Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial
Phase: PHASE3
Conditions: Acute Ischemic Stroke, Diabetes, Hyperglycemia
Sponsor: University of Virginia

SHINE                                             CONFIDENTIAL                     Version 2 – 10/23/2012 
Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial Protocol 
 
 
STUDY GROUP CHAIR 
 
Karen C. Johnston, MD, MSc 
 
 
CLINICAL PRINCIPAL INVESTIGATORS 
 
Askiel Bruno, MD, MS; Christiana E. Hall, MD, MS; Karen C. Johnston, MD, MSc 
 
Co-INVESTIGATORS 
 
Rattan Juneja, MD; Mark Conaway, PhD 
 
 
The NETT Statistical and Data Management Center 
PRINCIPAL INVESTIGATORS 
 
Valerie Durkalski, PhD; Yuko Palesch, PhD 
 
 
The NETT Clinical Coordinating Center 
PRINCIPAL INVESTIGATORS 
 
William Barsan, MD; William Meurer, MD, MS 
 
 
GLUCOSE MONITORING TEAM 
Medical Automation Systems an Alere Company 
Denise R. Zito 
 
 
SPONSOR 
NIH - National Institutes of Neurological Disease and Stroke 
U01 NS069498 
 

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Investigator's Agreement 
 
I have read the attached clinical protocol titled Stroke Hyperglycemia Insulin Network Effort 
(SHINE) dated 10/23/2012 and agree to conduct the protocol as written in this document. 
 
I agree to comply with the Declaration of Helsinki/Tokyo/Venice on Experimentation in Humans 
as required by the United States Food and Drug Administration regulations; the Code of Federal 
Regulations Title 21 parts 50, 56, 312, 800, as applicable; the Code of Federal Regulations Title 
45 part 46; International Conference on Harmonisation Good Clinical Practice Guidelines; and 
all other applicable guidelines. 
 
I understand this document contains confidential information of SHINE Executive Committee, 
the NETT CCC and SDMC and cannot be disclosed to anyone other than members of my staff 
conducting this trial and members of my Institutional Review Board or Ethical Committee.   
 
I agree to ensure that this information will not be used for any purpose other than the evaluation 
or conduct of this clinical trial without the prior written permission of the SHINE Executive 
Committee. 
 
 
_________________________________ 
 
 
_____________________________ 
Signature of Site Principal Investigator 
 
 
 
Date 
 
 
_________________________________ 
 
 
 
Printed name of Site Principal Investigator 
 
 
 
_________________________________ 
 
 
______________________________ 
Signature of Co-Principal Investigator 
 
 
Date 
(When applicable) 
 
_________________________________ 
Printed name of Co-Principal Investigator 
(When applicable) 

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1. 
SUMMARY ............................................................................................................................ 6 
2. 
OBJECTIVES ......................................................................................................................... 6 
2.1 
Specific Aim 1 ................................................................................................................ 6 
2.2 
Specific Aim 2 ................................................................................................................ 7 
3. 
BACKGROUND AND RATIONALE ................................................................................... 7 
3.1 
Background ..................................................................................................................... 7 
3.2 
Significance..................................................................................................................... 7 
3.3 
Hyperglycemia Correction Trials: Acute Ischemic Stroke ............................................. 9 
3.4 
THIS and GRASP Preliminary Data............................................................................. 10 
3.5 
Rationale ....................................................................................................................... 15 
4. 
STUDY PLAN ...................................................................................................................... 15 
4.1 
Study Design ................................................................................................................. 15 
4.2 
Study Population ........................................................................................................... 15 
4.3 
Study Therapy (insulin versus saline) ........................................................................... 16 
4.4 
Study Decision Support Tool for the Intervention Group ............................................ 16 
4.5 
Study Sites .................................................................................................................... 16 
4.6 
Estimated Study and Enrollment Duration ................................................................... 17 
5. 
ELIGIBILITY CRITERIA .................................................................................................... 17 
5.1 
Inclusion Criteria .......................................................................................................... 17 
5.2 
Exclusion Criteria ......................................................................................................... 17 
5.3 
Prohibited Therapy During Study Period ..................................................................... 19 
6. 
SUBJECT RECRUITMENT ................................................................................................ 19 
6.1 
Methods......................................................................................................................... 19 
6.2 
Screen Failure Logs ...................................................................................................... 20 
7. 
SUBJECT ENROLLMENT ................................................................................................. 20 
7.1 
Eligibility Assessment .................................................................................................. 20 
7.2 
Presentation of Informed Consent ................................................................................ 20 
7.3 
Randomization .............................................................................................................. 21 
7.3.1 Central Randomization Procedure ............................................................................ 21 
8. 
STUDY PROCEDURE ........................................................................................................ 21 
8.1 
Baseline Assessments ................................................................................................... 21 
8.1.1 Point of Care Finger Stick Blood glucose level ........................................................ 21 
8.1.2 Concomitant medications documentation ................................................................. 21 
8.1.3 Vital signs ................................................................................................................. 21 
8.1.4 NIHSS ....................................................................................................................... 22 
8.1.5 Neuro Worsening Assessment .................................................................................. 22 
8.1.6 Protocol Deviation Documentation........................................................................... 22 
8.2 
Treatment Procedures ................................................................................................... 22 
8.2.1 Decision Support Tool set up .................................................................................... 22 
8.2.2 Blinding Set Up......................................................................................................... 22 
8.2.3 Drug Dosage/ Drug Administration .......................................................................... 22 
8.2.4 Concomitant or Ancillary Therapy ........................................................................... 26 
8.3 
Clinical Guidelines ........................................................................................................ 26 
8.4 
Follow-up Procedure ..................................................................................................... 26 
8.5 
Notification of Death .................................................................................................... 26 

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8.6 
Procedure for Unblinding ............................................................................................. 27 
8.7 
Schedule of Events ........................................................................................................ 27 
9. 
DISCONTINUATION OF PARTICIPATION .................................................................... 27 
9.1 
Subject Removal from Therapy .................................................................................... 27 
9.2 
Subject Withdrawal ....................................................................................................... 28 
9.3 
Procedure for Discontinuation ...................................................................................... 28 
9.4 
Subject Lost to Follow-Up ............................................................................................ 28 
9.5 
Subject Transfers .......................................................................................................... 28 
10. 
OUTCOMES DEFINTIONS ............................................................................................ 28 
10.1 
Primary .......................................................................................................................... 28 
10.2 
Secondary ...................................................................................................................... 29 
11. 
DATA MANAGEMENT.................................................................................................. 29 
11.1 
Data Processing ............................................................................................................. 29 
11.2 
Data Security and Confidentiality ................................................................................. 29 
11.3 
Data Quality Assurance ................................................................................................ 30 
12. 
STATISTICAL CONSIDERATIONS.............................................................................. 30 
12.1 
Sample Size and Power Estimation .............................................................................. 30 
12.2 
Statistical Analyses ....................................................................................................... 31 
12.2.1 
Interim Analysis .................................................................................................... 31 
12.2.2 
Interim Safety Analysis......................................................................................... 31 
12.2.3 
Primary Efficacy Analysis .................................................................................... 31 
12.2.4 
Secondary Analyses .............................................................................................. 31 
12.2.5 
Safety Outcome Analyses ..................................................................................... 32 
13. 
ADVERSE EVENTS ........................................................................................................ 32 
13.1 
Adverse Events ............................................................................................................. 32 
13.2 
Clinically Important Adverse Events ............................................................................ 32 
13.3 
Adverse Event Exceptions ............................................................................................ 32 
13.4 
Obligation of Investigator ............................................................................................. 32 
13.5 
Reporting Procedures .................................................................................................... 33 
14. 
INVESTIGATIONAL DRUG DESCRIPTION ............................................................... 33 
15. 
REGULATORY AND ETHICAL OBLIGATIONS ........................................................ 33 
15.1 
Informed Consent.......................................................................................................... 33 
15.2 
Institutional Review Board (IRB) ................................................................................. 34 
15.2.1 
Initial Review and Approval ................................................................................. 34 
15.2.2 
Amendments ......................................................................................................... 34 
15.2.3 
Annual Renewal .................................................................................................... 35 
16. 
STUDY ORGANIZATION .............................................................................................. 35 
16.1 
Executive Committee .................................................................................................... 35 
16.2 
Data and Safety Monitoring Board ............................................................................... 35 
16.3 
Ancillary Studies ........................................................................................................... 36 
16.3.1 
Optional Insights on Selected Procoagulation Markers and Outcomes in Stroke 
Trial (I-SPOT) Ancillary Study ............................................................................................ 36 
17. 
References ......................................................................................................................... 37 
 

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ABBREVIATIONS 
 
Abbreviation 
 
Description 
ADA  
 
 
American Diabetes Association 
AE 
 
 
 
Adverse Event 
AHA  
 
 
American Heart Association 
ALIAS 
High-Dose Albumin Therapy for Neuroprotection in Acute 
Ischemic Stroke 
ASAP 
Acute Stroke Accurate Prediction 
ATLANTIS 
Alteplase Thrombolysis for Acute Noninterventional Therapy in 
Ischemic Stroke 
BG 
 
 
 
baseline glucose 
BI 
 
 
 
Barthel Index 
CCC  
 
 
Clinical Coordinating Center 
CI 
 
 
 
confidence interval 
CRF 
 
 
 
case report form 
D/C 
 
 
 
discharge 
DSMB  
 
 
Data and Safety Monitoring Board 
DVT  
 
 
deep venous thrombosis 
EC 
 
 
 
Executive Committee 
ED 
 
 
 
Emergency Department 
FDA  
 
 
Food and Drug Administration 
GIST-UK 
 
 
Glucose Insulin in Stroke Trial – United Kingdom 
GRASP 
 
 
Glucose Regulation in Acute Stroke Patients 
IA 
 
 
 
intra-arterial 
ICH 
 
 
 
intracranial hemorrhage 
IND 
 
 
 
Investigational New Drug 
IRB 
 
 
 
Institutional Review Board 
IV 
 
 
 
intravenous 
LAR  
 
 
Legally Authorized Representative 
MSM  
 
 
Medical Safety Monitor 
MOP  
 
 
Manual of Procedures 
NETT  
 
 
Neurological Emergency Treatment Trials 
NIH 
 
 
 
