Clinical trial NCT01369069
Conditions: Acute Ischemic Stroke Diabetes Hyperglycemia
Keywords: stroke diabetes hyperglycemia
Sponsor: University of Virginia
Start date: 2012-04-01; Completion date: 2018-11-19
Enrollment: 1151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial is a multicenter, randomized, controlled clinical trial of 1400 patients that will include approximately 60 enrolling sites. The study hypotheses are that treatment of hyperglycemic acute ischemic stroke patients with targeted glucose concentration (80mg/dL - 130 mg/dL) will be safe and result in improved 3 month outcome after stroke.

Detailed description:
Eligible subjects must be randomized within 12 hours of stroke symptom onset and either have type 2 diabetes and glucose concentrations of over 110 mg/dL or no history of diabetes and glucose concentrations of 150 mg/dL or higher on initial evaluation. The enrolling sites include the Neurological Emergencies Treatment Trials (NETT) sites as well as non NETT sites from all over the United States. The study evaluates the safety and efficacy of targeted glucose control (treatment group - IV insulin with target 80-130 mg/dl) verses control therapy of sub q insulin plus basal insulin with target glucose less than 180 mg/ dL.

Arms: arm 1: The intervention arm will have a targeted glucose concentration of 80-130 mg/dL. IV insulin drip will be titrated to keep glucose concentration in this range. arm 2: This standard care arm will get sub q insulin sliding scale to keep glucose concentration less than 180 mg/dL
Interventions: intervention 1: IV insulin to maintain target glucose concentration of 80-130 mg/dL intervention 2: Standard Care control - sliding scale insulin to keep glucose less than 180 mg/dL
Intervention descriptions: intervention 1: Intervention is to keep glucose concentration 80-130 mg/dL for up to 72 hours after randomization. IV insulin drip will be used to maintain glucose target. intervention 2: Sliding scale sub q insulin given will be given up to 4 times per day based on glucose concentration. It will be given only if glucose concentration greater than or equal to 180 mg/dL.

Protocol documents:
Prot_000.pdf: 
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 
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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 
(up to 4.5 hrs) or IA tPA are allowed as are IA therapies including use of 


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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 
evaluation and management of acute stroke patients will be trained to recognize 


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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 
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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 
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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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21. Kreisel SH, Berschin UM, Hammes HP, Leweling H, Bertsch T, Hennerici MG, 
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167-75.  
22. Moulin T, Tatu L, Crepin-Leblond T, Chavot D, Berges S, Rumbach T. The besancon 
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23. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent 
predictor of poor outcome after acute stroke? results of a long-term follow up study. 
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24. Bruno A, Biller J, P. AH,Jr, Clarke WR, Woolson RF, Williams LS, Hansen MD. 
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25. Demchuk AM, Tanne D, Hill MD, Kasner SE, Hanson S, Grond M, Levine SR. 
Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology. 
2001 Aug 14; 57(3): 474-80.  
26. Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick 
JP, Kwiatkowski TG, Fineberg SE. Admission glucose level and clinical outcomes in the 
NINDS rt-PA stroke trial. Neurology. 2002 Sep 10; 59(5): 669-74.  
27. Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission 
hyperglycemia predicts a worse outcome in stroke patients treated with intravenous 
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28. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the 
ECASS-II trial. Stroke. 2008 Oct; 39(10): 2749-55.  
29. Fuentes B, Castillo J, San Jose B, Leira R, Serena J, Vivancos J, Davalos A, Nunez 
AG, Egido J, Diez-Tejedor E. The prognostic value of capillary glucose levels in acute 
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30. Dziedzic T, Slowik A, Pera J, Szczudlik A. Association between hyperglycemia, 
heart failure and mortality in stroke patients. Eur J Neurol. 2009 Feb; 16(2): 251-6.  
31. Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, Tress BM, 
Davis SM. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance 
imaging and spectroscopy study. Ann Neurol. 2002 Jul; 52(1): 20-8.  
32. Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking 
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33. Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, Colman PG, 
Chambers BR, Davis SM. Persistent poststroke hyperglycemia is independently 
associated with infarct expansion and worse clinical outcome. Stroke. 2003 Sep; 34(9): 
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34. Ribo M, Molina CA, Delgado P, Rubiera M, Delgado-Mederos R, Rovira A, 
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35. Wong AA, Schluter PJ, Henderson RD, O'Sullivan JD, Read SJ. Natural history of 
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ischemic stroke: A mechanistic justification for a trial of insulin infusion therapy. Stroke. 
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37. Becker KJ. Targeting the central nervous system inflammatory response in ischemic 
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38. Gentile NT, Siren K. Glycemic control and the injured brain. Emerg Med Clin North 
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39. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral 
ischaemia: From experimental strategies to clinical use. Lancet Neurol. 2009 Apr; 8(4): 
398-412.  
40. Prass K, Dirnagl U. Glutamate antagonists in therapy of stroke. Restor Neurol 
Neurosci. 1998; 13(1-2): 3-10.  
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STAIR V meeting on acute stroke trials, technology and outcomes. Stroke. 2007 Feb; 
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42. Saver JL. Novel end point analytic techniques and interpreting shifts across the entire 
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Hirshberg E, Morris AH.  Multicenter validation of a computer based clinical decision 
support tool for glucose control in adult and pedicatric intensive care units.  J Diabetes 
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Tuomilehto J. Disorders of glucose metabolism in acute stroke patients: An 
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604-7.  
 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
 
