Protocol Overview for New Study Team Members - June 25, 2014

The Stroke Hyperglycemia Insulin Network Effort (SHINE) TrialNIH-NINDS U01 NS069498

NETT CCC U01 NS056975 NETT SDMC U01 NS059041

Toll free dial-in number: (888) 242-1836 ACCESS CODE: 7578031

Web address for virtual conference room:https://connect.umms.med.umich.edu/nett_seminar/

Study Overview and Treatment Protocols

Amy Fansler, MPH, CCRPSHINE Project Director

The Problem• Over 750,000 strokes/ year (~80% ischemic)• ~30-50% hyperglycemic on admission

• Hyperglycemia associated with worse clinical outcome• Hypoglycemia bad for ischemic brain

• Unknown if Rx of hyperglycemia improves outcome or if benefit outweighs risk

• No definitive guidance on glucose management

Phase III SHINE TrialNIH-NINDS U01 NS069498

• Multicenter (~60 sites), randomized, controlled trial• Phase III (definitive efficacy trial)• Hyperglycemic acute ischemic stroke patients• Comparison of standard SQ insulin versus insulin infusion

• Funded by NIH-NINDS• Conducted in conjunction with NIH-NINDS funded Neurological

Emergencies Treatment Trials Network (NETT)• Collaborating with NIH-NINDS Stroke Network

Phase III SHINE TrialNIH-NINDS U01 NS069498

Specific Aim 1• To determine the efficacy of tight glucose control to a target

range of 80-130 mg/dL with IV insulin infusion in hyperglycemic acute ischemic stroke patients within 12 hours of symptom onset as measured by mRS at 90 days after stroke.

Specific Aim 2• To determine the safety of tight glucose control with IV insulin

infusion in hyperglycemic acute ischemic stroke patients treated for up to 72 hours.

SHINE Eligibility Criteria - Inclusion• Age 18 years or older • Clinical diagnosis of ischemic stroke • Randomization w/in 12 hrs of stroke symptom onset

– recommended w/in 3 hrs of hospital arrival• Known history of type 2 diabetes mellitus and glucose

>110 mg/dL OR admission blood glucose ≥150 mg/dL in those w/o known diabetes mellitus

• Baseline NIHSS 3-22• mRS of 0 if NIHSS 3-7; mRS of 0-1 if NIHSS of 8-22 • Able to provide a valid informed consent

SHINE Eligibility Criteria – Exclusion

• Known type 1 diabetes mellitus • Substantial preexisting confounding illness • Receiving experimental therapy/ in other trial • Pregnancy • Other serious conditions (unlikely to live to f/u)• Inability to follow protocol or return for 90 day f/u• Renal dialysis (hemo or peritoneal)

Eligibility Glucose Tips• Recheck glucose if close – most recent counts (eg.

diabetic – glucose 108)• If glucose meets criteria, no need to check again for

study• Pt who gets insulin or glucose in the field/ED may still

be eligible• Borderline diabetes is not diabetes• Type 1 vs type 2 diabetes – call PI on call• Pts that require insulin drip not eligible

mRS Tips

NIHSS Tips• Must have NIHSS score within 30 min prior to

randomization

• Intubation is exclusion (can’t get NIHSS score)– if about to electively intubate – possible to get

quick NIHSS score (if can randomize w/in 30 min)

• Recheck NIHSS if close – most recent counts (eg. NIHSS 2 but fluctuating, NIHSS 24 but s/p tPA)

Question #1 - Eligibility

Consent Talking Points • We think you are having a stroke, and your blood sugar is high.• Did you know that when you have high blood sugar at the time

of your stroke, you are likely to have more trouble recovering?• We don’t know the best treatment for your blood sugar, and

because no one knows that, we have a research study to help us figure out what is best.

• We have 2 different ways of managing your blood sugar, and patients are assigned randomly (like the flip of a coin) to one way or the other.

• Everyone gets insulin to treat high blood sugar. Some patients will get it from shots, and some will get it from a drip.

Randomization

NOTE: The NIHSS must be assessed within 30 min prior to randomization and the time of symptom onset must not be greater than 12 hours or the randomization will be blocked.

