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The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke.

ABSTRACT: RATIONALE:Patients with acute ischemic stroke and hyperglycemia have worse outcomes than those without hyperglycemia. Intensive glucose control during acute stroke is feasible and can be accomplished safely but has not been fully assessed for efficacy. AIMS:The Stroke Hyperglycemia Insulin Network Effort trial aims to determine the safety and efficacy of standard vs. intensive glucose control with insulin in hyperglycemic acute ischemic stroke patients. DESIGN:This is a randomized, blinded, multicenter, phase III trial of approximately 1400 hyperglycemic patients who receive either standard sliding scale subcutaneous insulin (blood glucose range 80-179?mg/dL, 4·44-9·93?mmol/L) or continuous intravenous insulin (target blood glucose 80-130?mg/dL, 4·44-7·21?mmol/L) for up to 72?h, starting within 12?h of stroke symptom onset. The acute treatment phase is single blind (for the patients), but the final outcome assessment is double blind. The study is powered to detect a 7% absolute difference in favorable outcome at 90 days. STUDY OUTCOMES:The primary outcome is a baseline severity adjusted 90-day modified Rankin Scale score, defined as 0, 0-1, or 0-2, if the baseline National Institutes of Health Stroke Scale score is 3-7, 8-14, or 15-22, respectively. The primary safety outcome is the rate of severe hypoglycemia (<40?mg/dL, <2·22?mmol/L). DISCUSSION:This trial will provide important novel information about preferred management of acute ischemic stroke patients with hyperglycemia. It will determine the potential benefits and risks of intensive glucose control during acute stroke.

SUBMITTER: Bruno A

PROVIDER: S-EPMC3904437 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke.

Bruno Askiel A Durkalski Valerie L VL Hall Christiana E CE Juneja Rattan R Barsan William G WG Janis Scott S Meurer William J WJ Fansler Amy A Johnston Karen C KC

International journal of stroke : official journal of the International Stroke Society 20130319 2

<h4>Rationale</h4>Patients with acute ischemic stroke and hyperglycemia have worse outcomes than those without hyperglycemia. Intensive glucose control during acute stroke is feasible and can be accomplished safely but has not been fully assessed for efficacy.<h4>Aims</h4>The Stroke Hyperglycemia Insulin Network Effort trial aims to determine the safety and efficacy of standard vs. intensive glucose control with insulin in hyperglycemic acute ischemic stroke patients.<h4>Design</h4>This is a ran ...[more]

PMID: 23506245

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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.

Project description:ObjectiveAlterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS.ApproachThe Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin-antithrombin (TAT) complex; D-dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor-1 (PAI-1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two-way analysis of variance.ResultsA total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA (P = 0.02) and PAI-1 (P = .04) and FVIIa (P = .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes (P = .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes (P = .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome (P = .006).ConclusionsIntensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS.

Project description:ImportanceThe Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown.ObjectiveTo assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control.Design, setting, and participantsRandomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent.InterventionsIn total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed.Main outcomes and measuresThe primary outcome was stroke recurrence.ResultsThe trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250).Conclusions and relevanceIntensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention.Trial registrationClinicalTrials.gov identifier: NCT01198496.

Project description:ImportanceThere are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia.ObjectiveTo evaluate the effect of intensive blood pressure control on risk of dementia.Design, setting, and participantsRandomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018.InterventionsParticipants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683).Main outcomes and measuresThe primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia.ResultsAmong 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97).Conclusions and relevanceAmong ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point.Trial registrationClinicalTrials.gov Identifier: NCT01206062.

Project description:ObjectiveTo determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm.MethodsIn a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.ResultsOf 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥0.07).ConclusionsWe found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS.Classification of evidenceThis study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.Clinical trial registrationClinicaltrials.gov identifier NCT01422616.

Dataset Information

The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke.

Publications

The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke.

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