stroke hyperglycemia insulin network effort (shine) trial nih-ninds u01 ns069498 an overview of...

Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial

NIH-NINDS U01 NS069498

An Overview of SHINE

Contents

• Background• Trial Overview• Treatment Groups• Outcomes• I-SPOT Ancillary Study

SHINE Background

• Most animal stroke studies show that hyperglycemia at stroke onset leads to worse outcomes than normoglycemia:– Larger strokes – More brain edema – Greater hemorrhagic stroke transformation

J Cereb Blood Flow Metab 1997:17:553; Free Rad Biol Med 1997:23:986;

Stroke 1989;20:646

SHINE Background

• Most observational human studies reported independent associations between hyperglycemia (on admission as well as after hospitalization) and:– Greater infarct growth on MRI– Hemorrhagic stroke transformation when tPA used– Worse functional outcomes

Nat Rev Neurol 2010;6:145Lancet Neurol 2012;11:261

SHINE BackgroundHyperglycemia Impairs Thrombolysis/Recanalization

Nat Rev Neurol 2010;6:145

Acute & chronic hyperglycemia associated with impaired thrombolysis by enhancing thrombosis while inhibiting fibrinolysis

Ischemia with Ischemia withNormoglycemia Hyperglycemia

SHINE BackgroundHyperglycemia Impairs Tissue Reperfusion

Nat Rev Neurol 2010;6:145

Greater endothelial dysfunction leads to greater vasoconstriction even with recanalization

Ischemia with Ischemia withNormoglycemia Hyperglycemia

SHINE BackgroundHyperglycemia Increases Ischemic Tissue Damage

Nat Rev Neurol 2010;6:145

Greater oxidative stress, greater inflammatory response, greater acidosis, greater BBB leakage

Ischemia with Ischemia withNormoglycemia Hyperglycemia

SHINE BackgroundFavorable Outcome (mRS ≤1) at 3 months

Decreases as blood glucose increases

P=0.02 for all subjects

Neurology 2002;59:669

SHINE BackgroundSymptomatic ICH within 36 hrs of rt-PA

Increases as blood glucose increases

Neurology 2002;59:669

SHINE Background

• Greater tissue lactic acidosis• Increased local exitotoxic amino acids• Impaired recovery of elevated intracellular Ca2+

• Impaired cerebral vasoreactivity• Increased local free radicals• Increased blood-brain barrier leakage

Lancet Neurol 2012;11:261

Why might hyperglycemia during acute stroke be detrimental? Uncertain

SHINE Background

• Uncertainty whether the observed clinical associations are cause or effect or associated without causation– Is it the hyperglycemia makes strokes worse leading to worse

clinical outcomes or is it that more severe strokes and diabetes lead to worse clinical outcomes?

• Uncertainty when hyperglycemia is harmful:– during acute stroke with or without reperfusion?– with lacunar and non-lacunar strokes?

SHINE BackgroundEquipoise

• Will acute correction of hyperglycemia improve functional outcomes?

• Will patients without DM benefit from acute hyperglycemia correction?

• What is the treatment time window?• Is there a blood glucose threshold for favorable

outcome?• Will patients with lacunar strokes have better

outcomes with higher glucose?

SHINE Background1st Efficacy Trial: Glucose Insulin in Stroke Trial –

United Kingdom (GIST-UK)

• Stroke onset <24 hrs• 83% patients without DM• Relatively low blood glucose levels at baseline (~150

mg/dL)• Blood glucose in target range soon after treatment

started in both groups• Little separation of blood glucose levels between the 2

treatment groups (~10 mg/dL)• Trial stopped after only 40% of target enrolled; N=933• Primary outcome: death at 90 days

Lancet Neurol 2007;6:397

SHINE Background 1st Efficacy Trial: GIST-UK

Lancet Neurol 2007;6:397

SHINE Background 1st Efficacy Trial: GIST-UK

NSNS

Lancet Neurol 2007;6:397

SHINE BackgroundKey observations from 2 pilot NINDS clinical trials

• Hyperglycemia during acute stroke can be lowered in <6 hrs into target range with IV insulin protocols

• In patients without DM, hyperglycemia usually resolves rapidly without insulin treatment

• Hypoglycemia <60 mg/dL occurs in up to 40% of patients, but is usually asymptomatic

• Hypoglycemia occurs less frequently with computerized decision support tools

• Phase III trial warranted

Stroke 2008;39:384-9, Stroke 2009;40:3804-9

SHINE TrialNIH-NINDS U01 5NS069498

• Multicenter (~60 sites), randomized, controlled trial• Phase III (definitive efficacy trial)• Predominantly hyperglycemic acute ischemic stroke

patients• Comparison of standard SQ insulin vs IV insulin infusion• Funded by NIH-NINDS• Conducted in conjunction with NIH-NINDS funded

Neurological Emergencies Treatment Trials Network (NETT) and NIH-NINDS StrokeNet

In J Stroke 2014;9:246-51

SHINE TrialSpecific Aims

1. To determine the efficacy of tight glucose control to a range of 80-130 mg/dL with IV insulin infusion in hyperglycemic acute ischemic stroke patients w/in 12 hours of symptom onset as measured by mRS at 90 days.