 
 
 
Stroke Hyperglycemia Insulin Network Effort: 
The SHINE Trial 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Prepared by 
Valerie Durkalski, Ph.D., MPH 
SHINE Unblinded Statistician 
and 
Mark Conaway, PhD 
SHINE Blinded Statistician 
 
NETT Statistical and Data Management Center 
Data Coordination Unit 
Department of Public Health Sciences 
Medical University of South Carolina 
Charleston, SC 29425 
 
Version 2.0 
January 8, 2015


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SHINE Trial Statistical Analysis Plan 
Version 2.0 
 
TABLE OF CONTENTS 
 
 
1. 
STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS ........................... 1 
2. 
SYNOPSIS OF THE STUDY ................................................................................... 1 
3. 
OUTCOME VARIABLES .......................................................................................... 1 
3.1 
Primary Efficacy Outcome ............................................................................................ 1 
3.2 
Secondary Efficacy Outcomes .................................................................................... 2 
3.3 
Primary Safety Outcome .............................................................................................. 2 
4. 
SAMPLE SIZE DETERMINATION FOR THE PRIMARY EFFICACY OBJECTIVE . 2 
5. 
DEFINITION OF TARGET POPULATION AND STUDY SAMPLES ........................ 3 
5.1 
Target Population .......................................................................................................... 4 
5.2 
Intent-to-Treat Sample .................................................................................................. 4 
5.3 
Safety Analysis Sample ................................................................................................ 4 
5.4 
Per Protocol Sample ..................................................................................................... 4 
6. 
RANDOMIZATION ................................................................................................... 4 
7. 
BLINDING ................................................................................................................ 5 
8. 
MISSING DATA ....................................................................................................... 5 
9. 
CLINICAL SITE EFFECTS ....................................................................................... 6 
10. EFFICACY ANALYSIS ............................................................................................. 6 
10.1 
Primary Outcome Variable Analysis ....................................................................... 6 
10.1.1 
Statistical Hypothesis............................................................................................. 6 
10.1.2 
Primary Efficacy Analysis at the End of the Trial .............................................. 6 
10.1.3 
Interim Analysis Plan ............................................................................................. 7 
10.2 
Secondary Outcome Variable Analysis .................................................................. 9 
10.3 
Exploratory Analyses ................................................................................................. 9 
11. SAFETY ANALYSES ............................................................................................. 10 
11.1 
Safety Monitoring ..................................................................................................... 10 
11.2 
Analysis of Safety Outcomes ................................................................................. 11 
12. REFERENCES ...................................................................................................... 12 
13. APPENDIX A ......................................................................................................... 13 


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1. STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS 
 
This document provides the details of statistical analyses planned for the SHINE Trial, including 
interim analyses for efficacy and futility.  In addition, it discusses the statistical issues relevant to 
these analyses (e.g., sample data to be used, missing data). 
 
The Statistical and Data Management Center (SDMC) generates two statistical reports – an 
open report to be distributed to the SHINE Trial Executive Committee and the Data and Safety 
Monitoring Board (DSMB), and a closed report to be distributed only to the DSMB.  The timing 
of these reports is determined in consultation with the DSMB.  Reports will be sent from the 
NETT SDMC to the NINDS Liaison two weeks in advance of the scheduled meeting. 
 
Each report provides cumulative summary statistics on enrollment; subject status in the study; 
baseline characteristics; protocol violations; safety data, including AEs and SAEs, severity, 
expectedness (anticipated/unanticipated) and relatedness to the study treatment; and data 
management/quality information (e.g., timeliness and completeness of data entry by the Clinical 
Sites via the SHINE Trial Website; number of DCRs generated and resolved).  The statistics are 
provided for the overall study as well as by clinical center when applicable in the open report.  
For the closed report only, the statistics are also provided by treatment group (A vs B).  If a 
report coincides in timing with a planned interim analysis, the analysis results are appended to 
the report. 
 