National Institutes of Health 
NIHSS  
 
 
NIH Stroke Scale 
NINDS 
 
 
National Institute of Neurological Disorders and Stroke 
mRS  
 
 
modified Rankin Scale 
PI 
 
 
 
Principal Investigator 
PO 
 
 
 
by mouth 
q 
 
 
 
every 
RX 
 
 
 
treatment 
SAP 
 
 
 
Statistical Analysis Plan 
SAE 
 
 
 
Serious Adverse Event 
SDMC  
 
 
Statistical Data Management Center 
SHINE 
 
 
Stroke Hyperglycemia Insulin Network Effort 
SQ 
 
 
 
subcutaneous 

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ABBREVIATIONS 
 
Abbreviation 
 
Description 
SSQOL 
 
 
Stroke Specific Quality Of Life 
THIS  
 
 
Treatment of Hyperglycemia in Ischemic Stroke 
TOAST 
 
 
Trial of ORG 10172 in Acute Stroke Treatment 
tPA 
 
 
 
Tissue Plasminogen Activator 
 
 
 

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1. 
SUMMARY 
 
There is an increasing need for improved treatments for stroke patients as stroke is the 
most common cause of serious long term adult disability and the third most common 
cause of death in the United States.1 Hyperglycemia is seen in approximately 40% of 
acute ischemic stroke patients2,3 and has been associated with worse clinical outcomes.4,5 
Intravenous (IV) insulin therapy with tight glucose control has been found to improve 
clinical outcomes in some non-stroke acute illness trials.6,7 Current stroke guidelines 
emphasize the need for definitive clinical trials to determine best practice for managing 
hyperglycemia in acute stroke patients.8 A clear determination of the risk and benefit of 
glucose control with IV insulin would have a dramatic impact on acute ischemic stroke 
patient therapy. 
 
This Phase III multicenter, randomized, controlled trial will determine the efficacy and 
provide further safety data on glycemic control in stroke patients. The hyperglycemic 
acute ischemic stroke patients that meet all eligibility criteria will receive up to 72 hours 
of hyperglycemia control with IV insulin therapy or control therapy with subcutaneous 
(SQ) insulin. Treatment will be given within 12 hours of symptom onset and is 
recommended, but not required, to begin within 3 hours of arrival to the emergency 
department (ED). The primary efficacy outcome to be assessed at 90 days will be the 
severity adjusted difference in favorable outcome between the groups. Favorable 
outcome will be defined by a previously described baseline severity adjusted 
dichotomized modified Rankin scale (mRS).9-11 Outcome success will depend on the 
severity of the initial stroke (per NIH Stroke Scale Score (NIHSS)). The primary safety 
outcome will be the hypoglycemic event rate. Secondary outcomes will assess additional 
neurological and functional status using stroke severity, functional and quality scales12-14 
as well as glucose control success and adherence to the protocol dosing recommendations 
of the computerized decision support tool. This trial launches a highly collaborative 
model for stroke research providing a foundation for maximally generalizable results 
based on performance at academic, community, urban, rural, large and small hospitals 
throughout North America to produce a highly representative national population sample. 
A validated computer decision support tool will guide delivery of IV insulin therapy.  A 
baseline severity-adjusted dichotomized outcome analysis (responder analysis)9 will 
adjust for variability of individual patient characteristics to allow detection of the true 
clinically relevant treatment effect. In this setting an absolute 7% treatment effect is 
recognized as a threshold at or above which a profound effect on a large stroke 
population would be realized.  
  
2. 
OBJECTIVES 
 
2.1 
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.  
 

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o Hypothesis 1: Tight glucose control (target 80-130 mg/dL) with IV insulin 
infusion therapy using a validated computerized decision support tool, will 
increase the severity adjusted 90 day favorable outcome on the mRS by an 
absolute 7% or more, as compared to the control group. 
 
2.2 
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 hrs. 
 
o Hypothesis 1: Tight glucose control with IV insulin infusion therapy using a 
decision support tool is safe as determined by a severe hypoglycemia (<40 
mg/dL) rate that does not exceed that of the control group by more than 4%. 
 
3. 
BACKGROUND AND RATIONALE 
 
3.1 
Background 
Ischemic Stroke represents a large burden to society with only a single proven 
acute treatment.  IV Thrombolytic therapy has proven applicable to only a small 
minority of stroke patients who present within a narrow time window.  Even for 
those patients receiving this therapy, the chances of recovery to normal or near 
normal are only increased by approximately 30%.  Sorely needed are additional 
new stroke treatments applicable to a larger universe of early acute stroke patients 
which are safe and efficacious when delivered over an expanded time window.  
Hyperglycemia, seen in large numbers of acute stroke patients and well associated 
with poorer clinical outcomes, provides a compelling target for intervention. 
 
3.2 
Significance   
Stroke remains the third leading cause of death and leading cause of adult 
disability in the U.S.  The total cost of stroke for 2009 is estimated at nearly $69 
billion.1 Stroke occurs in nearly 800,000 people annually in the United States1 
with approximately 85% (637,500) of them being ischemic and approximately 
40% (250,000) of the ischemic strokes being hyperglycemic (≥130 mg/dL) at 
presentation to the hospital.2,3 An efficacious and effective treatment for 
hyperglycemia in this population would have an enormous impact. Preliminary 
data have demonstrated the safety and feasibility of insulin infusion therapy in 
acute ischemic stroke patients, but efficacy remains unknown.15-21 Hyperglycemia 
is associated with worse outcomes and yet hypoglycemia is bad for ischemic 
brain. Treatment for hyperglycemia with a very low hypoglycemia rate is highly 
likely to be beneficial. The stroke community has struggled with uncertainty 
regarding how hyperglycemic stroke patients should be managed and the most 
recent American Heart Association (AHA) guidelines suggest that the 
management uncertainty in acute stroke patients will require clarification by 
clinical trials.8 Health care providers are currently making clinical decisions 
regarding hyperglycemic management without adequate data. The guidelines 
classify the current evidence as C (consensus of experts) only. The information 
gained from this efficacy trial will guide clinical practice and provide answers 

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regarding the risk/benefit ratio of glucose control using insulin infusion therapy to 
improve stroke outcomes. Even a small beneficial effect of an absolute 7% 
(roughly half of IV tPA) is likely to gain the attention of physicians who care for 
stroke patients worldwide and likely to change current practice for over 250,000 
patients per year as great variability now exists in this setting of uncertainty. 
Evidence of unacceptable risk/benefit ratio would guide clinicians to avoid this 
therapy and redirect resources and efforts toward other promising acute stroke 
therapies. The additional information from the SHINE trial will provide 
knowledge that will advance the field and may improve clinical outcomes in 
stroke patients. 
 
 
Table 1. Studies assessing clinical outcomes associated with admission or in-hospital 
hyperglycemia in ischemic stroke adjusted for confounding factors. 
Study, 1st author, year 
Patients Main Result 
Mortality with admission hyperglycemia 
Moulin, 199722 
1776 
Increased 30 day mortality, RR 1.007 (1.004, 1.010) 
Williams, 20023 
 
634 
Increased 30 day mortality if glucose ≥130 mg/dL, HR 1.87 
(1.05,3.32), p=0.018 
Gentile et al, 20062 
960 
Increased mortality if glucose ≥130mg/dL, p<0.004 
 
Reduced favorable clinical outcome at 3 months with admission hyperglycemia 
Weir, 199723 
645 
p<0.001. Only patient w/o diabetes analyzed  
TOAST, Bruno, 199924  
1259 
p=0.03. All study patients (Rx and placebo) 
Demchuk, 200125 
616 
p= 0.03. All patients treated with tPA 
ATLANTIS, Bruno, 200226 
755 
p<0.001. All study patients, (tPA and placebo) 
NINDS tPA, Bruno, 200226 
624 
p=0.02. All study patients (tPA and placebo) 
CASES, Poppe, 200927 
1098 
RR=0.7 (0.5,0.9) if glucose >144mg/dL (tPA patients)  
 
Worse clinical outcomes with in-hospital hyperglycemia 
Gentile et al, 20062 
960 
Increased mortality if glucose ≥130 mg/dL, p<0.001 
ECAS-II, Yong, 200828 
587 
Reduced favorable outcome if glucose >140 mg/dL, 
OR=0.36 (0.13,0.71) 
Fuentes, 200929 
476 
Increased poor outcome if glucose ≥155 mg/dL, p=0.002 
Dziedzic, 200930 
689 
Increased 90 day mortality, HR 1.10 (1.03,1.18), p<0.01 
TOAST = Trial of ORG 10172 in Acute Stroke Treatment; 
ATLANTIS = the acute stroke rt-PA 3-5 hours after onset of symptoms treatment trial; 
NINDS rt-PA = the NINDS rt-PA Acute Stroke Trial; 
CASES = Canadian Alteplase Stroke Effectiveness Study 
 
Of importance is the finding that glucose concentrations after admission are also 
associated with worse clinical outcomes. These data suggest that clinical 
outcomes may be impacted by normalization of blood glucose in the first few 
days after stroke. 

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Table 2. Association between acute hyperglycemia and infarct volume on MRI 
1st author, yr 
Number of 
Subjects 
Definition 
of 
hyperglycemia 
Outcome 
associate 
with hyperglycemia 
Parsons, 
M 
200231 
40 
>144 mg/dL 
Larger 
infarcts, 
less 
penumbral salvage, higher 
brain lactate 
Els T, 200232 
31 
>178 mg/dL 
Greater lesion expansion 
Baird TA, 200333 
20 
>126 mg/dL 
Greater lesion expansion 
Ribo M, 200734 
47 
>140 mg/dL 
Greater lesion expansion 
 
In summary, the majority of data from observational studies show an independent 
association between both admission and in-hospital (first several days) 
hyperglycemia with worse clinical and imaging outcomes in acute ischemic stroke 
patients. 
 