Treatment Protocol Overview

Phase III SHINE Trial Design/ProtocolNIH-NINDS U01 NS069498

• ~1400 hyperglycemic acute ischemic stroke patients• 12 hr window from stroke symptom onset

• Treatment Groups– Intervention group - Insulin drip (80-130 mg/dL )– Control group - SQ insulin (80-179 mg/dL)

• Up to 72 hrs treatment• Single blind Rx; double blind outcomes• Primary outcome - 90 day mRS

Treatment Groups - General Concepts• Two groups: both glucose control, both insulin• All pts get IV infusion & SQ injections (up to 4/day)• Frequent glucose checks• 60 gram carbohydrate diet• All pts must be in unit that supports IV insulin• Daily NIHSS• Hypoglycemia prevention per protocol <80, <70 is

AE/assess symptoms• 72 hr treatment period (pausing & early d/c ok)• All sites provided with 1-2 study laptops

SHINE Intervention Group

• Infusion: IV insulin

• Injections: – SQ meal insulin, OR – SQ saline @ 0900/2100 if not taking PO

• Glucose checks: q1-2 hours per GlucoStabilizer®

• GlucoStabilizer® also instructs on insulin dosing and hypoglycemia protocol

SHINE Trial Portal

Intervention Group GlucoStabilizer®

Intervention Group Study Computer

Intervention GroupEstimating Meal Consumption

• Assess meal tray ~20 minutes after start of meal– All or nearly all Enter 60– None or nearly none No entry in GlucoStabilizer®– Partial Enter 30

• Do NOT enter any numbers other than 30 or 60 or will get wrong dose

• Give SQ meal insulin immediately based on computer recommendation

Intervention GroupEntering Meals in GlucoStabilizer®

Intervention Group Meal Insulin Dosing

Intervention Group Meal Insulin Dosing

Question #2 – Intervention Group

SHINE Control Group • Infusion: IV saline• Injections: SQ insulin (per sliding scale)• Escalating doses of insulin per sliding scale if not in

target which may include basal insulin• Glucose checks q1-3 hours

– Hourly for first 4 hours (BG to start, Q1, Q2, Q3, Q4, then– Q3 hours (3, 6, 9, 12, 15, 18, 21, 24)

• Study laptop displays dosing of IV saline, SQ insulin and hypoglycemia protocol

SHINE Trial Portal

Control Treatment Screen

1 32

Control Group – Level Changes• Level changes allow increase in insulin coverage for

subjects who need higher dosing

• All patients on Level 1 for first 24 hrs

• Level changes assessed every 24 hrs from time of randomization

• Advance to next level at 24/48 hrs if latest two glucose results are > 180mg/dL

Control Group – Level 2

Control Group - Level 3

• Advance to Level 3 at 48 hrs if latest two glucose results are > 180mg/dL

• Level 3 includes one-time dose of Lantus at 48 hrs from randomization

• Calculating basal insulin dose (40% of insulin given in prev 24 hrs)• Sum all insulin given in prev 24 hrs (all 4 doses)

• Multiply by 0.4 (>.05, round up)

• Continue SQ sliding scale insulin- Level 3

Control Group – Level 3

Question #3 – Control Group

Clinical Outcomes• Follow up visits

– 6 week phone call – mRS and SAEs– 3 month – mRS, NIHSS (in person), Barthel

Index, SSQOL, unblinding surveys, glucose control medications and SAEs

• Outcomes assessments must be blinded• Visit window +/-14 days from projected date

I-SPOT Ancillary Trial Nina Gentile, MD

I-SPOT PI

I-SPOT & SHINE• I-SPOT nested within the SHINE trial• Only sites participating in the SHINE trial will be

eligible to perform I-SPOT• Consent for I-SPOT embedded into SHINE

consent• Separately funded so sites will get additional

funds to perform I-SPOT• Requires 2 blood draws & QVSFS at 90 days

Blood Collection for I-SPOT:

Samples drawn at 2 time points

• Baseline after randomization but before study drug start

and • 48 hours (between 46 and 54 hours)