2. SYNOPSIS OF THE STUDY 
 
This multicenter, randomized, controlled clinical trial of approximately 1400 patients will be 
conducted at approximately 56 enrolling sites. Enrollment is anticipated to occur over 3.5 years. 
Patients will be randomly assigned to IV insulin therapy with target glucose 80-130 mg/dL or 
sliding scale SQ insulin (control therapy) with target glucose less than 180 mg/dL for up to 72 
hours. Therapy must be initiated within 3 hours of arrival at the enrolling center and within 12 
hours of stroke onset. The primary efficacy outcome will be the dichotomized mRS score at 90 
days post randomization adjusted for the baseline severity of stroke (responder analysis). The 
primary safety outcome will be severe hypoglycemia (<40 mg/dL). Additional safety outcomes 
will include overall hypoglycemia (blood glucose <55 mg/dL), symptoms and signs associated 
with hypoglycemia, and death. Secondary outcomes include functional outcomes at 90 days, a 
6 hr vs 12 hr enrollment analysis, measures of glucose control success and adherence to the 
computerized glucose monitoring system.  
 
3. OUTCOME VARIABLES 
 
3.1 
Primary Efficacy Outcome 
The primary efficacy outcome is the severity adjusted 90-day mRS. Favorable outcome 
is defined using a responder analysis method.1,2 This method is proposed for the SHINE 
trial to provide a more sensitive measure of clinical effect. The responder analysis 
dichotomizes mRS scores as “favorable” versus “not favorable” based on the baseline 
NIHSS measured at randomization. “Favorable” outcome is defined as an mRS score of 
0 in patients with baseline NIHSS of 3-7, mRS of 0-1 in patients with baseline NIHSS of 
8-14, and mRS of 0-2 in patients with baseline NIHSS of 15-22. These cutpoints, based 
on categorizing the study population by severity of stroke, were modeled after the 
cutpoints used in the reanalysis of the NINDS tPA stroke trials data and the ABEST-II 
trial. 3,4  
 


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3.2 
Secondary Efficacy Outcomes 
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 NIH Stroke Scale (NIHSS), Barthel Index (BI) and Stroke 
Severity Quality of Life (SSQOL).  
 
3.3 
Primary Safety Outcome 
The primary safety outcome is the proportion of subjects experiencing at least one 
severe hypoglycemia event (<40 mg/dL) during treatment. 
 
4. SAMPLE SIZE DETERMINATION FOR THE PRIMARY EFFICACY OBJECTIVE 
 
4.1 
Sample Size 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% 
(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 patients.    
 
Based on the above information and taking into consideration four planned interim analyses 
(see Section 10.1.4 for details), 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 adjusting for baseline NIHSS. 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 total number of patients required for 
randomization is 1400. 
 
4.2 
Sample Size Re-estimation Plan 
 
We recognize that sample size estimation is based on assumptions and if the control 
success rate is higher than 25% then we may begin to see a decrease in power. For 
example, if the control rate is as high as 30%, the power drops from approximately 80% to 
77% to detect a 7% absolute difference if one truly exists. To reduce the likelihood of an 
underpowered study due to an incorrect overall event rate assumption, we propose to 
conduct a sample size re-estimation prior to the 1st interim efficacy/futility analysis (i.e., once 
500 consecutively randomized subjects complete the 90-day mRS). The overall success 
rate of the population will be estimated using the interim data for the sole purpose of sample 
size re-estimation (not for interim testing of a treatment effect).  Combining sample size re-
estimation with the proposed group sequential design (GSD) will improve two aspects of the 
design – misspecification of the overall event rate (N-reestimation) and misspecification of 
the treatment effect (GSD) – while preserving the overall type I error rate. In addition, the 
GSD will help protect from unnecessarily continuing the trial even if the re-estimation 
suggests a larger overall sample size. 
 


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Following the approach of Gould and Shih5, sample size adjustment will be based on the 
observed overall event rate assuming a 7% absolute difference between treatment arms 
(the value specified under the alternative hypothesis).  If the observed overall event rate is 
greater than the assumed, then we may require additional observations.  The below table 
provides various hypothetical scenarios of the observed event rate and the required 
additional observations to maintain 80% power. 
 
 
Observed 
Overall Event 
Rate 
Estimated 
 Control Rate 
(assuming 7% 
difference) 
Power if No N-
Adjustment 
 
Additional 
Total N 
 Required to 
Maintain 
 Power at Final 
Analysis 
N for 1st 
interim 
analysis 
Delay of 1st 
interim look 
(months)* 
0.265 
0.23 
82% 
- 
500 
0 
0.285 
0.25 
81% 
- 
500 
0 
0.305 
0.27 
79% 
58 
522 
<1 
0.325 
0.29 
78% 
108 
540 
1-2 
0.345 
0.31 
77% 
154 
554 
1-2 
0.365 
0.33 
76% 
194 
570 
2-3 
0.385 
0.35 
75% 
228 
582 
2-3 
*assuming accrual rate of 33.3 patients per month 
 
