB/IEC according to ICH/GCP and local or site’s reporting requirements

Notifying EDCS of any deviations that require submission to the competent authority according to local requirements

Escalating concerns regarding deviation occurrence at site, e.g., severity of deviation, frequency of occurrence, inadequate reporting to CMPL and Monitor’s Line Manager as necessary

The CMPL is responsible for:

Ensuring that each deviation is accurate and up to date o Prior to finalizing each MVR, the CMPL reviews the PDs documented in the MVR,

FUL, and iDataFax, as part of the trip report review process. The CMPLs signature approving the trip report review confirms: All PDs documented meet the definition of a PD The PD descriptions are comprehensive enough to enable clinical PD review PD categorization is correct The actions taken/recommended to address the PD documented are appropriate

and complete The actions to-be-taken documented in the MVR are included as actions to be

followed and the resolution is documented Potentially significant site-specific PD trends have been identified for escalation

to the PM and/or MM PDs meeting the criteria for a Serious Breach or Escalated Quality Issue (EQI)

have been escalated according to current processes IRB/EC reporting requirements have been met per ICH GCP PDs documented in the MVR and FUL reconcile to ensure that all deviations are

consistently recorded

Escalation of deviations to PM and NoNO Inc CPL and MM

Identifying patterns/trends and escalating or highlighting to Monitors, including providing additional training if required

Supporting Monitors with determining whether an issue is a deviation

The Medical Monitor is responsible for:

Collaborating with the Project Manager, Lead biostatistician and the NoNO Inc to define study-specific protocol deviations and protocol deviation categorization rules

Reviewing major protocol deviations and determining if actions to address and/or prevent immediate hazards to the study subject or other immediate corrective action is needed

Reviewing and determining if actions to address and/or prevent immediate hazards to the study subject or other immediate corrective action is needed

Reviewing all major protocol deviations identified after the fact and documenting the decision on whether the subject can continue in the study

Escalating PDs identified during data review to the rest of the team

Providing details of minor and major categorization

Determining if a deviation meets the criteria of expedited reporting

Confirming if a deviation meets the criteria of serious breach or an escalated quality issue




Providing guidance to sites and monitors on potential protocol deviations and clarification to questions as needed

PD trending information identified via centralized data analytics review will be provided to the appropriate Monitor via the issue management process described in the CeDA Issue Management Process Section of the CMP. As appropriate, the centralized data analysts will share site related PD issues with the assigned Monitor for review and resolution.




21. CASE REPORT FORM Data entry will be performed using an Electronic Case Report Form.

21.1 Electronic Case Report Form (eCRF)

System: iDataFax

Version: iDataFax 2014.1.2

Location: Download Version Dropbox links: - For Mac: iDataFax 2014.1.2 Mac - For Windows: iDataFax 2014.1.2 Windows Sync links (if Dropbox does not work): - For Mac: iDataFax 2014.1.2 Mac - For Windows: iDataFax 2014.1.2 Windows After you have successfully installed iDataFax, you will need to enter the Server Name: datafax.cru.ucalgary.ca.

eCRF completion guidelines:

On the ESCAPE-NA-1 Study Webpage: www.escapena1.org And available in hyperlinks within iDataFax


Helpdesk email: [email protected].

Computer system requirements:

At a minimum Windows V7.0mcomputer system requirements needed to access EDC, e.g., Windows V7.0

Access – training required for inVentiv staff:

New users: A general overview of the iDataFax system can be reviewed at: https://drive.google.com/file/d/0B5CjjU_YK1CZakdtRnh0OG5abnc/edit?usp=sharing. However, as this video is for a prior version of iDF it will not be considered full training on the system. Anyone working in iDataFax should complete the training by reviewing the document “iDF - Getting started with iDataFax v2014.1.2 (ESCAPE NA-1)”. You will be emailed your user ID and Password. Training certificates: will not be provided. Training will be documented by signing the iDataFax training Log. At the end of the study this will be filed in the TMF. Escalation: If training is not completed by timelines provided above the CMPL will escalate to the Monitor LM

Access – training required for site staff:

New users: A general overview of the iDataFax system can be reviewed at: https://drive.google.com/file/d/0B5CjjU_YK1CZakdtRnh0OG5abnc/edit?usp=sharing. However, as this video is for a prior version of iDF it will not be considered full training on the system. Anyone working in iDataFax should complete the training by reviewing the document “iDF - Getting started with iDataFax v2014.1.2 (ESCAPE NA-1)”. You will be emailed your user ID and Password.



