Acute Ischemic Stroke, Diabetes, Hyperglycemia
Conditions
Keywords
stroke, diabetes, hyperglycemia
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.
Interventions
DRUGIV 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.
DRUGStandard 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.
Sponsors
Neurological Emergencies Treatment Trials Network (NETT)
Medical University of South Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Favorable Modified Rankin Scale (Yes/No) | 90 days (-14/+30 days) | 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. |
| Number of Participants With Severe Hypoglycemia (Blood Glucose < 40mg/dL) | 72 hours | Severe hypoglycemia (blood glucose \< 40mg/dL) is the primary safety outcome and will be measured during the 72 hour treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Favorable NIHSS | Follow up (Max 164 days) | 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. |
| Number of Participants With a Favorable Barthel Index | Follow up (Max 164 days) | 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. |
| Stroke Specific Quality of Life (SSQOL) | Follow up (Max 164 days) | Stroke Specific Quality of Life. Scores range from 1-5 with higher scores indicating better quality of life |
Other
| Measure | Time frame | Description |
|---|---|---|
| Death | 90 days (+30 days) | Death from any cause |
Countries
United States
Participant flow
Recruitment details
Between April 2012 and August 2018, a total of 70 United States sites were included in the trial, and 63 sites enrolled at least one patient.
Pre-assignment details
28977 patients were excluded after screening. Of those, 27344 did not meet eligibility criteria; 1156 were unable to provide informed consent or refused participation; 342 had other reasons and 135 did not specify a reason.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 581 |
| 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
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. | 570 |
| Total | 1,151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 8 | 9 |
| Overall Study | Withdrawal by Subject | 9 | 7 |
Baseline characteristics
| Characteristic | Total | Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL |
|---|---|---|---|
| Age, Continuous | 66 years | 66 years | 66 years |
| Baseline NIHSS at randomization | 7 NIHSS score range: 0 to 42 | 7 NIHSS score range: 0 to 42 | 7 NIHSS score range: 0 to 42 |
| Baseline NIHSS category at randomization Mild (NIHSS 3-7) | 582 Participants | 291 Participants | 291 Participants |
| Baseline NIHSS category at randomization Moderate (NIHSS 8-14) | 335 Participants | 158 Participants | 177 Participants |
| Baseline NIHSS category at randomization Severe (NIHSS 15-22) | 234 Participants | 121 Participants | 113 Participants |
| Eligibility POC blood glucose (mg/dL) | 187.5 mg/dL | 187 mg/dL | 188 mg/dL |
| Ethnicity (NIH/OMB) Hispanic or Latino | 178 Participants | 91 Participants | 87 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 909 Participants | 449 Participants | 460 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 64 Participants | 30 Participants | 34 Participants |
| Final diagnosis Ischemic stroke | 1066 Participants | 524 Participants | 542 Participants |
| Final diagnosis Other | 65 Participants | 34 Participants | 31 Participants |
| Final diagnosis Transient ischemic attack | 20 Participants | 12 Participants | 8 Participants |
| Medical History Atrial fibrillation | 230 Participants | 106 Participants | 124 Participants |
| Medical History Coronary artery disease | 326 Participants | 167 Participants | 159 Participants |
| Medical History Diabetes mellitus (Type 2) | 923 Participants | 455 Participants | 468 Participants |
| Medical History Hyperlipidemia | 677 Participants | 327 Participants | 350 Participants |
| Medical History Hypertension | 1015 Participants | 502 Participants | 513 Participants |
| Medical History Previous Ischemic stroke | 203 Participants | 99 Participants | 104 Participants |
| Medical History Previous large vessel atherosclerosis | 81 Participants | 39 Participants | 42 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 18 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 334 Participants | 154 Participants | 180 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 44 Participants | 23 Participants | 21 Participants |
| Race (NIH/OMB) White | 734 Participants | 368 Participants | 366 Participants |
| Sex: Female, Male Female | 524 Participants | 264 Participants | 260 Participants |
| Sex: Female, Male Male | 627 Participants | 306 Participants | 321 Participants |
| Thrombolysis or Thrombectomy Intraarterial drug therapy | 35 Participants | 21 Participants | 14 Participants |
| Thrombolysis or Thrombectomy Intravenous tPA | 725 Participants | 353 Participants | 372 Participants |
| Thrombolysis or Thrombectomy Mechanical treatment | 146 Participants | 72 Participants | 74 Participants |
| Thrombolysis or Thrombectomy None | 245 Participants | 124 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 54 / 581 | 65 / 570 |
| other Total, other adverse events | 384 / 581 | 134 / 570 |
| serious Total, serious adverse events | 209 / 581 | 198 / 570 |
Outcome results
Primary
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.
Time frame: 90 days (-14/+30 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Number of Participants With a Favorable Modified Rankin Scale (Yes/No) | 119 Participants |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Number of Participants With a Favorable Modified Rankin Scale (Yes/No) | 123 Participants |
Comparison: It was hypothesized that intensive blood glucose control would be efficacious and safe in acute ischemic stroke patients compared to standard glucose control.p-value: 0.5595% CI: [0.87, 1.08]Regression, Logistic
Primary
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.
Time frame: 72 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Number of Participants With Severe Hypoglycemia (Blood Glucose < 40mg/dL) | 15 Participants |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Number of Participants With Severe Hypoglycemia (Blood Glucose < 40mg/dL) | 0 Participants |
p-value: <0.00195% CI: [1.29, 3.87]Fisher Exact
Secondary
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.
Time frame: Follow up (Max 164 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Number of Participants With a Favorable Barthel Index | 271 Participants |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Number of Participants With a Favorable Barthel Index | 261 Participants |
p-value: 0.8895% CI: [-5.79, 6.75]Chi-squared
Secondary
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.
Time frame: Follow up (Max 164 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Number of Participants With a Favorable NIHSS | 152 Participants |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Number of Participants With a Favorable NIHSS | 166 Participants |
p-value: 0.7795% CI: [-8.33, 6.2]Chi-squared
Secondary
Stroke Specific Quality of Life (SSQOL)
Stroke Specific Quality of Life. Scores range from 1-5 with higher scores indicating better quality of life
Time frame: Follow up (Max 164 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Stroke Specific Quality of Life (SSQOL) | 3.75 score on a scale |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Stroke Specific Quality of Life (SSQOL) | 3.69 score on a scale |
p-value: 0.7495% CI: [-0.13, 0.25]Wilcoxon (Mann-Whitney)
Other Pre-specified
Death
Death from any cause
Time frame: 90 days (+30 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IV Insulin Drip With Target Glucose 80 mg/dL - 130 mg/dL | Death | 54 Participants |
| Sub Q Insulin to Keep Glucose Less Than 180 mg/dL | Death | 65 Participants |
p-value: 0.2495% CI: [0.58, 1.15]Chi-squared