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 as measured by rate of severe hypoglycemia (<40 mg/dL) in intervention group compared to the control group <4%.

SHINE TrialDesign Innovations

• Stratified randomization by IV tPA, stroke severity & site• Response-Adaptive Randomization – ↑ chance of

randomization to whichever group is doing better• Primary outcome: 90 day mRS – sliding dichotomy

• Total enrollment ~ 1400 subjects w/sample size re-estimation

• Futility and efficacy stopping boundaries• FDA cleared IV insulin decision support tool

Baseline NIHSS Favorable mRS outcome

3-7 08-14 0, 1

15-22 0, 1, 2

SHINE TrialDecision Support Tool - GlucoStabilizer®

• Designed at Indiana University/Clarian Health• Licensed by Medical Decision Network• FDA cleared and commercially available – used in

>65,000 patients• Considers individual patient response to insulin• Severe hypoglycemia rate (<40 mg/dL) - 1.67% of

patients and 0.07% of all glucose checks• Adherence to the recommendations – 99% – 91-98% in literature for decision support tools– 97% in GRASP

Crit Care Med 2008;36:1787-95, Stroke 2009;40:3804-9

SHINE TrialStatistical Power Estimations

• Favorable outcome rate in control group = 25% - based on pilot trials and relevant literature

• Favorable outcome in intervention group = 32% - judged to be the minimum clinically significant benefit (7% absolute difference)

• Estimated lost to follow-up = 3%• For an 80% power and a 2-sided type I error rate of

0.05 N=1400 (700/group)• Sample size re-estimation planned

SHINE Trial Eligibility – Inclusion Criteria

• Age ≥ 18 years• Diagnosis of acute ischemic stroke - neuroimaging

must exclude ICH• Type II DM & glucose >110 mg/dL OR no diabetes &

glucose ≥150 mg/dL • Baseline NIHSS 3-22 • Pre-stroke mRS of 0 if NIHSS 3-7; Pre-stroke mRS of

0-1 if NIHSS 8-22• Randomization w/in 12 hrs of stroke symptom onset• Valid informed consent

SHINE Trial Eligibility - Exclusion Criteria

• Type I DM • Condition confounding baseline neurological exam• Neurological or psychiatric illness likely to confound

primary outcome assessment at 90 days• Any experimental therapy for enrollment stroke – standard care IV tPA within 4.5 hrs, IA tPA & IA therapies w/

FDA cleared devices allowed. Non FDA cleared devices excluded

• Inability to follow the protocol or return for 90 day f/u• Serious conditions with unlikely 90 day survival• Pregnancy or breast-feeding• Any renal dialysis

SHINE TrialPre-stroke mRS Tips

SHINE Trial Baseline NIHSS & SHINE Eligibility

• NIHSS must be 3-22 and assessed ≤30 minutes prior to randomization

• Prior stroke deficits must not confound the acute stroke deficits

• Intubated patients are “untestable” for dysarthria and could be enrolled only if the NIHSS was scored before intubation and ≤30 minutes prior to randomization

SHINE Trial Qualifying Blood Glucose & SHINE Eligibility

• Must be done at the enrolling hospital• Must be a finger stick (capillary) blood • Consider rechecking if close to qualifying level and

time remains within the 12 hr window

SHINE TrialBlinding Strategy

• During acute treatment, single blind for patients/family

• All subjects receive study IV infusions and study SQ injections – some contain insulin & some contain saline placebo – only the clinical team members know which solutions contain insulin

• The primary & secondary outcomes are assessed by a blinded investigator resulting in a double blind outcome assessment

SHINE TrialTreatment Overview

• ~1400 hyperglycemic acute ischemic stroke patients• Single blind acute treatment; double blind final

outcome assessment

• 12 hr window from stroke symptom onset • Treatment Groups– Insulin drip 80-130 mg/dL – SQ insulin 80-179 mg/dL

• Up to 72 hrs treatment• Primary outcome - 90 day mRS - based on baseline

stroke severity strata

SHINE Treatment Groups General Concepts

• Two groups: both glucose control, both get insulin• All patients get IV drip & SQ injections (up to 4/day)• Frequent glucose checks to avoid hypoglycemia• All patients get 60 gram/meal carbohydrate diet• All patients must be in unit that supports IV insulin• Hypoglycemia prevention & management protocol

(Hold IV infusions & SQ injections for BG<80, give D50, check BG q15 min)

• 72 hr treatment period (early d/c OK)• Daily neuro & AE assessments• All sites provided with 1-2 study laptops