https://ln.sync.com/dl/ce296a300#8pzdkigk-6ti29vm3-iamqm936-funz6pmd

https://ln.sync.com/dl/f71f25350#32eaphf6-cpgvsg9f-m8y773q2-cg6sasfr










Training certificates: will not be provided. Training will be documented by signing the iDataFax training Log. At the end of the study this will be filed in the TMF. Escalation: If training is not completed by timelines provided above the CMPL will escalate to the CMPL

Access request process for site staff:

The ESCAPE-NA-1 iDataFax Site Master User List template is available at www.escapena1.org. The Study Coordinator will complete this ESCAPE-NA-1 iDataFax Site Master User List and email this to their site CRA along with a scanned copy of the iDF Training Log. The CRA will confirm the training is documented and select YES to confirm training is completed, and email the ESCAPE-NA-1 iDataFax Site Master User List to [email protected]. Once the CRU has activated/inactivated the applicable study site personnel they will post the current site form in Study Manager.

Review of eCRF access

After the initial site activation - If additional site staff is added the study coordinator will download the ESCAPE-NA-1 iDataFax Site Master User List from Study Manager and along with the signed iDataFax Training Form email this to the CRA. The CRA will confirm the additions and send the updated list to who will forward to [email protected].

Expect an activation to take 1-3 days once the request is received at CRU.

In addition, it is recommended that the eCRF access list is reviewed quarterly by the CRA to ensure the correct personnel have eCRF access or have had access removed CMPLs should review for monitor access and monitors should review for their site staff, including site PIs

Location of training:

https://drive.google.com/file/d/0B5CjjU_YK1CZakdtRnh0OG5abnc/edit?usp=sharing.

Access request process for inVentiv staff:

CMPL will determine which CM team members require EDC access and obtain name, email address and user role/access level. The ESCAPE-NA-1 iDataFax Site Master User List template is available at www.escapena1.org. The CMPL will complete this ESCAPE-NA-1 iDataFax Site Master User List and email to [email protected]. Account information including login and password will be send directly to the iHC user.

Access request process for site staff:

The study coordinator will complete the user list and will be confirmed by the CRA. The ESCAPE-NA-1 iDataFax Site Master User List template is available at www.escapena1.org. The Study coordinator will complete this ESCAPE-NA-1 iDataFax Site Master User List and email to their CRA for review. The CRA will

forward it to the [email protected] for activation.

Removal of eCRF access for inVentiv staff:

CMPL will complete this ESCAPE-NA-1 iDataFax Site Master User List and email to [email protected]. of the team member who’s access will be terminated and the date of termination














Removal of eCRF access for site staff:

If site staff leaves the study, the study coordinator will updated the ESCAPE-NA-1 iDataFax Site Master User List by changing the status of the person to “INACTIVE” and email it to the CRA, who will forward to [email protected].

Data entry timelines:

Delegated site personnel are expected to enter all data into the eCRF within 2 business days as it becomes available. FYI- sites will receive payment quarterly based on visits entered into iDataFax

Data queries:

Delegated site personnel are expected to enter a resolution to data queries into the eCRF within 5business days of the data query being issued. Monitors must NOT resolve a query on behalf of the site.

Data base Lock (DBL):

Site and study team member access to the eCRF will be changed to ‘read only’ access at the time of DBL. This change will be performed by Data Management and no action is required from Clinical Monitoring.

Access to data post DBL:

Once the plate has been promoted to Level 4, subject data in the eCRF will be accessible to site staff in read only format until subject data is sent to the PI. Subject data will be sent to the PI on an electronic storage device in PDF format approximately 4-8 weeks post DBL. This is required to be filed in the site’s ISF





22. TRIAL MASTER FILE

Format of TMF: electronic TMF (eTMF) hybrid paper and electronic TMF: Wet signatures will be provided on

paper

TMF database: inVentiv – Veeva Vault: https://login.veevavault.com/ NoNO Inc – isoTracker

Filing structure: inVentiv – DIA TMF Reference Model The TMF structure is standard across inVentiv and NoNO Inc/study-specific modifications will not be made to the structure

TMF Management Plan:

All Clinical Monitoring team members are required to complete training on the TMF Management Plan.

eTMF file structure: https://studycentral.inventivhealth.com/

eTMF access: Veeva Vault eTMF training must be completed prior to obtaining access to the Veeva Vault eTMF. Once training is completed access will be granted by emailing the PM for access.