3.3 
Hyperglycemia Correction Trials: Acute Ischemic Stroke 
The Glucose Insulin in Stroke Trial – United Kingdom (GIST-UK)20 was 
intended to be a definitive efficacy trial to address aggressive hyperglycemia 
correction in acute stroke patients (ischemic and hemorrhagic). Unfortunately, 
this multicenter, controlled trial did not provide adequate efficacy data as the trial 
was stopped early for financial reasons with only 40% enrollment, so was 
underpowered, 
and 
because 
both 
treatment 
groups 
achieved 
glucose 
concentrations in the treatment target range (72-126 mg/dL) that was intended 
only for the insulin infusion group.20 No difference in outcomes between the 
groups was detected.  Important information however can be gleaned from the 
GIST-UK trial that informs future trials. 
 
The GIST-UK trial excluded insulin treated patients with diabetes. Only 17% of 
the patients had diabetes (all non-insulin treated) while 83% did not have 
diabetes. Consequently, despite only saline infusion in the control group, the 
mean glucose during protocol treatment was in the intervention target range for 
both groups (Figure1). Though the treatment was safe, these data demonstrate that 
on average, patients without diabetes normalize their glucose concentrations 
spontaneously without need for glucose control intervention, as has been reported 
elsewhere.35 As animal data and observational clinical studies suggest it is likely 
that glucose concentration and not the presence of insulin is related to improved 
outcomes, the comparison of two groups in the same target range in the GIST-UK 
trial would not be expected to demonstrate a difference in clinical outcome. 
Despite the limitations of the GIST–UK trial it has informed the SHINE trial to 
include patients with diabetes to allow for the two treatment groups to have 
separation of glucose concentrations in two different target ranges. 

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In addition to our middle phase (pilot) trials, THIS and GRASP, described in the 
preliminary data section below, there are two additional published middle phase 
trials. Walters, et al19 studied the safety and feasibility of hyperglycemia 
correction in acute ischemic stroke in 25 patients with hyperglycemia (>110 
mg/dL) randomized within 24-hours after stroke onset to IV insulin therapy or IV 
saline (control) with continuation of previous oral antidiabetic drugs. Of these 
patients 52% had diabetes mellitus. The intervention lasted 48 hours and target 
glucose was 90-144 mg/dL in the insulin infusion group. The mean blood glucose 
achieved was 122 mg/dL in the insulin infusion group and 145 mg/dL in the 
control group. There was one episode of hypoglycemia with autonomic symptoms 
only in the insulin infusion group (glucose 72 mg/dL).  Importantly, they also 
demonstrated that glucose concentrations normalize with minimum intervention 
in patients without diabetes. The investigators concluded that glycemic control 
was safe and feasible. In another pilot trial, Kreisel et al21 randomized 40 patients 
with acute ischemic stroke within 24 hours regardless of admission blood glucose 
to standard subcutaneous or IV insulin treatment. The target glucose range in the 
insulin infusion group was 80-110 mg/dL. Of these patients 33% had diabetes 
mellitus. In patients without diabetes the glucose concentrations were normal 
throughout the 5 day protocol period in both treatment groups. In patients with 
diabetes, the glucose concentrations were higher in the standard treatment group 
than in the IV insulin treatment group (180-205 mg/dL in the standard group and 
120-150 mg/dL in the IV insulin group on days 1- 3). Hypoglycemia (<60 mg/dL) 
developed in 7 (35%) patients, with autonomic symptoms in 3 (15%), and none 
had neurological hypoglycemic symptoms. 
 
3.4 
THIS and GRASP Preliminary Data 
The investigators have substantial preliminary data from two NINDS funded pilot 
trials (THIS16 and GRASP17) as well as data from a recent NETT stroke trial that 
inform the design of SHINE. 
 
THIS Trial Description and Results 
The Treatment of Hyperglycemia in Ischemic Stroke (THIS) trial was an NINDS 
funded safety and feasibility multicenter pilot trial of aggressive hyperglycemia 
100
110
120
130
140
150
160
B aseline
8
16
24
Hours since start of treatment
Mean Glucose (mg/dL)
Saline (N=469)
GKI (N=464)
Figure 1. GIST-UK trial20 
glucose concentrations (data 
converted from mm/liter to 
mg/dL).  
Graph demonstrates that both 
groups are in the intervention 
target range (72-126 mg/dL). 

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reduction in acute ischemic stroke.16 Patients (N=46) were randomized within 12 
hours of stroke onset to continuous IV insulin infusion (N=31) (target 80-130 
mg/dL) or sliding scale SQ insulin injections up to four times daily if needed 
(control N=15). The baseline glucose threshold for inclusion was 150 mg/dL and 
91% were diabetic.  
 
The main findings in THIS were safety and feasibility.  Elevated glucose levels 
were lowered into target range with mean glucose nearly 60 mg/dL (31%) lower 
in the IV insulin group than the SQ insulin group (133 vs. 190 mg/dL) within four 
hours of starting therapy.  
 
THIS Safety Results  
There were no serious adverse events related to the IV insulin intervention. 
Overall, episodic hypoglycemia (<60 mg/dL) occurred in 11 patients (11/31, 
35%) in the IV insulin group. Seven of these hypoglycemic patients were 
asymptomatic. There was only one patient who had transient neurologic 
symptomatic hypoglycemia. No patient had severe (<40 mg/dL) or prolonged 
hypoglycemia. Ten patients (22%) were treated with standard IV tPA within three 
hours of stroke onset and no treatment related adverse events were seen in this 
subgroup. Glucose concentrations were consistently and significantly lower 
throughout the trial in the IV insulin group. The adjusted mean glucose difference 
between the groups during treatment was 66 mg/dL. Non-diabetic patients had 
glucose levels return to normal without aggressive treatment.  
 
THIS Clinical Outcomes 
There were no statistically significant differences in clinical outcomes between 
the two treatment groups. The primary exploratory analysis compared mRS ≤2 at 
3 months. Favorable outcome was more common in the aggressive treatment 
group, by an absolute 5%. Secondary favorable clinical outcomes were also more 
favorable in the IV insulin group. The largest difference was in the NIH Stroke 
Scale ≤2, with p=0.09 in favor of the IV insulin after adjusting for baseline 
inequalities. No patient was lost to follow up.   
 
 
GRASP Trial Description and Results 
The GRASP trial (N=74) was a multicenter randomized safety, feasibility, “dose 
finding” trial that included 3 treatment groups (usual, loose and tight control).17 
Patients were enrolled within 24 hours of stroke and treated for up to 5 days. 
Patients with diabetes in the trial had a mean glucose of 185 mg/dL and patients 
without diabetes had a mean glucose of 149 mg/dL at randomization. These data 
support a lesser need for insulin therapy in stroke patients without diabetes.   
 
GRASP Protocol Insulin Treatments 
 
1. Insulin Infusion Protocol (eProtocol-insulin) 
eProtocol-insulin is a computerized decision support tool used in the GRASP trial.  
Both loose and tight control groups received continuous insulin infusion based on 
eProtocol-insulin.  Overall, there was a 97% adherence to eProtocol 

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recommendations 
suggesting 
that 
nurses 
agreed 
with 
the 
computer 
recommendation and followed the study protocol.  
2. Control Group 
The control group was a community control with the intent to observe standard 
care and to inform the control group in future trials. A total of 88% of control 
patients were treated with SQ insulin.   
 
 
GRASP Safety 
Total hypoglycemia rates (<55 mg/dL) were 4% in the control group, 4% in the 
loose control group, and 30% in the tight control group. One patient in the loose 
control group had transient symptomatic hypoglycemia with a glucose of 50 and 
52 mg/dL that was rapidly corrected. A total of 26 patients (36% of enrolled 
subjects) received standard IV thrombolysis within 3 hours. The Data Safety 
Monitoring Board (DSMB) and the safety monitor had no safety concerns in this 
group. There were 10 (14%) deaths in this trial. No patient had severe or 
prolonged hypoglycemia. 
 
 
GRASP Glucose Concentrations and Feasibility  
The median glucose during treatment in the control group was 151 mg/dL, in the 
loose group was 151 mg/dL, and in the tight group was 111 mg/dL. Target 
glucose levels were achieved. They also demonstrate that IV insulin is not 
necessary for the loose target as the same glucose control can be achieved with 
SQ insulin.   
  
 
GRASP Recruitment/Enrollment 
Recruitment and enrollment were highly successful with completion of 
enrollment of 74 subjects within 18 months and ahead of schedule. The 
recruitment specialist was critically important to the recruitment success and 
because of her expertise and commitment she will oversee recruitment in the 
SHINE trial. 
 
GRASP/THIS Target Glucose Concentration (“dose”) Selection 
Both GRASP IV insulin doses are safe and feasible, but the tight control approach 
is appropriate to study in the phase III trial. GRASP data, combined with THIS 
trial data (target 80-130 mg/dL), the AHA guidelines (treat glucose over ~180 
mg/dL), the ADA guidelines (treat over180mg/dL) and the literature reviewed 
above support an intervention group target glucose of 80–130 mg/dL and a 
control group treated with SQ insulin for glucose >180 mg/dL.   Separation will 
be achieved as diabetics will be the study population and our preliminary data 
demonstrate we can adequately separate levels. 
 
 
GRASP/THIS Time Window 
GRASP had a 24 hour window for enrollment, but 58% of patients were enrolled 
<12 hours from stroke onset and 45% <9 hours. These data with the THIS trial 
demonstrate that patients can be enrolled within 12 hours to an acute IV insulin 
trial. A 12 hour window will allow tPA therapy for eligible patients, allow “wake 

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up stroke” enrollment and is supported by the literature.  Data suggest that both 
inflammation and excitotoxicity likely play a major role in the injury 
pathophysiology that tight glucose control is interrupting.36  TNF alpha may be a 
major component of the injury pathway and is expressed by 4 hours but doesn’t 
peak until 12 hours.37  A 12 hour window therefore may have greater ability to 
capture patients that will benefit from this therapy. The rapid sequence of 
evaluation and study enrollment  for acute stroke patients will assure that patients 
will be enrolled quickly and many will likely be early in the time window (as 
shown in GRASP).  This rapid enrollment will be maximized in our collaboration 
with the NETT and will allow a secondary analysis of time to treatment as we are 
likely to have a broad distribution of enrollment times.   
 