I-SPOT Training & Questions

• I-SPOT training can be found on the NETT website under SHINE

• Contact project manager, Hannah Reimer at hreimer@temple.edu or principal investigator Dr. Nina Gentile at ngentile@temple.edu with any questions

Recruitment and Retention

Katrina van de Bruinhorst, MA, CCRCSHINE Recruitment Specialist

Recruitment and Retention• Screen Failure Logs

– Only enter pts with ischemic stroke who present within 12 hours of symptom onset with a glucose >110

– ICH’s, pts with BG<110 and those who present >12 hours do not get reported

– Due on the 10th of the following month

• Recognition system

• Retention tips

Question #4 – Screen Fail Logs

Informed Consent Process and Monitoring

Donna Harsh, MSNETT Clinical Trial Monitor

Informed Consent Process

• 100% review of all subjects

• Ensure correct version of IC is signed, dated and timed by all participants

Informed Consent Process

• Documentation of informed consent process in medical records or subject binder– Risks, benefits and alternative treatments have

been explained– The subject /LAR was given ample time/

opportunity to ask questions and that the questions were answered to their satisfaction

– The subject/LAR was given a signed copy of the consent

• 100% review of CRFs for first 2 subjects• 100% review of eligibility and

randomization CRFs of all subjects• All SAEs• Sampling thereafter of CRFs ensure that the

protocol and procedures are being followed

CRF Verification

Source Documents

• The monitor will ensure that reported data is complete, accurate and verifiable from source documents

• What are acceptable source docs?– ED notes, EMS and flight run sheets, physician

notes, nursing notes, medical history notes, MAR, laboratory results, study worksheets and electronic case report forms (must be well defined)

PI Review and Affirmation• The site PI must review and affirm the

accuracy of the information reflected in all of the case report forms for each study participant.

• The End of Study Form requires a date of PI review and affirmation

Regulatory Documents & SAEs

Arthi Ramakrishnan, MS, CCRPSHINE Site Manager

SHINE Website and WebDCU Database

- SHINE Website - http://www.shinetrial.com - SHINE-related materials - protocol, regulatory parameters

document, DOA, and readiness checklist.- Trainings - protocol, data, mRS, NIHSS, WebDCU- Obtain UMich Friends account for access requested from Joy

Pinkerton (joypink@umich.edu), NETT Education coordinator

- WebDCU Database - https://webdcu.musc.edu/NETT- NETT regulatory database training is required to request for access

for study personnel who will be uploading regulatory documents- SHINE Data training is required for access to randomizing, and/or

entering subject data/CRF completion

Regulatory Parameters Document

This document will tell you: What regulatory documents, by spoke, are required for a

spoke to enroll What regulatory documents, by role, each study team

member needs to have upload What source documents need to be uploaded and when How to handle “expired” or “rejected” documents How to complete the fields in the table on the “Add New” or

“Add from Existing” forms Doc POSTED under Education and Training

Document Types in WebDCU• Use Regulatory Parameters Document for training and

documentation requirements

• People Document: Document specific to an individual. – CV, License, NIHSS and mRS Certifications, HSP, HIPAA, etc.

• Spoke Document: Document that applies to a site.– FWA, CLIA, IRB approval and ICF, DOA log, pharmacy plan,

etc.– Bi-weekly emails sent to hub project manager and/or

primary study coordinator to notify about expired/expiring documents

• Located in the SHINE Toolbox, the DOA log is required at the time of site activation and runs in parallel with PSTM Table and applicable training docs uploaded in WebDCU.

• When a team member leaves or new one boards, update and upload DOA log, update PSTM Table, and (as applicable) also submit an amendment to site IRB.

• For new team members, upload all training docs and certs before the team member performs study-related duties.

• *project spoke team member (PTSM) table is located in the NETT regulatory database.

Project Spoke Team Member Table and DOA Log

• An adverse event is any undesirable experience associated with the use of a medical product in a patient.

• When this AE leads to death, is life threatening, requires hospitalization (or prolongation), congenital anomaly or birth defect, disability or permanent damage or Required Intervention to Prevent Permanent Impairment it is a Serious Adverse Event and reportable within 24 hours of knowledge.

