protocol overview for new study team members - june 25, 2014 the stroke hyperglycemia insulin...
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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 [email protected] or principal investigator Dr. Nina Gentile at [email protected] 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 ([email protected]), 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 [email protected]
Budget & contracts questions Amy FanslerValerie Stevenson
(434) 982-6027 or [email protected]
General education and training Joy Pinkerton (734) 232-2138 or [email protected]
I-SPOT questions Hannah Reimer 215-707-5483 or [email protected]
Laptop questions Amy Fansler (434) 982-6027 or [email protected]
Monitoring Donna HarshCarol van Huysen
(734) 232-2136 or [email protected] 734-764-9254 or [email protected]
Regulatory & site readiness Arthi Ramakrishnan (734) 936-2454 or [email protected]
Recruitment questions Katrina van de Bruinhorst
(214)648-9248 or [email protected]
WebDCU support Kavita Patel (843) 876-1167 or [email protected]
Questions