If the sample size needs to be inflated, then we will preserve the information times for carrying 
out the interim analyses by deferring planned analyses until we have additional observations for 
each look (Strategy A of Gould and Shih). The fifth column of the above table specifies the 
sample size for the 1st look depending on the observed event rate detected at the sample size 
re-estimation.  An alternative approach would be to conduct the 1st interim look as planned (at 
n1=500) and defer the additional observations to the future looks.  If we proceed in this manner, 
the statistical boundaries require updating to correspond with new information times.  Since the 
delay of the interim analysis is no more than 3 months for any of the above scenarios, we 
choose to maintain the current information times.         
 
Because the trial’s power is not substantially impacted if the overall observed rate is 0.26-0.30, 
it is suggested that the recommendation to increase the original sample size only be considered 
if the observed rate is 0.31 or higher.  Ultimately it is the DSMB’s decision to recommend an 
increase in the total sample size and this decision should take into account the above proposed 
planned as well as the safety profile.  Administratively, prior to the 1st interim analysis the 
unblinded statistician will estimate the overall observed event rate and notify the DSMB 
members if the re-estimation indicates the need to increase the total sample size by 150 or 
more subjects.  This notification will include a brief report of the estimate as well as the safety 
data (adverse event information by treatment arm) and data quality (protocol deviations by 
treatment arm).  If the DSMB recommends an increase in the sample size, then the 1st interim 
analysis will be delayed until the appropriate numbers of subjects are enrolled and have the 
primary outcome data.  If the DSMB does not recommend an increase, then the unblinded 
statistician will proceed with the planned interim analysis. 
 
 
 
5. DEFINITION OF TARGET POPULATION AND STUDY SAMPLES 
 


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5.1 
Target Population 
 
The target population for the SHINE trial is patients 18 years of age and older who have a 
clinical diagnosis of ischemic stroke and a known history of type 2 diabetes mellitus and 
glucose >110 mg/dL or admission blood glucose ≥150 mg/dL in those without known 
diabetes mellitus.    
 
5.2 
Intent-to-Treat Sample  
 
As the primary analysis, all efficacy and safety outcome measures will be analyzed under 
the intent-to-treat principle (ITT). Under this principle, the evaluable sample includes all 
subjects who are randomized. Each subject will be analyzed according to the treatment 
group to which they were randomly assigned at the time of randomization. 
 
5.3 
Safety Analysis Sample 
 
All randomized subjects are included in the safety analysis sample. 
 
5.4 
Per Protocol Sample 
 
In addition to the defined ITT analysis sample, a per protocol sample is defined as a subset 
of the ITT sample.  This sample will be used for secondary sensitivity analyses of the 
primary and secondary outcomes.  The per protocol will include all randomized subjects that 
do not have the following protocol deviations: 
 
• 
Eligibility violation 
• 
Treatment never started 
• 
Missing 90-day primary outcome (not including missing due to death prior to the 90 
days) 
• 
Stroke mimics defined as any diagnosis other than ischemic stroke or TIA  
 
 
6. RANDOMIZATION 
 
A web-based central randomization system will be developed by the SDMC and installed on the 
WebDCU™ SHINE study website using a combination of covariate balance and response-
adaptive randomization (RAR) method.6 The randomization design is aimed to preserve the 
randomness of treatment assignment, prevent serious imbalance in important baseline 
prognostic variables and promote subject recruitment while preserving the statistical test power. 
In summary, the probability of treatment assignment under the proposed scheme will be based 
on the prevention of serious imbalance in the pre-specified prognostic variables and the 
favorable outcome rate of each treatment arm. The specific prognostic variables at the time of 
randomization are: baseline NIHSS strata (3-7; 8-14; 15-22); use of IV thrombolysis (Y/N); and, 
site. Favorable outcome will be based on the baseline severity adjusted dichotomized mRS as 
previously described.  
 
The SHINE Randomization algorithm will be fully detailed and documented in the SHINE 
Randomization Plan and Validation Documents.  These documents will be developed prior to 
the enrollment initiation and stored in a secure location at the SDMC. The documents will be 
archived with the study database at the end of the trial. In summary, the trial will start with a 1:1 


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allocation scheme focusing on covariate balance. The RAR will be implemented once an 
adequate amount of primary outcome information is collected. With RAR, each enrolling subject 
will have a higher probability (greater than 50% chance) of being assigned to the treatment arm 
with the higher success rate based on previous subjects’ responses. The SDMC’s computer 
system will run both the 1:1 allocation and the RAR. Participating sites and members of the 
study team will not notice any difference between the randomization schemes and sites will only 
need to press one randomization button on the computer screen to obtain the assigned 
treatment during the course of the study. To ensure proper randomization, the unblinded 
statistical programmer will have access to the randomization information in order to oversee the 
quality control of the computer program.  
 
