Protocol Overview for New Study Team Members - June 25, 2014 The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial NIH-NINDS U01 NS NETT CCC U01 NS NETT SDMC U01 NS Toll free dial-in number: (888) ACCESS CODE: Web address for virtual conference room:

Study Overview and Treatment Protocols Amy Fansler, MPH, CCRP SHINE 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 Trial NIH-NINDS U01 NS 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 Trial NIH-NINDS U01 NS Specific Aim 1 To determine the efficacy of tight glucose control to a target range of 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/Protocol NIH-NINDS U01 NS ~1400 hyperglycemic acute ischemic stroke patients 12 hr window from stroke symptom onset Treatment Groups –Intervention group - Insulin drip ( mg/dL ) –Control group - SQ insulin ( 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 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 Group Estimating 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 Group Entering Meals in GlucoStabilizer®

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 13 2

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 or principal investigator Dr. Nina Gentile at with any

Recruitment and Retention Katrina van de Bruinhorst, MA, CCRC SHINE 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 12 hours do not get reported –Due on the 10 th of the following month Recognition system Retention tips

Question #4 – Screen Fail Logs

Informed Consent Process and Monitoring Donna Harsh, MS NETT 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, CCRP SHINE Site Manager

SHINE Website and WebDCU Database -SHINE Website - -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 NETT Education coordinator -WebDCU Database - -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 s 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, CCRP SHINE 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 Enrollment 55 Sites enrolling; 46 sites have enrolled at least 1 subject TOP ENROLLERS NYP – 55 Emory – 46 OSU –33 Kentucky – 24

SHINE Trial Recruitment

Who to Contact 24 hour emergency contacts: SHINE Study Hotline – WebDCU Emergency Randomization Hotline – I-SPOT Study Hotline – Protocol questionsAmy Fansler(434) or Budget & contracts questionsAmy Fansler Valerie Stevenson (434) or General education and trainingJoy Pinkerton(734) or I-SPOT questionsHannah Reimer or Laptop questionsAmy Fansler(434) or MonitoringDonna Harsh Carol van Huysen (734) or or Regulatory & site readinessArthi Ramakrishnan(734) or Recruitment questionsKatrina van de Bruinhorst (214) or WebDCU supportKavita Patel(843) or

Questions