 
GRASP/THIS Treatment Period 
The GRASP trial treated patients for 5 days or until discharge with the intent of 
establishing the time period for inpatient therapy.  The GRASP data clearly 
demonstrate that 5 days was not feasible and that 4 days was too long for most 
patients due to current acute stroke length of stay.  Three days was the longest 
feasible treatment window and was successful in both trials. Additionally, human 
data suggest better outcomes in patients with glucose control for first 3 days 
compared to those with hyperglycemia.38  Pathophysiologic mechanisms that may 
be involved include protein synthesis dependent protection mechanisms that 
continue for up to 3 days.39  Additionally, inflammatory mechanisms (suspected 
to be involved) are known to continue for several days.  Animal model data 
suggest that 3 days of anti-inflammatory treatment can reduce infarct volume.40  
These mechanistic data plus our pilot feasibility data strongly suggest that a 3 day 
treatment period is ideal. Mild stroke patients will be discharged as clinically 
indicated which may be <3 days.   
 
GRASP/THIS Meal Insulin 
The GRASP and THIS trials used a simple algorithm for estimating carbohydrate 
consumption and providing meal insulin.  One unit/15 grams carbohydrate 
consumed will be used in SHINE.  
 
GRASP Exploratory Efficacy Outcomes (N=73 patients with 3 month 
outcomes) 
None of the efficacy outcome relationships reached statistical significance, but 
have been used to estimate the control group outcome rates and predict the 
population most likely to benefit from treatment.  The primary exploratory 
analysis analyzed modified Rankin score ≤1 at 3 months and the tight group had 
the most favorable outcomes. Three months outcomes were captured on 99% of 
patients.  
 
Responder Analysis  
Based on the well-known statistical principle of loss of information with the use 
of dichotomized outcomes and the recent literature suggesting that more 
innovative and powerful analyses may be necessary for “neuroprotection” trials,41-

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44 we chose to apply the “responder analysis” (baseline adjusted severity) also 
referred to as “stratified dichotomy analysis” to the SHINE trial. This analysis has 
been described previously9 and has confirmed the benefit of tPA in both part 1 
and part 2 of the NINDS tPA trials, demonstrating increased power to detect the 
treatment effect.10  
 
The SHINE trial defines a dichotomized mRS score as “favorable” versus “not 
favorable” based on the baseline NIHSS at randomization as defined previously9, 
10  
 
Table 3. Stroke Severity Adjusted Stratified Dichotomy9 analysis. 
Trial (NIHSS 3-22 for 
all) 
Favorable clinical outcome on mRS 
 
Control (95% CI) 
IV Insulin (95% CI) 
GRASP (BG ≥150) 
2/11=18% (3,52) 
6/15 = 40% (8,68) 
THIS 
  3/15 = 20% (5,37) 
4/31 = 13% (4,30) 
NINDS tPA (BG≥150) 
18/72= 25% (15,37) 
N/A 
ASAP  
55/211= 26% (20,32) 
N/A 
BG ≥150=baseline glucose ≥150 mg/dL; ASAP = NINDS Acute Stroke 
Accurate Prediction trial45 
 
 
 
 
 
 
Selection of Control and Treatment Group Rates 
To determine the appropriate control rate, we assessed the responder analysis 
from four relevant trials (Table 3).   Standard previously published definitions of 
favorable outcome are used in this trial.9  Additionally, requested control rate 
information on a subset similar to the SHINE study population from the Executive 
Committee of a contemporary stroke trial (ALIAS part 1) has been used in the 
development of the SHINE protocol.  The control population estimates in the 4 
trials suggest a reasonable favorable outcome rate of ~20-25% in an acute stroke 
population similar to that to be enrolled in SHINE. The expected control rate is 
not anticipated to be an underestimate based on preliminary data.  Based on these 
analyses of 4 recent data sets and 1 old data set (NINDS tPA), we are confident 
that they support our expected control population rate of favorable outcome 
(25%). These pilot trials are not intended to be underpowered efficacy trials and 
therefore do not inform the expected treatment effect. The STAIR group has 
suggested that an absolute treatment effect of 2-8% is appropriate for 
neuroprotection trials.46 A treatment effect rate of 4-6% was felt to be too small 
an absolute benefit for insulin infusion therapy as it is labor-intensive even if very 
safe. An absolute treatment effect of 7-8% will change clinical practice and 
therefore we used an effect size of 7% for our sample size estimation. 
Summary Table 3: 4 data sets are analyzed using responders analysis.  
Control population estimates suggest ~20-25% baseline favorable outcome 
in a population similar to the SHINE trial population.  

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Decision Support Tool  
The decision support tool, GlucoStabilizer, is an FDA cleared device that has 
been utilized in over 50,000 patients.  The tool has demonstrated extremely low 
rates of severe hypoglycemia (<40 mg/dL).  The severe hypoglycemia rate during 
use is 1.67% of patients and 0.07% of total glucose readings. 
 
Decision support tools have been used in previous studies, and the insulin 
infusion patients in the GRASP Trial used eProtocol-insulin, a similar decision 
support tool.  Adherence to the recommendations using decision support tool 
devices has been reported to be 91-98%,47, 48 and it was 97% in the GRASP trial 
using eProtocol17. 
 
 
Summary Preliminary Results 
The GRASP and THIS trials have shown that insulin infusion therapy for tight 
glucose control is safe and is feasible in hyperglycemic acute ischemic stroke 
patients. Additionally, these trials have identified the appropriate glucose target, 
timing, treatment period, patient population for enrollment, expected loss to 
follow up rate, expected recruitment rate, and expected control group outcome 
rates. These pilot data ideally inform the design of the SHINE Trial.   
 
3.5 
Rationale 
The goal in the treatment group is glucose levels within the target range of 80-130 
mg/dL. This requires that the target range be rapidly established and maintained 
with minimal variability for up to 72 hours. IV insulin infusion due to its rapid 
onset and offset of action and its superior degree of frequent titratability provides 
the ideal intervention to achieve and tightly maintain the target range goal across 
the study period.  The use of computerized decision support tools is now part of 
standard care.   
 
4. 
STUDY PLAN 
 
4.1 
Study Design 
SHINE is a multicenter, randomized, controlled clinical trial of approximately 
1400 patients to be conducted at 17 Neurological Emergencies Treatment Trials 
(NETT) hubs and their spoke hospitals as well as approximately 10 non-NETT 
sites. 
 
4.2 
Study Population 
The study population will include hyperglycemic acute ischemic stroke patients of 
either gender who are 18 years of age or older.  They will have a history of type 2 
diabetes and hyperglycemia or in the absence of diabetes, must have a baseline 
glucose levels ≥150 mg/dL.  To be eligible, treatment must begin within 12 hours 
of stroke symptom onset and is recommended, but not required, to begin within 3 
hours of arrival to the Emergency Department. Participation is limited to those 
with baseline NIHSS scores 3-22. 

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4.3 
Study Therapy (insulin versus saline) 
Insulin is indicated for the treatment of hyperglycemic conditions and the 
maintenance of euglycemia in the setting of diabetes mellitus.  It is also known to 
be effective in normalizing blood glucose when hyperglycemia results from other 
conditions.  It is frequently used for both the inpatient and outpatient management 
of patients with diabetes.  Insulin given by IV or subcutaneous (SQ) route 
stimulates carbohydrate metabolism and facilitates transfer of glucose into cardiac 
muscle, skeletal muscle and adipose tissue, and glucose is converted to glycogen. 
In addition, lipogenesis is stimulated with inhibition of lipolysis from adipose 
cells; protein synthesis is stimulated.  An Investigational New Drug (IND) 
approval is not required for this protocol.  
 
Major adverse reactions 
Common – Skin site reactions (SQ), Lypodystrophy, Mild hypoglycemia 
Serious – Moderate to Severe Hypoglycemia 
 
The SHINE trial will use a validated computerized electronic decision support 
tool for the IV insulin group only. IV insulin or saline infusions will be adjusted 
by the nurses to maintain the assigned glucose target.  The nurses will consider 
the recommendation made by the computer for the IV insulin group and will 
follow the protocol for the saline adjustments.   
 
4.4 
 Study Decision Support Tool for the Intervention Group 
The decision support system, GlucoStabilizer, has been developed by Medical 
Automation Systems an Alere Company and cleared for use by the FDA.  The 
system provides an alert to the nurse for the next required glucose check.  Other 
decision support tool rules moderate the insulin dose recommendation depending 
upon previous glucose readings or steep drops in glucose values. Nurses will have 
the option of accepting or declining the recommended insulin rates. Nurses are 
encouraged to use clinical judgment and reject any recommendation that seems 
inappropriate but will be required to stop the insulin drip when notified to do so 
by the decision support tool. 
 
For blood glucose <80 mg/dL, the decision support tool will instruct the treating 
team to discontinue the insulin infusion, and investigators will be required to stop 
the insulin infusion at that time. Sites will be monitored for rates of adherence to 
the decision support tool recommendation for those patients receiving IV insulin 
infusion. All glucose measurements, insulin dosing, times of glucose checks and 
acceptance of recommendations are captured in the electronic system. 
 
4.5 
Study Sites 
Study sites will include The Neurological Emergency Treatment Trials (NETT) 
sites and non NETT sites.  Details of study sites are listed in the Manual of 
Procedures (MOP).   
 

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4.6 
Estimated Study and Enrollment Duration 
The project period will begin in late 2011.  Enrollment is expected to begin in 
2012.  Enrollment is anticipated to take 3.5 – 4 years and follow up is 3 months.  
Final data analysis and close out activities will occur after completion of 
enrollment and patient follow up.   
 
 
5. 
ELIGIBILITY CRITERIA 
 
5.1 
Inclusion Criteria 
 
(1) 
Age 18 years or older  
 
(2) 
Clinical diagnosis of ischemic stroke defined as acute neurological deficit 
occurring in one or more cerebral vascular territories. Neuroimaging must 
be done to exclude intracranial hemorrhage (ICH). 
 
(3) 
Protocol treatment must begin within 12 hours after stroke symptom onset 
and is recommended, but not required, to begin within 3 hours after 
hospital arrival. If time of symptom onset is unclear or patient is 
awakening with stroke symptoms, the time of onset will be the time the 
patient was last known to be normal. 
 