7. BLINDING  
 
The study is conducted in a single blind manner with double blind outcome assessment. The 
site treatment team will be unblind to treatment assignment however the study subject and 90-
day outcome assessor are both blind to the treatment assignment. Treatment allocation is 
concealed and subjects will not be told of their actual treatment until the trial completion unless 
emergency unblinding is required. 
 
The SDMCs unblinded staff will produce two identical sealed envelopes that contain 
identification of treatment codes.  Prior to initiation of the Trial, one envelope of (2) is given to 
the NINDS Liaison to the DSMB. Another is maintained in a locked file cabinet at the SDMC in 
its limited access central file room. 
 
The DSMB is partially unblinded for the closed reports (data reported by A and B only).  
However, if it so wishes, it may be completely unblinded at any time during the Trial.  If the 
DSMB wishes to be unblinded on a particular subject only, the NINDS Liaison to the DSMB 
should email the request to the unblinded SDMC biostatistician. 
 
 
8. MISSING DATA 
 
Under the ITT principle, all subjects who are randomized are included in the analysis. Although 
every attempt will be made to prevent incomplete data, a certain amount of missing data is 
inevitable due to losses to follow up or withdrawn consents.  The investigators also need to 
consider primary outcome data that is collected late (i.e., past the pre-specified data entry 
timelines of +/-14 days).  Based on discussions with the SHINE Executive Committee and 
clinical expertise, primary outcome data (i.e., 90-day mRS) collected past the data entry 
timelines will only be used for the primary analysis if the collection falls within -14 days/+30 days 
from the scheduled date.  Data collected outside the 30-day window (only allowed up to 180 
days to collect data) will be considered missing for the primary outcome.  
 
A thorough analysis of variables, reasons and patterns of missing data will be conducted. Based 
on other large acute stroke trials that capture 90-day mRS, we anticipate no more than a 3% 
lost to follow up rate.  At the time of each planned analysis (interim and final), the unblinded 
statistician will report the amount of missing primary outcome data.  Multiple imputation using 
SAS PROC MI and MIANALYZE will be used to impute the missing 90-day mRS outcome data.  
In summary, 5 imputed data sets will be generated using PROC MI. The imputation model will 
include the primary analysis variables (90-day mRS, treatment, baseline NIHSS, thrombolysis 
use) plus age, gender and 6-week mRS. Each imputed data set will be analyzed according to 
the specified primary analysis (Section 10.1.2) and MIANALYZE will be used to combine the 


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results from the multiple imputed data sets to obtain a single set of parameter estimates.  The 
multiple imputation method assumes missing at random (MAR) which means that the probability 
of missing outcome data can depend on the observed values of the individual but not on the 
missing values of the individual.  Although we anticipate minimal missing data, sensitivity 
analyses will be conducted to assess the impact of any bias due to missing data.  The primary 
analysis will be re-run using the following methods: 
 
• 
Complete case analysis (only those with 90-day outcome) 
• 
Worst case analysis (assume any subject with missing 90 day outcome to be 
considered a ‘failure’)  
• 
Inclusion of primary outcome data collected outside the defined window 
 
If the treatment effect is robust, we expect these sensitivity analyses to yield similar inferences, 
particularly if the missing data are minimal (~3%). Any discrepancies between the sensitivity 
analyses and the primary analysis results will be investigated to understand the reason for the 
discrepancy. 
 
 
9. CLINICAL SITE EFFECTS  
 
Several procedures have been incorporated into the study design (i.e., procedure manual, 
training and certification programs, protocol violation monitoring, blinding) to reduce center 
effects; however, these effects should not be ignored for this trial. The distribution of center 
demographics will be examined. Means, standard deviations, proportions and 95% confidence 
intervals will be presented. Center and center*treatment interaction terms will be included in a 
secondary analysis of the primary outcome as a random effect. 
  
10. EFFICACY ANALYSIS 
 
10.1 
Primary Outcome Variable Analysis 
 
10.1.1 Statistical Hypothesis 
 
The set of statistical hypotheses is: 
 
H0: b coefficienttreatment = 0 
 versus  
HA: b coefficienttreatment ≠ 0 
 
where b coefficienttreatment is the regression coefficient for the variable ‘treatment’ .  
 
10.1.2 Primary Efficacy Analysis at the End of the Trial 
 
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 variables 
included in the randomization scheme.  The primary statistical analysis will develop a 
generalized linear model using the PROC GENMOD procedure in SAS® v9 with 
treatment group as the factor of interest and baseline NIHSS strata (3-7, 8-14, 15-22) 
and thrombolysis use (Yes/No; includes both IV and IA therapies) as covariates. A Wald 


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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. Specific covariates include age, gender, race, ethnicity, admission 
blood glucose, previous stroke, lacunar subtype, and time between stroke onset and 
treatment. If statistically significant differences are evident, then post-hoc analyses will 
be conducted to determine if differences had an effect on the conclusions from the pre-
specified primary analysis. 
 
