Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial (SHINE)

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.

Study Overview

• Status: Completed
• Conditions: Hyperglycemia; Diabetes; Acute Ischemic Stroke
• Intervention / Treatment: Drug: IV insulin to maintain target glucose concentration of 80-130 mg/dL; Drug: Standard Care control - sliding scale insulin to keep glucose less than 180 mg/dL

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.

• Study Type: Interventional
• Enrollment (Actual): 1151
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
    • Tucson, Arizona, United States, 85713
      • University of Arizona Medical Center - South Campus
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Los Angeles, California, United States, 90095
      • Ronald Regan Medical Center
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
    • San Francisco, California, United States, 94114
      • California Pacific Medical Center - Davies Campus
    • San Francisco, California, United States, 94114
      • California Pacific Medical Center-Pacific Campus
    • San Francisco, California, United States, 94117
      • UCSF Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30322
      • Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital - Midtown
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University Of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai-Grace Hospital
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital-Royal Oak
    • Troy, Michigan, United States, 48085
      • William Beaumont Hospital-Troy
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center, Fairview
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • JFK Medical Center
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Bronx, New York, United States, 10451
      • Lincoln Medical and Mental Health Center
    • Brooklyn, New York, United States, 11203
      • Kings County Hospital
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate University Hospital of Brooklyn
    • Buffalo, New York, United States, 14210
      • Buffalo General Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • The Mount Sinai Medical Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
    • New York, New York, United States, 11219
      • Maimonides Medical Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Summa Akron City Hospital
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • Wexner Medical Center
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19102
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian
    • Pittsburgh, Pennsylvania, United States, 15219
      • UPMC - Mercy
    • York, Pennsylvania, United States, 17403
      • Wellspan York Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37205
      • St. Thomas Neuroscience Research Institute
  • Texas
    • Austin, Texas, United States, 78705
      • Seton Medical Center
    • Austin, Texas, United States, 78701
      • Dell Seton Medical Center at UT
    • Dallas, Texas, United States, 75390
      • UT Southwestern-Parkland Memorial Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern-Zale Lipshy University Hospital
    • Harlingen, Texas, United States, 78552
      • Valley Baptist Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Memorial Herman Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. Randomization must be within 12 hours after stroke symptom onset and treatment 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.; Other Names: Continuous intravenous insulin
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	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.; Other Names: Sliding scale insulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Favorable Modified Rankin Scale (Yes/No)	Favorable for the primary efficacy outcome is defined as modified Rankin Scale (mRS) score of 0 in patients with mild stroke (baseline NIHSS 3-7), mRS 0 or 1 in patients with moderate stroke (baseline NIHSS 8-14), and mRS 0, 1 or 2 in patients with severe stroke (baseline NIHSS 15-22) at 90 days with a pre-specified range of acceptable days of 76 -120 days. The mRS is a stroke outcome scale used to assess functional status after stroke. It consists of seven levels (0-6) where 0 indicates no residual symptoms at all, 5 indicates severe disability and 6 indicates death. The person collecting the mRS score was to be blinded to the participant's treatment group assignment.	90 days (-14/+30 days)
Number of Participants With Severe Hypoglycemia (Blood Glucose < 40mg/dL)	Severe hypoglycemia (blood glucose < 40mg/dL) is the primary safety outcome and will be measured during the 72 hour treatment period.	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Favorable NIHSS	The NIHSS (National Institutes of Health Stroke Scale) score ranges from 0 to 42, with higher scores indicating greater neurological deficits. A favorable NIHSS was defined as a score of 0 or 1 on the NIHSS at 90 days post randomization.	Follow up (Max 164 days)
Number of Participants With a Favorable Barthel Index	Favorable outcomes for the Barthel Index was defined as a score of 95-100 on the BI at 90 days post randomization. Barthel - Barthel Index for Activities of Daily Living (ADL) assesses functional independence, generally in stroke patients. Scores range from 0-100 with higher scores indicating greater ability to perform activities of daily living.	Follow up (Max 164 days)
Stroke Specific Quality of Life (SSQOL)	Stroke Specific Quality of Life. Scores range from 1-5 with higher scores indicating better quality of life	Follow up (Max 164 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death from any cause	90 days (+30 days)

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Medical University of South Carolina; National Institute of Neurological Disorders and Stroke (NINDS); Neurological Emergencies Treatment Trials Network (NETT)
• Investigators: Study Chair: Karen C Johnston, MD, MSc, University of Virginia; Principal Investigator: Christiana Hall, MD, MS, UT Southwestern; Principal Investigator: Askiel Bruno, MD, MS, Augusta University; Principal Investigator: Valerie Durkalski, PhD, Medical University of South Carolina; Principal Investigator: Kevin Barrett, MD, Mayo Clinic

Publications and helpful links

General Publications

• Johnston KC, Bruno A, Pauls Q, Hall CE, Barrett KM, Barsan W, Fansler A, Van de Bruinhorst K, Janis S, Durkalski-Mauldin VL; Neurological Emergencies Treatment Trials Network and the SHINE Trial Investigators. Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial. JAMA. 2019 Jul 23;322(4):326-335. doi: 10.1001/jama.2019.9346. Erratum In: JAMA. 2019 Nov 5;322(17):1718.
• Arteaga DF, Ulep R, Kumar KK, Southerland AM, Conaway MR, Faber J, Wintermark M, Joyner D, Sharashidze V, Hirsch K, Giurgiutiu DV, Hannawi Y, Aziz Y, Shutter L, Visweswaran A, Williams A, Williams K, Gunter S, Haughey HM, Bruno A, Johnston KC, Patel VN; SHINE Trial Investigators. Collateral status, hyperglycemia, and functional outcome after acute ischemic stroke. BMC Neurol. 2022 Nov 4;22(1):408. doi: 10.1186/s12883-022-02943-4.
• Connor JT, Broglio KR, Durkalski V, Meurer WJ, Johnston KC. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial: an adaptive trial design case study. Trials. 2015 Mar 4;16:72. doi: 10.1186/s13063-015-0574-8.
• Garofolo KM, Yeatts SD, Ramakrishnan V, Jauch EC, Johnston KC, Durkalski VL. The effect of covariate adjustment for baseline severity in acute stroke clinical trials with responder analysis outcomes. Trials. 2013 Apr 11;14:98. doi: 10.1186/1745-6215-14-98.
• Bruno A, Durkalski VL, Hall CE, Juneja R, Barsan WG, Janis S, Meurer WJ, Fansler A, Johnston KC; SHINE investigators. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke. Int J Stroke. 2014 Feb;9(2):246-51. doi: 10.1111/ijs.12045. Epub 2013 Mar 19.

Helpful Links

• General information of trial

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2012
• Primary Completion (ACTUAL): November 19, 2018
• Study Completion (ACTUAL): November 19, 2018

Study Registration Dates

• First Submitted: June 6, 2011
• First Submitted That Met QC Criteria: June 7, 2011
• First Posted (ESTIMATE): June 8, 2011

Study Record Updates

• Last Update Posted (ACTUAL): December 23, 2019
• Last Update Submitted That Met QC Criteria: December 13, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: diabetes; stroke; hyperglycemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hyperglycemia; Stroke; Ischemic Stroke; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: 15959; U01NS069498 (NIH)