(4) 
Known history of type 2 diabetes mellitus and glucose >110 mg/dL OR 
admission glucose ≥150 mg/dL in those w/o known diabetes mellitus 
 
(5) 
Baseline NIHSS score of 3-22 
 
(6) 
Pre-stroke modified Rankin Scale score = 0 for patients with an NIHSS 
score of 3-7.  Pre-stroke modified Rankin Scale score = 0 or 1 for patients 
with an NIHSS score of 8-22. 
 
(7) 
Able to provide a valid informed consent to be in the study (self or their 
authorized legally accepted representative).  The approved consent form 
must be signed and dated in accordance with federal and institutional 
guidelines. 
 
 
5.2 
Exclusion Criteria 
 
(1) 
Known history of type1 diabetes mellitus  
 
(2) 
Substantial pre-existing neurological or psychiatric illness that would 
confound the neurological assessment or other outcome assessment 
(3) 
Having received experimental therapy for the enrollment stroke.  IV tPA 
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FDA cleared devices. Non FDA cleared devices are considered 
experimental and are excluded.  
 
(4) 
Known to be pregnant or breast-feeding at the time of study entry 
 
(5) 
Other serious conditions that make the patient unlikely to survive 90 days 
 
(6) 
Inability to follow the protocol or return for the 90 day follow up 
 
(7) 
Renal dialysis (including hemo or peritoneal dialysis)  
 
 
Justification for Eligibility Criteria 
Only ≥18 year old ischemic stroke subjects will be included since ischemic 
strokes in the pediatric population are substantially different from adult strokes. 
The population under age 18 is excluded to avoid confounding the results. 
 
The 12-hour eligibility requirement was chosen as this is almost universally 
before the development of maximum edema in acute ischemic stroke patients, but 
is a wide enough time window to be inclusive of most patients allowing 
generalizable results and is supported by the preliminary data. Treatment within 3 
hours of arrival to the Emergency Department will assure the avoidance of 
treatment delays in hopes of maximizing treatment effect as suggested by much of 
the animal and human data in acute ischemic stroke. This will also allow the 
patients to be treated with standard IV tPA as per published eligibility criteria and 
then enrolled in the trial.  An enrollment blood glucose >110 mg/dL in patients 
with type 2 diabetes or ≥150 mg/dL in patients without diabetes was based on 
our preliminary data and other data suggesting this group is most likely to benefit. 
As demonstrated by GIST-UK20, THIS16, GRASP17, Walters19 and Kriesel21 
hyperglycemia frequently resolves spontaneously in most patients without 
diabetes. Thus, patients without diabetes mellitus or admission hyperglycemia 
will be excluded. Both THIS16 and GRASP17 trials and an observational study45 
demonstrated that most patients enrolled with hyperglycemia ≥150 mg/dL 
remained hyperglycemic during hospitalization unless they received intravenous 
insulin. The vast majority of patients with admission glucose ≥150 mg/dL ha 
undiagnosed diabetes or impaired glucose metabolism (insulin resistance) as has 
been reported,49-51 thus making them good subjects for this trial. Patients with an 
NIHSS score of 3-7 will be required to have a pre-stroke mRS score of 0 to be 
eligible.  This is intended to allow patients to reach the success criteria defined by 
the stratified dichotomy outcome.  Patients with an NIHSS of 8-22 will be eligible 
if they have a pre-stroke mRS score of 0 or 1.  Patients with type I diabetes 
mellitus are excluded for safety reasons. Usual care for type I diabetes patients 
during acute illness usually includes intravenous insulin infusion accompanied by 
dextrose otherwise these patients would be at risk of diabetic ketoacidosis. Since 
withholding standard care is unacceptable, these patients are excluded. Patients 

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with type I diabetes will be identified based on medical history.   Study 
definitions of type 1 and type 2 diabetes are provided in the MOP. 
 
Patients with a neurological or psychiatric illness likely to confound the final 
outcome assessment will be excluded since their baseline deficits and outcomes 
cannot be accurately obtained. Any patient deemed by the enrolling physician to 
have a condition that confounds the enrollment neurological exam will be 
excluded. Patients receiving experimental stroke therapies will be excluded due 
to uncertain effects of such therapies on outcomes. Standard care IV tPA or IA 
tPA according to the AHA/ASA guidelines will be allowed.8 The pilot trials 
demonstrated safety in the population treated with IV tPA. The increased risk of 
symptomatic hemorrhagic transformation of infarcts observed in IV tPA treated 
stroke patients with hyperglycemia25, 26, 52 may be reduced with glucose control. 
Intra-arterial (IA) treatments that are standard care, including the use of FDA 
cleared devices, will be allowed.  FDA cleared devices must be employed 
according to their Instructions for Use.  Non FDA cleared devices or other 
experimental interventions will not be allowed.  No clear data are available on the 
risk/benefit ratio of these interventions and they could confound the results. 
Pregnant women will be excluded since the standard care for this population 
often includes IV insulin treatment for hyperglycemia. Patients unlikely to 
return at 90 days will be excluded since the primary efficacy outcome is 
measured at that time. Renal dialysis patients will be excluded including those 
requiring hemodialysis and peritoneal dialysis due to inability to accurately follow 
glucose levels and variability in insulin requirements that would put patients at 
risk.   
 
5.3 
Prohibited Therapy During Study Period 
No other diabetes treatment medication besides the assigned protocol treatment 
will be allowed during the treatment period because such additional medications 
would confound the study. All oral agents that are used for the treatment of 
hyperglycemia are unauthorized.  The use of non FDA cleared devices for IA 
therapy is not allowed. Patients taking PO diets must eat protocol specified diets 
as defined in the MOP. 
 
6. 
SUBJECT RECRUITMENT 
 
6.1 
Methods 
The methods used for recruitment of subjects in the study will be devoid of any 
procedures that may be construed as coercive.  The recruitment process will not 
involve any restrictions on sociodemographic factors including gender or ethnic 
characteristics of the patient population.  However, the composition of the study 
population will depend on patient sources available to the enrolling sites.  
 
Patients will be recruited by members of the research teams at enrolling sites.  
Stroke teams and Emergency Medicine teams involved in the immediate 
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potentially eligible candidates and to rapidly refer them for formal screening by 
appropriate study team personal. When a patient is found eligible, they or their 
Legally Authorize Representative (LAR) as appropriate to the situation will be 
approached for discussion of the trial and informed consent.   
 
Recruitment and enrollment will usually occur at the acute portal of entry to the 
enrolling site.  Most often this will be in the Emergency Department, but this 
could also occur in a hospital inpatient unit directly receiving an acute stroke 
patient in transfer from another facility as long as arrival is within the specified 
enrollment window. 
 
6.2 
Screen Failure Logs 
Screen failure logs at each site must be entered into the study database listing all 
patients with acute ischemic stroke who have presented within 12 hours of onset 
and are hyperglycemic but not randomized into the SHINE Trial.  Documentation 
will include reasons for non-enrollment.  Screening data will be reviewed to 
assure that full efforts are being made with respect to recruitment and enrollment 
and to identify any patterns with regard to ineligibility or reasons for non-
enrollment.   
 
7. 
SUBJECT ENROLLMENT 
 
7.1 
Eligibility Assessment 
All patients who present within 12 hours of onset of an acute ischemic stroke will 
be screened for eligibility for entry into the study.  Rapid referral to the study 
team should be made immediately upon recognition of potentially eligible 
candidates. Hyperglycemia as defined in the eligibility criteria will be a major 
trigger for consideration for enrollment. 
 
As in all trials, the goal is to achieve a high level of compliance with protocol 
requirements by assuring during the eligibility assessment that the potential 
subject or LAR is fully informed and agrees to the protocol requirements.  In 
addition, patients with a strong likelihood of non-adherence as described in the 
inclusion and exclusion criteria should not knowingly be randomized.  Careful 
assessment of the patient’s understanding of the trial is required prior to 
enrollment.  
 
7.2 
Presentation of Informed Consent 
Consent will be obtained by either the site Principal Investigator or by a member 
of the study team as described in the MOP.  The consent should be the IRB-
approved version corresponding to the version of the protocol approved when the 
screening was initiated.  Informed consent is to be obtained from the patient or 
patient’s LAR. For the SHINE study, there is no activity required in the screening 
process that is not typically included within the reasonable scope of standard care 
evaluation for acute stroke patients; therefore, unless called for by local regulatory 

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request, patients would be approached for consent only after the clinical screening 
process had established eligibility. 
 
7.3 
Randomization  
 
7.3.1 Central Randomization Procedure   
A web-based central randomization system developed by the NETT 
Statistical Data Management Center (SDMC) and installed on the 
WebDCUTM SHINE study website.  
 
Subjects will be assigned to one of the treatment groups according to the 
randomization scheme developed at the SDMC.  Randomization must be 
done centrally using the WebDCUTM for all patients entered in the trial.  
In the event that the site cannot access the randomization module of 
WebDCUTM, emergency randomization procedures as defined in the study 
MOP should be followed. 
 
8. 
STUDY PROCEDURE 
 
8.1 
Baseline Assessments 
 
8.1.1 Point of Care Finger Stick Blood glucose level 
Accu-Chek Comfort Curve Test Strip System is a glucose dehydrogenase 
based system of quantitatively measuring the concentration of glucose in 
whole blood.  A minimum blood sample of 4μL is the required volume on 
the strip.  The reportable range of glucose concentration is 10 – 600 
mg/dL.  This is the SHINE study preferred test strip. Strips must be stored 
at < 90◦ F or 32◦ C.  Strips should be used at temperatures between 57◦ - 
104◦ F and less than 85% humidity.  Hematocrit must be between 20-55% 
for glucose measurements >200mg/dL.   Avoid using test strips during 
xylose absorption testing, in patients receiving maltose infusion, at 
altitudes above 10,150 feet, in situations of decreased peripheral blood 
flow to the fingers, galactose level >10 mg/dL, maltose >16 mg/dL, 
bilirubin 
(unconjugated) 
>20 
mg/dL, 
lipemia 
>5,000 
mg/dL, 
acetaminophen levels >8 mg/dL, uric acid >10 mg/dL.  
 