10.1.3 Interim Analysis Plan 
 
The study is designed using four interim looks for both efficacy and futility of the primary 
outcome and one final look for a total of 5 planned analyses of the primary outcome. The 
interim analysis plan uses the error spending function method with O'Brien and Fleming 
(OBF) type stopping guidelines7-9. The error spending function distributes the type I and 
II error rates across the interim monitoring points giving the flexibility of changing the 
intervals of monitoring while still preserving the overall type I and II error rates. The OBF-
type boundary is considered conservative as its boundaries make it difficult to terminate 
a study early on by requiring extreme early evidence of efficacy or futility. It spends 
smaller amounts of alpha at the first look and gradually increases the spending as more 
information is acquired.  The trial may be stopped for overwhelming efficacy of one 
treatment group over the other or for futility at the planned interim analyses if the test 
statistic crosses the respective boundaries.   
 
The current plan is to conduct the first interim analysis after approximately 500 
randomized subjects complete the primary outcome assessment (90-day mRS). 
Assuming an accrual rate of 33.3 patients per month, it is anticipated that the 1st look will 
occur roughly 2.5yrs from the start of enrollment. Subsequent analyses will occur after 
every additional 200 subjects complete the 90-day mRS (i.e., 700, 900, and 1100). The 
interval may be altered if requested by the DSMB. The stopping boundaries are defined 
using the gamma family spending functions with a gamma value of -4 (closely resembles 
OBF boundaries)10. Specific to the futility boundaries, they are derived as non-binding 
meaning that if a futility boundary is crossed there is the ability for it to be overruled 
without inflation of the type 1 error rate.  If the crossing of an efficacy boundary is 
overruled, then this decision can impact the type II error rate but not the type I error rate.  
EAST® 5 software (Cytel Corporation) was used for the boundary calculations.  
 
The below graph depicts the stopping boundaries based on the test statistic at each 
planned look. The inner wedge represents rejection of the alternative (futility) and the 
outer boundaries represent rejection of the null (overwhelming efficacy). The boundaries 
have the property that under the null hypothesis of no difference the overall probability of 
crossing either outer boundary does not exceed the overall type I error rate and under 
the alternative hypothesis the overall probability of crossing the inner boundary does not 
exceed the type II error rate.  Appendix A provides further details on the properties of the 
stopping boundaries. 
 
 
 
 


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The following table lists the test statistics (shown in the above graph) and the 
corresponding p value as well as the probability of crossing either of the boundaries 
(futility or efficacy) at a particular look. Using the 5th column as an example, under the 
null hypothesis of no difference, the probability of crossing the specified boundary for 
either efficacy or futility is 0.05 at the 1st look, 0.10 for the 2nd look and so forth. Overall 
the probability of stopping the study (for futility) by the 4th look is 0.75 under the null and 
0.66 under the alternative (stopping for efficacy). 
 
Analysis 
Approximate 
Sample Size 
Minimum Test 
Statistic 
Z value (p value) 
to reject Ho 
Minimum Test 
Statistic 
Z value (p value)  
to reject Ha 
Boundary Crossing 
 Probabilities 
Under H0 
Boundary Crossing 
 Probabilities 
Under H1 
1 
500 
2.97 (0.003) 
0.06 (0.949) 
0.05  
0.12 
2 
700 
2.86 (0.004) 
0.13 (0.896) 
0.10  
0.13 
3 
900 
2.65 (0.008) 
0.45 (0.652) 
0.27 
0.19 
4 
1100 
2.42 (0.016) 
1.05 (0.293) 
0.33 
0.22 
Final 
1400 
2.02 (0.043) 
2.02 (0.043) 
0.25 
0.34 
   
 
 
The SDMC will be responsible for conducting these analyses and compiling the reports 
for the DSMB. Since several factors need to be taken into consideration before stopping 
a study, safety and study progress also will be taken into consideration by the DSMB 


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and Executive Committee in the decision to stop the study if an efficacy or futility 
boundary is crossed.   
 
