Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial

• modified Rankin Scale Score [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  a 3 month (post stroke) modified Rankin scale score is the primary efficacy outcome measure.
• Hypoglycemia [ Time Frame: 72 hours ] [ Designated as safety issue: Yes ]
  Severe hypoglycemia (blood glucose < 40mg/dL) is the primary safety outcome and will be measured during the 72 hour treatment period

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.

Eligible subjects must be within 12 hours of stroke symptom onset and have diabetes and glucose concentrations of over 110 mg/dL on initial evaluation. The enrolling sites will include the Neurological Emergencies Treatment Trials (NETT) sites as well as non NETT sites from all over the United States. The study will evaluate 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. The primary outcome will be functional outcome at 3 months as measured by the modified Rankin Scale (mRS) Score. The primary safety outcome will be severe hypoglycemia defined as <40 mg/dL. Enrollment will occur over 3.5 - 4 years.

• Acute Ischemic Stroke
• Diabetes
• Hyperglycemia

• Drug: IV insulin to maintain target glucose concentration of 80-130 mg/dL
  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.
• Drug: Standard Care control - sliding scale insulin to keep glucose less than 180 mg/dL
  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.

• Experimental: IV insulin drip with target glucose 80 mg/dL - 130 mg/dL
  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.
  Intervention: Drug: IV insulin to maintain target glucose concentration of 80-130 mg/dL
• Active Comparator: Sub Q insulin to keep glucose less than 180 mg/dL
  This standard care arm will get sub q insulin sliding scale to keep glucose concentration less than 180 mg/dL
  Intervention: Drug: Standard Care control - sliding scale insulin to keep glucose less than 180 mg/dL

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 blood 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.

Exclusion Criteria:

1. Known history of type 1 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 FDA cleared devices. Non FDA cleared devices are considered experimental and are excluded.
4. 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)

• Neurological Emergencies Treatment Trials Network (NETT)
• Medical University of South Carolina
• Medical Automation Systems, an Alere Company
• National Institute of Neurological Disorders and Stroke (NINDS)