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Considering hyperglycemia and thrombolysis in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.

ABSTRACT: Hyperglycemia is associated with enhanced cortical toxicity and larger infarct volumes following focal cerebral ischemia. Initial blood glucose in acute ischemic stroke patients may also contribute to a differential response to thrombolysis (i.e., administration of tissue plasminogen activator (t-PA)) and affect risk of symptomatic intracerebral hemorrhage (sICH). The Stroke Hyperglycemia Insulin Network Effort (SHINE) study is a phase III single-blinded, randomized control trial comparing an intensive level of glucose control with standard of care glucose control in hyperglycemic stroke patients. In stratifying randomization by treatment with intravenous t-PA, the SHINE trial offers a unique opportunity to evaluate an association between euglycemic control and outcomes from stroke thrombolysis in a prospective, comparative study. We hypothesize that normalization of blood glucose in the acute stroke setting may reduce risk of thrombolysis-induced sICH. With enrollment recently underway, the stratified results from the SHINE trial could substantially influence future treatment decisions for hyperglycemic stroke patients.

SUBMITTER: Southerland AM

PROVIDER: S-EPMC3457651 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Considering hyperglycemia and thrombolysis in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.

Southerland Andrew M AM Johnston Karen C KC

Annals of the New York Academy of Sciences 20120901

Hyperglycemia is associated with enhanced cortical toxicity and larger infarct volumes following focal cerebral ischemia. Initial blood glucose in acute ischemic stroke patients may also contribute to a differential response to thrombolysis (i.e., administration of tissue plasminogen activator (t-PA)) and affect risk of symptomatic intracerebral hemorrhage (sICH). The Stroke Hyperglycemia Insulin Network Effort (SHINE) study is a phase III single-blinded, randomized control trial comparing an in ...[more]

PMID: 22994224

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Project description:BackgroundThe 'Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT)' project is a collaborative effort supported by the National Institutes of Health (NIH) and United States Food & Drug Administration (FDA) to explore how adaptive clinical trial design might improve the evaluation of drugs and medical devices. ADAPT-IT uses the National Institute of Neurologic Disorders & Stroke-supported Neurological Emergencies Treatment Trials (NETT) network as a 'laboratory' in which to study the development of adaptive clinical trial designs in the confirmatory setting. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial was selected for funding by the NIH-NINDS at the start of ADAPT-IT and is currently an ongoing phase III trial of tight glucose control in hyperglycemic acute ischemic stroke patients. Within ADAPT-IT, a Bayesian adaptive Goldilocks trial design alternative was developed.MethodsThe SHINE design includes response adaptive randomization, a sample size re-estimation, and monitoring for early efficacy and futility according to a group sequential design. The Goldilocks design includes more frequent monitoring for predicted success or futility and a longitudinal model of the primary endpoint. Both trial designs were simulated and compared in terms of their mean sample size and power across a range of treatment effects and success rates for the control group.ResultsAs simulated, the SHINE design tends to have slightly higher power and the Goldilocks design has a lower mean sample size. Both designs were tuned to have approximately 80% power to detect a difference of 25% versus 32% between control and treatment, respectively. In this scenario, mean sample sizes are 1,114 and 979 for the SHINE and Goldilocks designs, respectively.ConclusionsTwo designs were brought forward, and both were evaluated, revised, and improved based on the input of all parties involved in the ADAPT-IT process. However, the SHINE investigators were tasked with choosing only a single design to implement and ultimately elected not to implement the Goldilocks design. The Goldilocks design will be retrospectively executed upon completion of SHINE to later compare the designs based on their use of patient resources, time, and conclusions in a real world setting.Trial registrationClinicalTrials.gov NCT01369069 June 2011.

Project description:Importance:Hyperglycemia during acute ischemic stroke is common and is associated with worse outcomes. The efficacy of intensive treatment of hyperglycemia in this setting remains unknown. Objectives:To determine the efficacy of intensive treatment of hyperglycemia during acute ischemic stroke. Design, Setting, and Participants:The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with hyperglycemia (glucose concentration of >110 mg/dL if had diabetes or ?150 mg/dL if did not have diabetes) and acute ischemic stroke who were enrolled within 12 hours from stroke onset at 63 US sites between April 2012 and August 2018; follow-up ended in November 2018. The trial included 1151 patients who met eligibility criteria. Interventions:Patients were randomized to receive continuous intravenous insulin using a computerized decision support tool (target blood glucose concentration of 80-130 mg/dL [4.4-7.2 mmol/L]; intensive treatment group: n?=?581) or insulin on a sliding scale that was administered subcutaneously (target blood glucose concentration of 80-179 mg/dL [4.4-9.9 mmol/L]; standard treatment group: n?=?570) for up to 72 hours. Main Outcomes and Measures:The primary efficacy outcome was the proportion of patients with a favorable outcome based on the 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) that was adjusted for baseline stroke severity. Results:Among 1151 patients who were randomized (mean age, 66 years [SD, 13.1 years]; 529 [46%] women, 920 [80%] with diabetes), 1118 (97%) completed the trial. Enrollment was stopped for futility based on prespecified interim analysis criteria. During treatment, the mean blood glucose level was 118 mg/dL (6.6 mmol/L) in the intensive treatment group and 179 mg/dL (9.9 mmol/L) in the standard treatment group. A favorable outcome occurred in 119 of 581 patients (20.5%) in the intensive treatment group and in 123 of 570 patients (21.6%) in the standard treatment group (adjusted relative risk, 0.97 [95% CI, 0.87 to 1.08], P?=?.55; unadjusted risk difference, -0.83% [95% CI, -5.72% to 4.06%]). Treatment was stopped early for hypoglycemia or other adverse events in 65 of 581 patients (11.2%) in the intensive treatment group and in 18 of 570 patients (3.2%) in the standard treatment group. Severe hypoglycemia occurred only among patients in the intensive treatment group (15/581 [2.6%]; risk difference, 2.58% [95% CI, 1.29% to 3.87%]). Conclusions and Relevance:Among patients with acute ischemic stroke and hyperglycemia, treatment with intensive vs standard glucose control for up to 72 hours did not result in a significant difference in favorable functional outcome at 90 days. These findings do not support using intensive glucose control in this setting. Trial Registration:ClinicalTrials.gov Identifier: NCT01369069.

Dataset Information

Considering hyperglycemia and thrombolysis in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.

Publications

Considering hyperglycemia and thrombolysis in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.

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