 
10.2 
Secondary Outcome Variable Analysis 
 
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. All secondary analyses will be 
conducted using the intention to treat study population. Favorable outcomes for the 
NIHSS and BI are defined as: a score of 0 or 1 on the NIHSS and a score of 95-100 on 
the BI at 90 days post randomization. Because there are only three secondary efficacy 
outcomes, adjustment for multiplicity will not be made. Each of these dichotomous 
outcomes will be analyzed using a chi-square test at a significance level of 0.05. With a 
study sample size of 1400, we have 80% power to detect absolute differences in 
favorable outcome for the: NIHSS of 7% (assuming control group is 25%) and BI of 8% 
(assuming control group is 40%). The SSQOL 90-day score will be analyzed as a 
continuous outcome.  Mean scores overall and for each domain will be compared 
between the two treatment arms, adjusting the alpha level for multiple testing. 
Secondary analyses of all secondary outcomes will adjust for the specific covariates that 
are listed above in the primary analysis section as well as additional covariates identified 
at the time of analysis.  
 
In addition to the above clinical outcomes, we also will examine/compare blood glucose 
measurements over time as well as protocol conduct metrics between treatment arms: 
time to target, time in target, early/late time to treatment and adherence to the 
computerized glucose monitoring system. 
 
Secondary Outcome 
Definition 
Descriptive Statistics 
Time to Target 
(Randomization Time  – Time 
Target is met (hrs)); target 
met defined as BG of 70-180 
in the control arm and BG of 
70-130 in the treatment arm. 
Two-sided 95% confidential 
intervals; means,  Comparison 
of means between treatment 
arms. 
Time in Target 
Blood Glucose Measurements 
During Treatment 
Proportion of measurements 
out of target; area under the 
curve; box plots over time 
(every 4hrs) by treatment arm 
and by primary outcome.  
Time to Treatment 
Randomization Time - Stroke 
Onset Time (hrs) 
Comparison 
of 
means 
between treatment arms. 
Time on Treatment 
Randomization 
Time 
– 
Infusion stop time (Form 15) 
Comparison 
of 
means 
between treatment arms. 
  
 
10.3 
Exploratory Analyses 
 
A sensitivity analysis of the primary outcome will be conducted using the per protocol 
population (as defined in Section 5.4). In addition, a sensitivity analysis of including TIAs in 
the stroke mimic definition will be conducted for the per protocol analysis.  If discrepancies 
between the results exist, reasons for the differences will be explored. At the end of the 


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study, study investigators may wish to explore other relationships between the treatment 
and outcomes and/or covariates. Because the number of subgroup analyses could be large, 
all subgroup analyses will be conducted using a two-tailed significance level of 0.01.  The 
Publication Committee of the SHINE Trial will review proof of concept papers with analysis 
plan submitted by any investigators wishing to do so before any further analyses are 
conducted by the study statisticians. 
 
 
11. SAFETY ANALYSES 
 
11.1 
Safety Monitoring 
 
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 subjects 
experiencing a severe hypoglycemia event (<40 mg/dL) during the treatment period and 
death rate within 90 days post randomization. It is anticipated that the respective event rates 
in the control arm will be 0% for severe hypoglycemia and 14% for death. For severe 
hypoglycemia, the absolute difference in event rates between the two treatment arms will be 
monitored using two-sided 95% confidence intervals. Stopping the trial due to harm will be 
considered if at any time the lower limit of the severe hypoglycemia interval exceeds 4%. 
For death rate, an unadjusted relative risk will be estimated. Stopping the trial due to harm 
will be considered if at any time the 95% confidence interval excludes 1.  These point 
estimates will be provided in each DSMB Closed Report.  The table below provides different 
scenarios of when the boundary for safety may be crossed. 
 
Severe Hypoglycemia Events 
N per group 
Total Subjects 
with Event in 
Control Arm (%) 
Total Subjects 
with Event in Exp 
Arm (%) 
Risk Difference 
(∆) 
Lower Limit of 
95% CI for ∆ 
50 
0 (0) 
7 (14) 
14 
4.4 
50 
1 (2) 
9 (18) 
16 
4.7 
100 
0 (0) 
10 (10) 
10 
4.1 
100 
2 (2) 
14 (14) 
12 
4.7 
200 
0 (0) 
16 (8) 
8 
4.2 
200 
4 (2) 
22 (11) 
9 
4.2 
500 
0 (0) 
31 (6.2) 
6.2 
4.1 
500 
10 (2) 
45 (9) 
7 
4.2 
700 
0 (0) 
41 (6) 
6 
4.1 
700 
14 (2) 
59 (8.4) 
6.4 
4.1 
 
 
Death Events 
N per group 
Total Subjects 
with Event in 
Control Arm (%) 
Total Subjects 
with Event in Exp 
Arm (%) 
Unadjusted 
Relative Risk 
Lower Limit of 
95% CI for RR 
50 
5 (10) 
14 (28) 
2.8 
1.09 
50 
7 (14) 
17 (34) 
2.4 
1.10 
100 
10 (10) 
22 (22) 
2.2 
1.10 
100 
14 (14) 
27 (27) 
1.9 
1.08 
200 
20 (10) 
35 (17.5) 
1.8 
1.05 


