Transcript Predictive Risk Modeling in Stroke

Protocol Overview for New Study Team
Members - June 25, 2014
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The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial
NIH-NINDS U01 NS069498
NETT CCC U01 NS056975 NETT SDMC U01 NS059041
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 NS069498
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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 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
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Age 18 years or older
Clinical diagnosis of ischemic stroke
Randomization w/in 12 hrs of stroke symptom onset
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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
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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 NS069498
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~1400 hyperglycemic acute ischemic stroke patients
12 hr window from stroke symptom onset
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Treatment Groups
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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
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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 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
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
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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, 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<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, 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
CRF Verification
• 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
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 - 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
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Use Regulatory Parameters Document for training and
documentation requirements
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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
Project Spoke Team Member Table
and DOA Log
• 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.
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*project spoke team member (PTSM) table is located in the NETT regulatory database.
Serious/Adverse Event (SAE)
• 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.
SAE Templates
• 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.
6-Month Retraining
• 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.
Study Update
Amy Fansler, MPH, CCRP
SHINE Project Director
Study Update
• 55 sites enrolling (~60 total sites expected)
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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
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
HFHS
SUNY Downstate
Temple
University Hospital of Brooklyn
Hackensack University MC
Temple University Hospital
UCLA
Long Beach Memorial MC
UCLA Medical Center
Georgia Regents University
Henry Ford Hospital
Maimonides Medical Center
CPMC Davies
UCSF
CPMC Pacific
University of Michigan
San Francisco General
Kentucky
University of Kentucky
UCSF Medical Center
Maryland
University of Maryland
Abington Memorial
Mayo Jacksonville
Mayo Clinic, Jacksonville
MCW
Froedtert Memorial
York Wellspan Hospital
MGH
Mass General
Austin Brackenridge
HCMC
Minnesota
University of Kansas
Valley Baptist MC
OSF
OSF Saint Francis
OHSU
Harborview MC
Pittsburgh
Stanford
SUNY Downstate
Austin Seton
Memorial Hermann
NYP Columbia
Penn State
UT Houston
Hospital of UPenn
UMMC Fairview
NYP
OSU
UPenn
Utah
UTSW
University of Utah
UTSW - Zale
UTSW - Parkland
Summa Akron City MC
UVA
University of Virginia
Wexner Medical Center
Vanderbilt
Vanderbilt University MC
Beaumont Royal Oak
Penn State Hershey MC
UPMC Mercy
WSU
Beaumont Troy
UPMC Presbyterian
Detroit Receiving Hospital
Stanford University MC
Sinai Grace
Kings County Hospital
Lincoln Medical
WVU
West Virginia University
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
Protocol questions
Amy Fansler
(434) 982-6027 or [email protected]
Budget & contracts questions
Amy Fansler
Valerie 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 Harsh
Carol 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]
24 hour emergency contacts:
SHINE Study Hotline – 800-915-7320
WebDCU Emergency Randomization Hotline – 1-866-450-2016
I-SPOT Study Hotline – 774-234-7768
Questions