SHINE TrialControl Group

• Target glucose: 80-179 mg/dL• Glucose checks: q1-q3 hrs (+/- 15 min)• IV infusion: normal saline (placebo) – 4-5 cc/hr • SQ injections: human regular insulin per sliding scale,

given only @ 6:00, 12:00, 18:00, & 24:00• Escalating doses of insulin per sliding scale if not in

target, including a one-time dose of basal insulin @ 48 hrs in level 3

• Laptop displays SQ insulin sliding scale dosing and hypoglycemia protocol

SHINE Trial Static Control Treatment Screen

SHINE TrialControl Group Possible Level Advances

SHINE TrialIntervention Group

• Target glucose: 80-130 mg/dL• Glucose checks: q1-2 hrs (+/- 15 min) per

GlucoStabilizer®• IV infusion: human regular insulin – rate directed by

GlucoStabilizer® program based on glucose levels• SQ injections: – Normal saline (placebo) 0.05 cc @ 9:00 & 21:00 if NPO or on

continuous tube feeds OR– Rapid acting analog insulin after meals

SHINE TrialOutcomes

• Primary efficacy: baseline stroke severity adjusted 90 day mRS (sliding dichotomy)

• Secondary efficacy:– 90 day NIHSS– 90 day Barthel Index– 90 day SSQOL (Stroke Specific Quality of Life)

• Primary safety: severe hypoglycemia (BG<40mg/dL)

SHINE TrialCenters and Leadership

• Karen C. Johnston, MD, MSc (UVA) – Administrative PI• Askiel Bruno, MD, MS (GRU) – Protocol PI• Christiana Hall, MD, MS (UTSW) – Recruitment PI• William Barsan, MD (Univ of Michigan) NETT Clinical

Coordinating Center PI• Valerie Durkalski, PhD (MUSC) NETT Statistics and Data

Management Center PI

• Clinical enrolling sites: – NETT network – 22 hub/spoke complexes– StrokeNet sites to be included– 11 ancillary sites

SHINE TrialCenters

SHINE RecruitmentApril 2012 – July 2014

Age (mean yrs) 65Men (%) 56Race (%): White African American Asian Other

682723

Ethnicity (%): Non-Hispanic Hispanic Unspecified

84142

Symptom onset to randomized (median) 6 hrs 19 min

SHINE TrialData as of 6/3/2014 (N=381)

Baseline NIHSS (median)NIHSS strata (%) 3-7 8-14 15-22

8

483022

Qualifying POC glucose (mg/dL) 188

Pre-stroke diagnosed diabetes mellitus (%) 77

Lacunar stroke subtype (%) 23

IV tPA treated (%) 60

All IA treated (%) 11

SHINE TrialData as of 6/3/2014 (N=381)

SHINE TrialData as of 6/3/2014 (N=381)

Day 1 Day 2 Day 30

20

40

60

ICU Step-down Ward

Perc

ent

Hypoglycemia events: Subjects with any hypoglycemia (<70 mg/dL)(%) Subjects with any severe hypoglycemia (<40 mg/dL)(%) Subjects with neurological worsening for >24 hrs with

glucose ≤55 mg/dL (%) Subjects with seizure related to glucose <70 mg/dL (%)

302.10

0Mortality (%) 8.9

SHINE TrialData as of 6/3/2014 (N=381)

I-SPOT & SHINEInsights on Selected Procoagulation Markers and

Outcomes in Stroke Trial - 1U01 NS079077• I-SPOT seeks to determine if intense BG control

compared with standard BG treatment results in reductions in markers of blood coagulation

• Determine the relationships between blood glucose, markers of blood coagulation and thrombosis, and SHINE clinical outcomes

• Markers:– Whole blood Tissue Factor - PCA– Coagulation factors VII, VIIa, and VIII– Plasma TAT, Fragmin 1.2, D-dimer; – Tissue factor pathway inhibitor– Plasminogen activator inhibitor-1

I-SPOT & SHINEInsights on Selected Procoagulation Markers and

Outcomes in Stroke Trial – 1U01 NS079077• I-SPOT is a multi-center study nested within the

SHINE trial• A subset of 315 patients enrolled in the SHINE trial

will be enrolled in the I-SPOT study • Baseline & 48-hr blood samples collected, spun,

frozen, & batch sent to the main lab at Temple University

I-SPOT & SHINEInsights on Selected Procoagulation Markers and

Outcomes in Stroke Trial – 1U01 NS079077 Inclusion: • Must also be enrolled in the SHINE trialExclusions:• Thrombolytic treatments, e.g. IV or IA tPA• Full anticoagulation, e.g. heparin, warfarin, etc.• Moderate-severe hepatic insufficiency (INR>1.5, if

known, or history of variceal bleeding, or hepatic encephalopathy)

• History of thrombotic or hypercoagulable condition: e.g. antiphospholipid antibody syndrome, antithrombin III, Protein C or S deficiencies, congenital/Inherited factor deficiencies, sickle cell disease.

I-SPOT & SHINEInsights on Selected Procoagulation Markers and

Outcomes in Stroke Trial – 1U01 NS079077

• Allowed interventions– SQ DVT prophylactic anticoagulation doses– Standard antiplatelet treatments