TMF filing requirements:

Documents should be uploaded directly to the TMF within 15 days of document generation/receipt

Documents will be sent to Document Management at:

inVentiv Health Clinical

ATTN: DOCM/Central Files (16NO4X001)

1001 Winstead Drive

Suite 200

Cary, NC 27513

Tel: +1 919 337-1576

for filing within 15 days of document collection/generation/receipt

Filing of documents collected from sites:

The Monitor is responsible to ensure timely submission of documents collected from site to the TMF within 15 business days of document collection/receipt. The Monitor will ensure that all documents are completed appropriately, contain appropriate signatures, dates are legible and logical and ensure no patient identifying information is included.

Document translation

English versions of documents should be filed in the TMF. The original language document plus translation certificate and/or back translations will also be filed as required.

Document naming convention:

Study identifier_country_ site #_subject number_topic or as provided by CTMS

Original, hard copy documents:

All original, hard copy versions of wet signature documents must be retained as well as an electronic copy filed in the eTMF. The shipping details for the original hard copy documents are included in the TMF Management Plan.

Note to file: The study-specific NTF template is located at: https://studycentral.inventivhealth.com/

Communication filing requirements:

Communication between Clinical Monitoring and site/inVentiv team/NoNO Inc should be filed in the TMF (and ISF as necessary) if

https://login.veevavault.com/





related to the following topics: Patient rights, safety or well being

Data integrity

Deviations from ICH GCP, local regulations, protocol

PI oversight concerns

Breaches of confidentiality

Important decisions

Quality Issues

Issue resolution or completion of action items

Training

Amendments/Changes in procedures

Notification of milestones

Communication relating to the following does not require filing in the ISF (or TMF): Back and forth communication to schedule/confirm a visit date

Non-study related conversations




23. INVESTIGATOR SITE FILE Each site is required to maintain an Investigator Site File (ISF). The assigned Monitor will be responsible to ensure completeness and correctness of the ISF in accordance with the ISF Table of Contents (TOC), ICH/GCP and local regulations during on-site visits. The PI is responsible for ensuring the ISF is accurate, complete and appropriately maintained. The ISF TOC is located at https://studycentral.inventivhealth.com/ and www.escapena1.org The study-specific ISF checklist should be used to ensure all required site level documentation is filed in the ISF and TMF. The ISF Checklist template is located at https://studycentral.inventivhealth.com/. The CMPL is responsible for updating the study-specific checklist template as new documents are generated and Monitors are responsible for adding these new documents/updates to their site-specific checklists. The completed checklists are working documents and should be submitted periodically to the CMPL to support the TMF completeness review and QC. The checklist should be retained at the point of site closure within the TMF. Prior to the SIV Monitors will be responsible for the following for their assigned sites:

To request preparation and shipment of the ISF tabs by DOCM as per the current process for producing and distributing the ISF tabs o The request should be submitted at least one calendar month prior to the SIV date where

possible o DOCM will notify the Monitor once the site-specific ISF tabs have been shipped to the site o The Monitor will notify the site of the shipment and request acknowledgement of receipt

and discuss population of the ISF by the site prior to the SIV. During an onsite SIV

The Monitor will review the ISF to ensure completeness o Document review on the ISF Checklist o Document missing documents or any ISF deficiencies in the SIV report

During an onsite RMV

Review of critical study documents as defined on the ISF Checklist should occur at every RMV, as required

Complete review of the ISF should occur at every RMV

Document each review on the ISF Checklist

Document missing documents or any ISF deficiencies in the RMV report During an onsite COV

Complete a full ISF review o Document on the ISF Checklist o Document missing documents or any ISF deficiencies in the COV report

During a remote COV

The Monitor will ask the site to confirm the completeness and accuracy of the ISF

Identify any new documents received since last RMV

Confirm that all required essential documents are maintained and will be archived according to local regulatory timelines







Include in the visit report site’s confirmation of completeness or any ISF deficiencies reported by site

Reconciliation of ISF and TMF Reconciliation of the ISF and TMF will occur to cross-check that (non-subject confidential) documents filed in the ISF are also filed in the TMF and vice versa as applicable. Prior to the close out visit a full reconciliation of the ISF with the TMF should occur to enable the Monitor to file documents in the ISF during the onsite COV and collect documents to file in the TMF after the COV as required. Filing responsibilities and requirements The site staff are responsible for filing documents in the ISF. Monitors will provide the site with documents generated by inVentiv. Communication filing requirements Communication between CM and site/inVentiv team/NoNO Inc/University of Calgary should be filed in the ISF (and TMF as necessary) if related to the following topics:

Patient rights, safety or well being

Data integrity

Deviations from ICH GCP, local regulations, protocol

PI oversight concerns

Breaches of confidentiality

Important decisions

Training

Amendments/Changes in procedures

Notification of milestones Communication relating to the following does not require filing in the ISF (or TMF):

Back and forth communication to schedule/confirm a visit date

Non-study related conversations Document maintenance Study- and site-specific documents are often updated during study conduct. EDCS is responsible for collecting all study documentation from sites during the submission phase of the study. After the initial handover meeting from EDCS to Clinical Monitoring, Clinical Monitoring is responsible for collecting updates to the majority of documents as indicated below and filing in the ISF and TMF as applicable. Where necessary, the Monitor should contact the Country Submission Specialist (CSS) or Study Maintenance Specialist (SMS) to enable the update and IRB/IEC submission.