8.1.2 Concomitant medications documentation 
Concomitant medications will not be systematically collected on the case 
report form; however some relevant medications taken just before and 
during the treatment period will be captured in the study database.  
Additionally, medications that relate to glucose control will be captured 
from just prior to treatment through completion of the study period.   
  
8.1.3 Vital signs 
Routine vital signs per AHA guidelines for acute stroke patients will be 
followed. 

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8.1.4 NIHSS 
The NIHSS will be obtained prior to randomization (baseline) by an 
investigator who is NIHSS certified.  The NIHSS will be repeated at least 
once daily during the treatment period, and it is strongly recommended 
that this be completed by a certified investigator.  It is required that the 
Day 90 NIHSS is scored by an NIHSS certified investigator. 
 
8.1.5 Neuro Worsening Assessment 
Any clinically relevant neurological worsening will trigger a clinical 
assessment including an NIHSS score.  The SHINE study definition of 
neurological worsening will be considered any clinical change that is 
associated with a ≥4 point increase on the NIHSS score.   
 
8.1.6 Protocol Deviation Documentation 
Protocol deviations will be assessed throughout the study period and will 
be captured in WebDCUTM.  The details of identifying and reporting 
protocol deviations are described in the MOP. 
 
8.2 
Treatment Procedures 
 
8.2.1 Decision Support Tool set up 
Study laptops capable of internet connection will be supplied to all 
participating sites. All appropriate site personnel will be trained in the use 
of the tool.  The decision support tool and control accounts are housed and 
run on a central dedicated secure server and are not resident on the laptop. 
The laptop serves as a convenient portal to access the central system. The 
FDA cleared computerized decision support tool will simplify and 
streamline study procedures both for bedside nurses and local study teams, 
and thereby substantially minimize possibilities for protocol deviations. 
Details of the decision support tool can be found in the MOP. 
 
8.2.2 Blinding Set Up  
o The SHINE trial is single blinded to the subject throughout the study 
(the treating team will be unblinded to treatment) and then is double 
blinded to include the examiner for the 90 day efficacy outcome 
assessment.    
o Patients in both groups will receive an IV treatment (insulin or saline) 
and subcutaneous treatment (insulin or saline).    
 
8.2.3 Drug Dosage/ Drug Administration 
 
8.2.3.1 Control group protocol  
IV Saline with Subcutaneous Insulin Injections Target Blood 
Glucose <180 mg/dL 
 

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8.2.3.1.1 Subcutaneous Insulin Sliding Scale and IV Saline 
(Placebo) for SHINE Control Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.3.1.2 IV Saline Instructions (as per Table 4) 
Patients randomized to the control group will receive 
continuous IV saline.   
 
The IV saline will be adjusted using the glucose 
concentration from each finger stick check according to 
Table 4.  This will include glucose checks at least every 1 
hour for the first 4 hours and then every 3 hours for the 
remainder of the treatment protocol. 
 
A hypoglycemia protocol will be initiated for any patient 
whose glucose concentration drops below 80 mg/dL (see 
Section 8.2.3.3). 
 
The details of the IV saline protocol are provided in the 
MOP. 
 
8.2.3.1.3 
SQ 
Human 
Regular 
Insulin 
Sliding 
Scale 
Instructions (as per Table 4) 
Table 4. Subcutaneous Insulin Sliding Scale and IV Saline (Placebo) 
for SHINE Control Group 
 
Check finger stick glucose q 1 hr for the first 4 hours, then q 3 hrs (3:00, 6:00, 9:00, 12:00, 
15:00, 18:00, 21:00, and 24:00), but give SQ insulin if indicated only  4/day (6:00, 12:00, 
18:00, and 24:00) 
IV Saline 
 
SQ Human Regular Insulin (Humulin R or Novolin R) Sliding Scale 
 
 
ml/hr 
Glucose 
(mg/dL) 
Level 1 
Insulin dose 
(units) 
Level 2 
Insulin dose 
(units) 
Level 3 
One time SQ basal insulin 
and continue Level 2 
Insulin dose (units) 
5 
>450 
8 
16 
16 
400-450 
7 
14 
14 
351-399 
6 
12 
12 
300-350 
5 
10 
10 
251-299 
4 
8 
8 
200-250 
3 
6 
6 
180-199 
2 
4 
4 
4 
80-179 
0 
0 
0 
0 
<80 
See hypoglycemia protocol below (Section 8.2.3.3) 

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Patients randomized to the control group will receive 
subcutaneous insulin only up to four times a day as needed 
according the sliding scale in Table 4.   
 
The glucose concentration will be checked using finger 
stick testing at least every 1 hour for the first 4 hours and 
then every 3 hours for the remaining treatment period as 
per Table 4.  The subcutaneous insulin will only be given at 
6:00, 12:00, 18:00 and 24:00 as needed.   
 
All patients will start at Level 1 sliding scale dosing as 
shown in Table 4.  If glucose concentrations on that dosing 
schedule are not adequately controlled (<180 mg/dL), 
patients will begin Level 2 on the second day.  If they are 
still not adequately controlled at Level 2, they will advance 
to Level 3 on the third day.  Level 3 treatment will include 
basal insulin (glargine, Lantus) at a dose of 40% of 
previous day’s entire insulin dose and then continuation of 
the Level 2 sliding scale dosing as shown in Table 4. 
 
The details of the subcutaneous protocol are provided in the 
MOP. 
 
8.2.3.2 Intervention  group  
IV Insulin with Subcutaneous Meal Insulin or Saline Injections 
Target Glucose Concentration 80-130 mg/dL 
 
8.2.3.2.1 IV Insulin Instructions 
Patients randomized to the intervention group will receive 
continuous IV insulin.   
 
The decision support tool will require finger stick glucose 
checks at least every 1 hour for the first 4 hours and then 
approximately every 1 to 2 hours for the remainder of the 
treatment period. 
 
The dosing will be recommended by the decision support 
tool.  The required timing of the glucose check will also be 
indicated by the decision support tool.  The decision 
support tool uses information about the specific patient to 
make the recommendation of best dosing to keep the 
glucose concentration in target.   
 
A hypoglycemia protocol will be initiated for any patient 
whose glucose concentration drops below 80 mg/dL (see 
Section 8.2.3.3). 

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The details of the decision support tool and the insulin 
infusion dosing are provided in the MOP. 
 
8.2.3.2.2 SQ Insulin and Saline Instructions 
Subcutaneous injections will be given at meal time up to 
three times a day for patients who are eating.   
 
Patients who are not eating or are receiving continuous tube 
feeds will receive placebo saline subcutaneous injections 
2/day at 9:00 and 21:00 to simulate the 0-4 SQ insulin 
injections in the control group. 
 
The details of the subcutaneous insulin/saline dosing are 
provided in the MOP.   
 
8.2.3.3 Hypoglycemia Protocols for Control and Intervention  
 Groups 
 
Hypoglycemia protocol (Glucose concentration <80 mg/dL) 
All insulin therapy will be stopped in the event that glucose 
falls below 80 mg/dL and the following protocol will be 
initiated: 
 Stop all IV insulin and hold all subcutaneous insulin 
(stop all IV saline and saline subcutaneous 
injections as well). 
 Stat draw of a serum sample is to be sent to the 
laboratory for confirmation if glucose <70 mg/dL. 
 Glucose administration 
 Control Group – A dose of IV D50 25 ml 
(1/2 amp D50) will be given until blood 
glucose is ≥80 mg/dL. 
 Intervention Group – A dose of IV D50 will 
be given.  The specific dose will be 
determined by the decision support tool 
based on the glucose concentration.  
 Recheck blood glucose in 15 minutes, and repeat 
treatment every 15 minutes if needed until glucose 
is ≥80 mg/dL. 
 Once glucose is ≥80 mg/dL: 
 Restart IV insulin or saline per protocol 
 Restart SQ insulin or saline per protocol  
 
The details of the hypoglycemia protocol are provided in 
the MOP.   

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Severe Hypoglycemia (Glucose <40 mg/dL) 
All glucose measurements <40 mg/dL will be captured as 
severe hypoglycemia, and measurements <70 mg/dL will be 
captured as hypoglycemia. Each event will be characterized 
as symptomatic or asymptomatic based on symptoms and 
signs determined by the hypoglycemia assessment tool 
described in the MOP.  All spontaneous symptomatic 
complaints will trigger a stat glucose measure.   
 
Nonverbal patients will be assessed for only the physiologic 
signs of hypoglycemia. 
 
8.2.3.4 Suggested Care Post Study Treatment (based on ADA 
guidelines)53,54 
At the completion of study treatment, the hospital treating team 
(not the study team) will determine the best long-term glucose 
control therapy for each patient.  Investigators will be encouraged 
to follow the most recent ADA guidelines.   
 
8.2.4 Concomitant or Ancillary Therapy 
Throughout the study period, all AHA guidelines for acute stroke care8 
will be followed.  This includes standard care for acute ischemic stroke 
patients such as swallowing evaluation prior to initiation of PO intake, 
DVT prophylaxis and early secondary stroke prevention therapy.  Blood 
pressure and temperature recommendations also will be followed.   
Rehabilitation evaluation will be considered for every subject.   
 
8.3 
Clinical Guidelines 
As above, the AHA acute ischemic stroke guidelines for standard clinical care 
will be followed for all subjects.  
 
8.4 
Follow-up Procedure 
The goal of the study is to achieve complete, accurate follow-up for the three 
month study period.  Subjects will be contacted at 6 weeks by phone for reports of 
SAEs, to capture early follow up information and to make arrangements for the 3 
month study follow up visit during which time the primary clinical outcome 
(mRS) and secondary outcomes will be captured.  Any subject unable to return in 
person will undergo a 3 month study follow up visit by phone.   
 