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200 
28 (14) 
45 (22.5) 
1.6 
1.05 
500 
50 (10) 
74 (15) 
1.5 
1.06 
500 
70 (14) 
98 (20) 
1.4 
1.06 
700 
70 (10) 
99 (14) 
1.4 
1.06 
700 
98 (14) 
132 (19) 
1.4 
1.06 
 
 
11.2 
Analysis of Safety Outcomes 
 
All adverse events and serious adverse events will be summarized by AE code in terms of 
frequency of the event, number of subjects having the event, severity, expectedness 
(anticipated/unanticipated) and relatedness to the study treatment.  Clinically important 
adverse events including neurological worsening lasting greater than 24hours and 
associated with glucose concentration of < 55mg/dL and severe hypoglycemia (glucose <40 
mg/dL) will be summarized.  The proportion of subjects experiencing each of these events 
will be provided by treatment arm with two-sided 95% confidence intervals and unadjusted 
relative risks will be provided.   
 
In addition to the continual monitoring of adverse events by the safety monitor and DSMB 
and the planned statistical monitoring for safety (described above), final analyses of 
specified safety outcomes will be conducted. The proportion of subjects experiencing severe 
hypoglycemia during the treatment period will be compared between the two treatment arms 
using Fisher’s exact test.  For the 90-day death outcome, the log-rank test will be used to 
compare survival curves between the two treatment arms. Providing the assumption of 
proportional hazards is valid, a Cox proportional hazards model will be used to analyze time 
to death within 90 days from randomization adjusting for use of thrombolysis treatment, 
baseline NIHSS score and age.  All tests for safety will use a two-tailed significance level of 
0.05. 
 
 
 


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12. REFERENCES 
 
1. Adams HP, Jr., Leclerc JR, Bluhmki E, Clarke W, Hansen MD, Hacke W. Measuring 
outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis 
2004;18:124-9.  
2. Saver JL. Novel End Point Analytic Techniques and Interpreting Shifts Across the Entire 
Range of Outcome Scales n Acute Stroke Trials. Stroke 2007; 38 3055-3062. 
3. Adams JP, Jr. Effron MB, Torner J et al Emergency Administration of Abciximab for 
Treatment of Patients with Acute Ischemic Stroke: Results of an International Phase III 
Trial. Stroke 2008; 39: 87-99. 
4. Saver JL, Yafeh B. Confirmation of tPA treatment effect by baseline severity-adjusted 
end point reanalysis of the NINDS-tPA stroke trials. Stroke 2007;38:414-6. 
5. Gould AL and Shih WJ. Modifying the Design of Ongoing Trials Without Unblinding. Stat 
Med 1998; 17: 89-100.   
6. Hu Rosenberger WF. The theory of response adaptive randomization in clinical trials. 
New York: Wiley; 2006. 
7. Lan, K. and D. DeMets, Design and analysis of group sequential tests based on type-I 
error spending rate function. Biometrika 1983;74:149-54. 
8. O'Brien, P.C. and T.R. Fleming, A multiple testing procedure for clinical trials. 
Biometrics, 1979; 35(3): p. 549-56. 
9. Pampallona, Tsiatis and Kim. Interim monitoring of group sequential trials using 
spending functions for the type I and II error probabilities. Drug Information Journal 
2001; 35:1113-1121. 
10. Hwang, Shih, DeCani. Group sequential designs using a family of type I error probability 
spending functions. Stat Med 1990; 9: 1439-1445. 


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13. APPENDIX A 
 
The below graphs are based on simulation studies under various effect sizes (10,000 trials per 
effect size with a sample size of 1000 for each trial). The graphs illustrate the percentage of 
trials stopped at each interim look broken down by rejection of the alternative (futility) in red and 
rejection of the null (efficacy) in blue.  For example, graph 1 shows the percentage of trials 
stopped when the effect size is the assumed alternative of 0.07.  Blue represents stopping for 
overwhelming efficacy.  Approximately 12% of the trials stop at the 1st look which coincides with 
our conservative stopping boundaries.  Roughly 11% stop for overwhelming efficacy and ~1% 
stop for futility.  Cumulative, we can see that ~66% of the trials stop prior to the final look. 
Overall, our rejection rate of the null is 81% and our rejection of the alternative (claiming futility) 
is 18.8% (which is our type II error for scenario 1).    
 
Graph 4 illustrates the rejection rates under the null hypothesis of no effect. About 4% of the 
trials stop at the 1st look and 75% stop prior to the final look. Overall our rejection of the null is 
4.8% (type I error under scenario 4). The other two scenarios illustrate the rejection rates when 
the effect size is somewhere between the null and alternative – 60% of the time we will stop 
early if the effect size is 0.03 and ~50% when the effect size is 0.05.