Document Role responsible for Additional Requirement/s

Updating Filing in TMF




Document Role responsible for Additional Requirement/s

ICF EDCS EDCS Monitor to ensure all site-level ICF changes have been reviewed and agreed with EDCS prior to and after IRB submission. Monitor to send approved ICF to site and copy CMPL on communication

IRB/IEC and RA/CA submissions / notification, e.g., Protocol amendment, annual progress report

EDCS EDCS EDCS will handover to Monitor as per current process

Protocol Amendment Signature Pages, Updated IB signature pages

EDCS /Monitor

EDCS /Monitor

EDCS or Monitor responsibility may depend on submission requirements in local country

FDA 1572 Monitor Monitor Monitor to send copy to CSS where applicable if updates require review by country authorities, Monitor to send copy to PC/CTA (US requirements) and uploadl to Study Manager by site, paper version to iHC TMF

Financial Disclosure Form Monitor Monitor Upload to Study Manager by site, paper version to iHC TMF

Privacy and Authorization Form

Monitor N/A File in eShare only Update required every 5 years Collect for new site staff team members before collecting any personal data

CVs Monitor Monitor Updated CV required every 2 years

Medical licenses Monitor Monitor Updated license as per expiration date (if applicable)

New/updated ICH/GCP certificates

Site Monitor

Local lab certification (Canada only)

Site Monitor Not required for sites completing standard of care testing only.

Hazardous material (i.e., IATA) training updates

Site Monitor

Document Translation Requirements Documents provided by or generated by EDCS, e.g., IRB/IEC submission documentation, patient facing materials such as ICFs, patient diaries, advertisements, will be translated as per the current process for translating study documents. Where applicable, documents provided by sites, e.g., autopsy report, death certificate, lab reports, will require translation by an inVentiv approved translation vendor. Translations and any certificates of translation for translated documents should be filed in the TMF. They will also be filed in the ISF as per local country/site requirements. Archiving and Document Retention Requirements




Sites must retain the complete study ISF for 25 years as per Canadian requirements and as the sponsor in Canadian, as per the minimum length of time as specified in their Clinical Trial Agreement or in accordance with local regulatory requirements, whichever is longer. Sites will provide details of their archiving facility or the long term location of the ISF at the COV.




24. APPENDIX 1 - LOGS AND TEMPLATES TO BE USED DURING THE STUDY The following table includes details of all logs, templates, forms and checklist plus any monitoring tools which will be used during the study (note that visit reports are not included and that study-specific annotated visit reports will not be produced/used).

Document inVentiv or NoNO Inc template

Role responsible for making document study-specific, site-specific and for entering data

Timeframe for implementation of revised documents at site

Recommended method of sending document to site

Link to document* Comments

Note to File inVentiv Study specific – CMPL Site specific – Monitor / Site staff Enter data – Monitor / Site staff

SIV email / take at next visit


Telephone contact report

inVentiv Study specific – CMPL Site specific – Monitor Enter data – Monitor

SIV N/A – internal document


Summary site contact log




Visit confirmation letter templates




Visit follow up letter templates

inVentiv Study specific – CMPL Site specific –
















Monitor Enter data – Monitor

Privacy & Authorization Form

inVentiv Study specific – EDCS Site specific – Monitor / site staff Enter data – Site staff

SIV email https://studycentral.inventivhealth.com/ Monitor to collect from SIV to COV. EDCS collect prior to SIV

SIV agenda inVentiv Study specific – CMPL Site specific – Monitor Enter data – Monitor

SIV Email to site https://studycentral.inventivhealth.com/

Site visit log inVentiv Study specific – CMPL Site specific – Monitor / Site staff Enter data – Monitor / Site staff

SIV In ISF, additional pages by email


Study Task Delegation Log

NoNO Inc Study specific – CMPL Site specific – Monitor / Site staff Enter data – Site staff


www.escapena1.org

Site staff training log - SIV

inVentiv Study specific –NoNO Enter data –
















Monitor / Site staff

Site staff training log

NoNO Inc Study specific –NoNO Enter data – Monitor / Site staff



Enrollment Log NoNO Inc Study specific – NoNO Enter data – Site staff


www.escapena1.org

Source data agreement

inVentiv Study specific – CMPL Site specific – Monitor / Site staff Enter data – PI