8.5 
Notification of Death 
For each death, an AE form must be completed documenting the cause of death.  
An event that leads to death is always an SAE, although it may not be related or 
unexpected. The underlying cause of death will be required to be reported.  
Concurrent disease processes such as sepsis, pneumonia, etc. should be 
investigated.  Within 24 hours of the discovery of a treatment related death, the 

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site should submit the information into the AE case report form. This entry will 
trigger an automatic e-mail notification to the independent safety monitor.  A 
written report containing all relevant clinical information will be submitted to 
WebDCU™ within 5 calendar days of discovery of the death.  This information 
will be reported to the sites for submission to their IRBs and submitted to the 
DSMB.   
 
8.6 
Procedure for Unblinding 
Unblinding will not be necessary in the SHINE trial as the treating team will be 
unblinded to subject treatment.  The 6 week follow-up phone call and the 90 day 
outcome assessment will be performed by a blinded study investigator and a 
blinding/unblinding survey will be completed by the subject and the investigator 
at the completion of the 3 month visit. 
 
8.7 
Schedule of Events  
 
Table 5. Abbreviated Schedule of events in SHINE trial 
 
Event  
 
Screen* 
 
Baseline* 
Up to 3 
days of 
Rx 
Complete 
Rx/ 
D/C** 
 
6 wks 
 
90 days 
Informed Consent  
x 
 
 
 
 
 
Eligibility Assessment 
x 
 
 
 
 
 
Randomization  
 
x 
 
 
 
 
Study drug given  
 
x --- 
------► 
 
 
 
Finger stick glucose check 
x 
x --- 
------► 
 
 
 
mRS55, BI13 
 
 
 
 
x 
x 
NIHSS12 
 
x 
x (daily) 
x 
 
x 
SSQOL14 
 
 
 
 
 
x 
SAE/AEs*  
 
x --- 
------► 
-------► 
-----► 
x 
Protocol Deviations 
 
x --- 
------► 
------► 
------► 
x 
Neuro worsening  
 
x --- 
------► 
-------► 
 
 
Lacunar subtype 
 
 
 
x 
 
 
 
*Screening is during eligibility assessment; baseline is at time of randomization. AEs will be 
followed through the treatment period only. SAEs will be reported throughout the study. 
 
**Completion of 72 hr treatment period unless discharged prior to 72 hrs 
 
9. 
DISCONTINUATION OF PARTICIPATION 
 
9.1 
Subject Removal from Therapy 
As participation in the SHINE trial is voluntary, the subject or LAR may decline 
study therapy at any time. In addition, the treating physician may stop the study 
therapy if there is a safety concern. The subject will continue to be followed 
through the 90 Day visit unless informed consent is withdrawn.  
 

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9.2 
Subject Withdrawal 
The subject has the right to voluntarily withdraw from the study at any time for 
any reason without prejudice to his/her future medical care by the physician or at 
the institution.  
 
For the occasional subject who withdraws consent, the date and reason for 
consent withdrawal should be documented.  Subject data will be included in the 
analysis up to the date of the consent withdrawal.  
 
A distinction will be made between subjects who fail to complete all forms on 
schedule or who miss some follow up assessments and the withdrawal of consent.  
Missed or rescheduled visits will be documented, but the subject will continue to 
be followed in the future according to protocol requirements, and all follow-up 
data will be included in the analysis. 
 
9.3 
Procedure for Discontinuation 
The procedure to be followed at the time a subject/LAR withdraws consent from 
the trial: 
 
(1) 
Check for the development of adverse events. 
 
(2) 
Complete the End-of-Study form and include an explanation of why the 
subject is withdrawing. 
 
(3) 
Subject or LAR will be required to document in writing his or her desire to 
withdraw. 
 
9.4 
Subject Lost to Follow-Up 
In the event that all possible attempts to locate the subject have failed, a formal 
letter will be submitted to the Executive Committee (EC).  The letter must 
document all efforts made by the investigator to contact the subject.  When the 
EC is satisfied that all methods have been tried and have failed, the subject will be 
coded as lost to follow-up and the delinquency status will be removed.  
 
9.5 
Subject Transfers 
Whenever a subject's medical care transfers to another clinical setting, every 
attempt must be made to obtain continued follow-up data and information on self-
administered forms.  The study coordinator should be notified immediately when 
this occurs, so that appropriate arrangements can be made, wherever possible for 
the subject to continue to participate in the study. 
 
 
10. 
OUTCOMES DEFINTIONS 
 
10.1 
Primary 

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The primary outcome is the severity adjusted 90-day mRS. “Favorable” outcome 
is defined as mRS score of 0 in subjects with baseline NIHSS of 3-7, mRS of 0-1 
in subjects with baseline NIHSS of 8-14, and mRS of 0-2 in subjects with 
baseline NIHSS of 15-22.9, 10 All NETT and non-NETT investigators will be 
trained and certified in the same manner.    
 
10.2 
Secondary 
o NIHSS 
o Barthel Index (BI) 
o Stroke Specific Quality Of Life (SSQOL) scale 
 
Favorable outcomes for the NIHSS and BI are defined as: a score of 0-1 on the 
NIHSS and 95-100 on the BI. The SSQOL will be analyzed as a continuous 
outcome. 
 
11. 
DATA MANAGEMENT 
 
11.1 
Data Processing 
Data management will be handled by the NETT SDMC which is housed in the 
Data Coordination Unit (DCU) in the Division of Biostatistics and Epidemiology 
at the Medical University of South Carolina (MUSC). All study activities will be 
conducted in coordination with the study co-PIs, the hubs/spokes, and the NETT 
CCC and SDMC, and will use an electronic data acquisition method where all 
clinical data on enrolled subjects will be entered by the hub/spoke personnel in 
real time. The latest version of each CRF will be available as a PDF file on the 
study website for use as worksheets and source documents by study personnel.  
 
The study data will be managed (including data queries) by the SDMC using the 
WebDCU™ system. This user-friendly web-based database system, developed by 
the SDMC, will be used for regulatory document management, subject 
randomization, data entry, data validation, project progress monitoring, subject 
tracking, user customizable report generation and secure data transfer. 
 
11.2 
Data Security and Confidentiality 
During the course of the trial, user access to the files with subject identifiers, 
treatment assignment and files with study outcomes will be restricted to core staff 
with any exceptions to be approved by the Executive Committee.  
 
In addition to use of passwords and other security measures, all documents 
containing identifying information on individuals or physicians are considered 
confidential materials and will be safeguarded to the greatest possible extent.  No 
information, which identifies a specific person, hospital, or physician, will be 
released to, or discussed with anyone other than study staff members. 
 
Because the SDMC uses a web-based system, source documents and CRFs will 
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by unique study identification codes. All data will be stored in a manner that is 
HIPAA compliant, without the ability to track the information back to a specific 
subject except through a password protected system. All collected information 
about a subject will be stored by a unique identification code. All SDMC 
personnel are certified by the NIH Office of Human Subjects Research in the 
Protection of Human Research Subjects course. 
 
11.3 
Data Quality Assurance 
Upon entry of CRFs into the study database, quality control procedures will be 
applied at each stage of data handling in order to ensure compliance with GCP 
guidelines, integrity of the study data and document processing system reliability.  
 
All sites will be monitored by the CCC and monitors will review source 
documents and case report form information.  An quality assurance record audit 
will be implemented.  Audit findings will be used to identify and correct problems 
in data collection. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Sample Size and Power Estimation 
The primary outcome variable is the overall proportion of subjects experiencing a 
favorable outcome 90-days post randomization, where favorable is defined by the 
dichotomized mRS score as adjusted to the baseline NIHSS (stroke severity). Our 
preliminary data suggest a 25% rate of favorable outcome in the control group at 
90 days is reasonable. A clinically relevant absolute difference in success rates 
between the two interventions is chosen as 7% (see preliminary data) (success 
ratecontrol=25%; success rateinfusion=32%). If the IV insulin group does not have at 
least a 7% or higher success rate than the control group, then IV insulin within 12 
hours of symptom onset will not be considered a worthwhile therapy for 
hyperglycemic acute ischemic stroke subjects.    
 
Based on the above information and taking into consideration the planned interim 
analyses, the study is powered to assure 80% likelihood of identifying a 
difference in success rates greater than or equal to 7%. Sample size estimation is 
based on the comparison of independent proportions.  This estimation approach is 
conservative as the proposed regression analysis is generally more powerful than 
chi square test on individual outcomes. The maximum sample size required for 
randomization is 1314 subjects (657/treatment group). Although every attempt 
will be made to avoid drop outs and losses to follow up, the required sample size 
is inflated for a 3% non-adherence rate. The 3% rate is consistent with pilot data 
and the ALIAS study rates.  The estimated total of subjects required is a 
maximum of 1400.  The analysis plan does include a sample size re-estimation so 
this number could potentially change.   Details of the re-estimation are in the 
Statistical Analysis Plan (SAP).  
 
 

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12.2 
Statistical Analyses 
 
12.2.1 Interim Analysis 
Details of all planned statistical analyses including the interim analyses 
will be provided in the study SAP. In summary, four interim analyses for 
futility and overwhelming efficacy are planned.  These analyses will use 
the error-spending function method with stopping guidelines that are 
similar to the O'Brien and Fleming (OBF) type stopping boundaries. The 
proposed timelines can be altered based on the input from the DSMB. The 
SDMC will conduct these analyses and compile the reports for the DSMB. 
 
12.2.2 Interim Safety Analysis 
The safety monitor and DSMB will receive periodic safety reports of all 
adverse events and serious adverse events.  Statistical monitoring for 
safety will be limited to severe hypoglycemia (<40 mg/dL) during the 
treatment period and death rate within 90 days post randomization.  
Details on this monitoring plan are in the SAP.  
 
12.2.3 Primary Efficacy Analysis 
The primary outcome analysis of the 90-day mRS will use a stratified 
dichotomy methodology for assessing improvement as defined in the 
Primary Outcome section above. Outcome differences will be analyzed 
under the intention-to-treat principle, therefore all randomized subjects 
will be included in the primary analysis sample. To assess efficacy, the 
treatment groups will be compared with respect to the proportion with 
favorable outcome 90 days post randomization after controlling for the 
prognostic variables included in the randomization scheme.  A Wald chi-
square test will be performed to compare the treatment group proportions 
using a two-tailed significance level of 0.05.  Adjusted relative risks will 
be reported with two-sided 95% confidence intervals. 
 