Serious/Adverse Event (SAE)

• The medical monitors only able to view the SAE CRF; hence the narrative description is vital.

• Narrative templates available for most common SAEs located in SHINE Toolbox

• Report SAEs with all available information regarding patient enrollment, treatment, and SAE event.

• Follow up information can be added as it becomes available.

SAE Templates

• Retraining is required for sites that have not enrolled within 6-months after to activation, or since last patient was enrolled, or since last retraining.

• For SHINE, retraining includes:– protocol and data training, – nursing in-services,– PI’s attestation document for retraining

• Various materials are posted, specifically for re-training.

6-Month Retraining

Study Update

Amy Fansler, MPH, CCRPSHINE Project Director

Study Update• 55 sites enrolling (~60 total sites expected)

– All NETT network sites– Most StrokeNet sites participating (5 additional

StrokeNet preparing)• 394 subjects enrolled – June 24, 2014

• DSMB meeting – January 2014 – Continue as planned– No safety concerns– Next DSMB – July 2014

SHINE Sites – 55 Enrolling SUNY Downstate

Maimonides Medical Center

University Hospital of Brooklyn

Temple Hackensack University MC

Temple University Hospital

UCLA Long Beach Memorial MC

UCLA Medical Center

UCSF

CPMC Davies

CPMC Pacific

San Francisco General

UCSF Medical Center

UPenn Abington Memorial

Hospital of UPenn

York Wellspan Hospital

UT Houston

Austin Brackenridge

Austin Seton

Memorial Hermann

Valley Baptist MC

Utah University of Utah

UTSW UTSW - Zale

UTSW - Parkland

UVA University of Virginia

Vanderbilt Vanderbilt University MC

WSU

Beaumont Royal Oak

Beaumont Troy

Detroit Receiving Hospital

Sinai Grace

WVU West Virginia University

Arizona University of Arizona MC

Baylor Baylor College of Medicine

Buffalo SUNY Buffalo/Kaleida General

Cincinnati University Hospital

Emory Emory University Hospital

Grady Memorial Hospital

GRU Georgia Regents University

HFHS Henry Ford Hospital

University of Michigan

Kentucky University of Kentucky

Maryland University of Maryland

Mayo Jacksonville Mayo Clinic, Jacksonville

MCW Froedtert Memorial

MGH Mass General

Minnesota HCMC

UMMC Fairview

University of Kansas

NYP NYP Columbia

OSF OSF Saint Francis

OHSU Harborview MC

OSU Summa Akron City MC

Wexner Medical Center

Penn State Penn State Hershey MC

Pittsburgh UPMC Mercy

UPMC Presbyterian

Stanford Stanford University MC

SUNY Downstate Kings County Hospital

Lincoln Medical

SHINE Trial – Participating Sites

SHINE Enrollment55 Sites enrolling; 46 sites have enrolled at least 1 subject

TOP ENROLLERSNYP – 55

Emory – 46OSU –33

Kentucky – 24

SHINE Trial Recruitment

Who to Contact

24 hour emergency contacts:SHINE Study Hotline – 800-915-7320

WebDCU Emergency Randomization Hotline – 1-866-450-2016I-SPOT Study Hotline – 774-234-7768

Protocol questions Amy Fansler (434) 982-6027 or acf7h@virginia.edu

Budget & contracts questions Amy FanslerValerie Stevenson

(434) 982-6027 or acf7h@virginia.edu

General education and training Joy Pinkerton (734) 232-2138 or joypink@umich.edu

I-SPOT questions Hannah Reimer 215-707-5483 or hreimer@temple.edu

Laptop questions Amy Fansler (434) 982-6027 or acf7h@virginia.edu

Monitoring Donna HarshCarol van Huysen

(734) 232-2136 or dharsh@umich.edu 734-764-9254 or cvanh@umich.edu

Regulatory & site readiness Arthi Ramakrishnan (734) 936-2454 or arthrama@umich.edu

Recruitment questions Katrina van de Bruinhorst

(214)648-9248 or katrina.vandebruinhorst@utsouthwestern.edu

WebDCU support Kavita Patel (843) 876-1167 or pateka@musc.edu

Questions