SIV In ISF www.escapena1.org

ISF checklist inVentiv / NoNO

Study specific – CMPL Site specific – Monitor Enter data – Monitor

SIV N/A – internal document only

https://studycentral.inventivhealth.com/ File in TMF after site closure

SAE reporting forms

NoNO Inc Study specific NoNOSite staff Enter data – Site staff


www.escapena1.org iDataFax - eform

Pregnancy reporting forms

NoNO Inc Study specific – NoNO Enter data – Site staff


www.escapena1.org

Study Drug Dispensing log

NoNO Inc Study specific – NoNOSite


www.escapena1.org
















specific – Monitor / Site staff Enter data – Site staff

Temperature log NoNO Inc Study specific – NoNO Site specific – Monitor / Site staff Enter data – Site staff


www.escapena1.org

Sample Temperature log

NoNO Inc Study specific – NoNOSite specific – Monitor / Site staff Enter data – Site staff


www.escapena1.org

Study Drug End of Study form

NoNO Inc Study specific – NoNO Enter data – Monitor / site staff

SIV Take to site or email

www.escapena1.org

SDV/Monitoring checklist


SIV Take to RMVs https://studycentral.inventivhealth.com/ Use of checklist is optional

Monitoring clarification log

inVentiv Study specific – CMPL Site specific – Monitor

SIV Take to RMVs https://studycentral.inventivhealth.com/ Used to document queries for paper-CRF














Enter data – Monitor

studies. For EDC studies, only used to capture ISF or IP findings

Site Management Change form


SIV N/A – internal document only


* Insert link to study level document so that site level documents where applicable, can be developed from the study level document.





25. APPENDIX 2 -MONITORING AND DATA REVIEW PLAN

All plates/forms listed below will go through the Level 1 to Level 7 QC/review plan. Plates listed in black will have the Level 4 review completed by the CRA while onsite. Plates listed in green will have the Level 4 review completed by the Coordination Team centrally.

Plates/Pages per CRF

CRF Name Baseline Post-angio

Day 1

Day 2 Day

5 Day 30

Day 90

Recurring SDV

Plan for CRAs

SDV Plan for U of C

SDV/ Review Plan

(24h) (48h) 100% Reduced Central

13 9 7 2 5 5 9 6 29 16 11

Unique Forms

Randomization X 100% NA 1

Eligibility Criteria (Inclusion)

X 100% NA 1

Eligibility Criteria (Exclusion)

X 100% NA 1

Demographics/Enrollment (ICF)

X 100% NA 1

Past Medical/Surgical history

X Reduced NA 1

Vital Signs X X X X X Reduced NA 5

Labs/Bloodwork X X Reduced NA 2

ECG X X Reduced NA 2

tPA use X 100% NA 1

Study Drug Infusion X 100% NA 1

Endovascular Procedure X NA 100% 1

Angiographic Complications

x

NA 100% 1

Management of ipsilateral ICA

x

NA 100% 1

Endovascular Procedure Device Form

X NA 100% 1

Immunogenicity Samples X X Reduced NA 2

PK Samples X Reduced NA 1




Collateral Genetics Sub-Study

x NA 100% 1

Imaging

Assessment of Ischemic Change x

NA 100% 1

Assessment of Occlusion Location and Collaterals x

NA 100% 1

Post Treatment CTA Assessment for recanalization

X NA 100%

1

Neuroimaging Transmittal form

X NA 100% 1

Assessment Scales

NIHSS X X X X X X X 100% NA 7

Barthel Index X X X 100% NA 3

mRS X X X X 100% NA 4

EQ-5D-5L X X 100% NA 2

MoCA X NA 100% 1

BNT15 X 100% NA 1

SNAP X NA 100% 1

Stroke Mechanism At time of study completion X 100% NA 1

Hospitalization Summary At time of original hospital

discharge X 100% NA

1

End of Study/Completion Status

At time of study completion X 100% NA 1

Recurring Forms

Previous Medications x Reduced NA 1

Concomitant Medications Days 0-30 x Reduced NA 1

Protocol Deviations Days 0-90 x Reduced NA 1

Protocol Violation (Major) Days 0-90 x 100% NA 1

AE Days 0-30 x 100% NA 1

SAE Days 0-90 x 100% NA 1

Please note: 3 unique forms, 50 forms/patient + 5 Recurring forms (AE/SAE/PD/PV/ConMed) + 4 forms not included in ESCAPE-NA-1 study)




Date post:	20-Aug-2020
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