Additional analyses will identify potential confounding (prognostic) 
variables to be used as covariates in subsequent secondary analyses of the 
primary outcome using generalized linear modeling techniques. Specific 
covariates include age, gender, race, ethnicity, admission blood glucose, 
previous stroke, time between stroke onset and treatment and lacunar 
subtype. If statistically significant differences are evident, post-hoc 
analyses will be conducted to determine if differences had an effect on the 
conclusions from the pre-specified primary analysis.   
 
12.2.4 Secondary Analyses 
This study is designed to test the primary hypothesis. However, it also 
offers the opportunity to conduct analyses to evaluate important additional 
neurological and functional outcomes using the NIHSS, BI and SSQOL. 
The secondary analyses will be conducted using the intention to treat 
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will include time to randomization from symptom onset and protocol 
conduct metrics between treatment arms: time to target, time in target, 
time to treatment and adherence to the decision support tool.     
 
12.2.5 Safety Outcome Analyses 
In addition to the continual monitoring of adverse events by the safety 
monitor and DSMB and the planned statistical monitoring for safety, final 
analyses of specified safety outcomes will be conducted as specified in the 
SAP.   
 
13. 
ADVERSE EVENTS 
 
13.1 
Adverse Events 
Adverse event reporting and procedures are described in detail in the MOP.  
 
Adverse events will be defined and severity graded according to the Common 
Terminology Criteria for Adverse Events, (CTCAE), found in the MOP. AEs will 
be submitted online through WebDCU™ and coded centrally using MedDRA. 
Guidelines for report content and structure will be provided in the MOP. All 
adverse events occurring during treatment and all serious adverse events 
occurring during the study will be recorded. The site PI or Study Coordinator is 
responsible for entering any and all AEs and SAEs into the database and updating 
the information (e.g., date of resolution, action taken) as needed.   
 
Study personnel will evaluate subjects while in the hospital and at each telephone 
communication and follow up for the presence of AEs (during treatment only) and 
SAEs.  
 
13.2 
Clinically Important Adverse Events 
The following adverse events should be handled as serious. 
 
o Neurological worsening lasting greater than 24 hours and associated with 
glucose concentration of <55 mg/dL. 
o Severe Hypoglycemia (glucose <40 mg/dL).   
 
13.3 
Adverse Event Exceptions 
Death due to the natural history of ischemic stroke will be recorded as a non-
related serious adverse event.  Additionally, all serious but known complications 
of stroke (i.e. malignant brain edema) will be recorded as non-related serious 
adverse events.     
 
13.4 
Obligation of Investigator 
At the time of enrollment, an assessment of ongoing medical conditions and/or 
signs or symptoms will be recorded.  Upon initiation of study protocol, all adverse 
events, whether or not attributed to the study intervention, observed by the 
Investigator or reported by the subject, will be recorded on the appropriate Case 

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Report Forms.  Attributes will include a description, date of onset and resolution, 
duration, severity, assessment of relatedness to the intervention, action taken, and 
outcome.  All adverse events must be followed to resolution or until the end of the 
study treatment period, whichever comes first.   
 
If the adverse event is sufficiently severe, the investigator is obligated to conduct 
a termination assessment, and if appropriate, should halt study treatment.  The 
subject should be provided with medical supervision and appropriate treatment 
until symptoms cease. 
 
13.5 
Reporting Procedures 
In order to assure prompt and complete reporting of adverse events or 
complications of intervention, the following general guidelines are to be observed. 
 
All adverse events, whether serious or not, will be collected through completion 
of study therapy. Adverse events will be captured by the treating team and the 
study team based on history, physical exam, medical records and laboratory 
findings. The independent safety monitor will review non serious AEs regularly. 
 
Serious adverse events (SAE) will be captured throughout the 3 month study 
period. All SAEs, including those that are judged to be related to study therapy, 
and especially severe hypoglycemia, will be data entered by the site personnel 
into the study database within timelines defined in the MOP. Upon data entry, the 
system will trigger an automatic e-mail notification to the independent Medical 
Safety Monitor (MSM) stating that an SAE has occurred. The MSM will access 
the information via the password protected web based system for review and 
report safety concerns to the DSMB. 
 
14. 
INVESTIGATIONAL DRUG DESCRIPTION 
 
The investigational drug is insulin which is FDA approved for the treatment of 
hyperglycemia.  Therefore, it will be labeled, stored, prepared and distributed through the 
hospital pharmacy as it otherwise would.  Blinding procedures (to maintain the subject 
blind) will take place and are described in detail in the MOP. 
 
15. 
REGULATORY AND ETHICAL OBLIGATIONS 
 
15.1 
Informed Consent 
In accordance with US FDA regulations (21 CFR 50) and guidelines (Federal 
Register, May 9, 1997, Vol. 62, Number 90 - ICH Good Clinical Practice 
Consolidated Guideline) it is the investigator’s responsibility to ensure that 
informed consent is obtained from the subject or subject’s LAR before 
participating in an investigational study, after an adequate explanation of the 
purpose, methods, risks, potential benefits and subject responsibilities of the 
study. Procedures that are to be performed as part of the practice of medicine and 
which would be done whether or not study entry was contemplated, such as for 

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diagnosis or treatment of a disease or medical condition, may be performed and 
the results subsequently used for determining study eligibility without first 
obtaining consent.  On the other hand, informed consent must be obtained prior to 
initiation of any screening procedures that are performed solely for the purpose of 
determining eligibility for research.  
 
Each subject/LAR must be given a copy of the informed consent.  The original 
signed consent must be retained in the institution’s records and is subject to 
review by the sponsor, DCU, the FDA or representative from another agency that 
performs the same function, and the IRB responsible for the conduct of the 
institution.  All elements listed in the International Conference on Harmonisation 
Good Clinical Practice guidelines must be included in the informed consent. 
 
Informed consent will be obtained by either the site Principal Investigator or by 
individuals approved by the site Principal Investigator and whose names have 
been submitted to the NETT Regulatory Database.  Informed consent will be 
obtained from the subject or subject’s LAR after the details of the protocol have 
been reviewed.  The individual responsible for obtaining consent will assure, prior 
to signing of the informed consent, that the subject has had all questions regarding 
therapy and the protocol answered. 
 
15.2 
Institutional Review Board (IRB) 
In accordance with US FDA regulations (21 CFR 56) and guidelines (Federal 
Register, May 9, 1997 Vol. 62 Number 90 - International Conference on 
Harmonisation Good Clinical Practice Consolidated Guideline) all research 
involving human subjects and changes to the research plan must be reviewed and 
approved by an IRB. 
 
15.2.1 Initial Review and Approval 
A copy of the protocol, proposed informed consent form, other written 
subject information, and any proposed advertising material must be 
submitted to the enrolling site’s IRB for written approval.  A copy of the 
IRB approval of the protocol and informed consent form must be 
submitted to the NETT Regulatory database and approved before 
recruitment of subjects into the study. 
 
15.2.2 Amendments 
Protocol amendments may only be made with the prior approval of 
Executive Committee.  The site Principal Investigator must agree to, and 
obtain approval from the IRB, for all protocol amendments and revisions 
to the informed consent document.  The site Principal Investigator should 
notify the IRB of serious adverse events occurring at the site and other 
adverse event reports recorded in the study database, in accordance with 
local procedures and Section 13.5 of this protocol.  Copies of all approvals 
and approved versions of the informed consent must be submitted to the 
central regulatory document database housed within WebDCU™. 

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15.2.3 Annual Renewal 
The site Principal Investigator will be responsible for obtaining annual 
IRB approval renewal throughout the duration of the study.  Copies of the 
site Principal Investigator’s reports and the IRB’s continuance of approval 
must be submitted electronically to the central regulatory document 
database. 
 
16. 
STUDY ORGANIZATION 
 
16.1 
Executive Committee 
In addition to the SHINE leadership, the Executive Committee (EC) has overall 
responsibility for assuring the scientific, clinical and ethical integrity of the study.  
The executive committee will include the NINDS Project Officer, administrative 
core leadership, the NETT CCC leadership and SDMC leadership.   
 
The details of the executive committee functions and membership are detailed in 
the MOP. 
 
16.2 
Data and Safety Monitoring Board 
The NINDS-appointed DSMB will plan to meet semi-annually with interim 
conference calls as needed, to review interim data relating to the trial.  The 
functions of the DSMB will include: 
 
(1) 
Review of all adverse effects or complications related to the trial 
interventions; 
 
(2) 
Review of interim data on the primary and secondary outcomes according 
to prespecified monitoring guidelines; 
 
(3) 
Monitor accrual; 
 
(4) 
Review summary reports relating to performance of centers relative to 
compliance with protocol requirements; 
 
(5) 
Recommend to the Executive Committee that: 
 
a) Trial continue as planned; 
 
b) Trial be modified with justification of modification as DSMB deems 
appropriate; 
 
c) Trial should be stopped with disclosure of basis for recommendation. 
 

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In general, clinical investigators will not be present at the Closed Sessions of the 
DSMB, but may on occasion be requested to present or provide information to 
assist the DSMB in carrying out its functions appropriately. 
 
16.3 
Ancillary Studies 
General information on proposals for SHINE ancillary studies and detailed 
procedures for approved and funded ancillary studies can be found in the MOP.  
Sites will not be required to participate in any ancillary study that requires 
additional data collection, but they will be encouraged to participate in accepted 
studies. 
 
16.3.1 Optional Insights on Selected Procoagulation Markers and 
Outcomes in Stroke Trial (I-SPOT) Ancillary Study 
 
Participants who consent to the SHINE trial may be asked to consent to an 
optional ancillary study. Subjects who consent to I-SPOT will provide blood 
samples at 2 time-points (baseline and 48 hours). Those patients who decline 
the ancillary study may still participate in the SHINE trial. 
 
The I-SPOT trial will recruit 315 SHINE patients. Blood coagulation marker 
levels will be measured before and at 48 hours after the start of treatment. 
Baseline and temporal changes in biomarkers levels will be compared between 
SHINE treatment groups.  Details of I-SPOT can be found in the ancillary trial 
protocol and laboratory manual.   

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