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Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial

Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial. Protocol Training. NIH-NINDS U01 NSO69498. The Problem. Over 750,000 strokes/ year (~80% ischemic) ~30-50% hyperglycemic on admission Hyperglycemia associated w/ worse clinical outcome Hypoglycemia bad for ischemic brain

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Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial

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  1. Stroke Hyperglycemia Insulin Network Effort (SHINE) Trial Protocol Training NIH-NINDS U01 NSO69498

  2. The Problem • Over 750,000 strokes/ year (~80% ischemic) • ~30-50% hyperglycemic on admission • Hyperglycemia associated w/ worse clinical outcome • Hypoglycemia bad for ischemic brain • Unknown if Rx of hyperglycemia improves outcome • Unknown if risks of aggressive Rx outweigh benefit • Stroke community deals with hyperglycemic acute stroke patients every day without evidence on what is best

  3. Specific Aims Specific Aim 1 • To determine the efficacy of tight glucose control to a target range of 80-130 mg/dL with IV insulin infusion in hyperglycemic acute ischemic stroke patients within 12 hours of symptom onset as measured by mRS at 90 days after stroke. Specific Aim 2 • To determine the safety of tight glucose control with IV insulin infusion in hyperglycemic acute ischemic stroke patients treated for up to 72 hrs.

  4. Study Design • Phase III, randomized, blinded, controlled trial • ~60 sites, ~1400 patients • Single blind; double blind outcome assessment • 12 hrs from symptom onset (rec 3 hrs door to Rx) • Treatment Groups • Insulin drip – target 80-130 mg/dL • Control -SQ insulin – target <180 mg/dL • Up to 72 hours treatment • 90 day outcome – mRS (sliding dichotomy) • 80% power to detect 7% absolute improvement in favorable outcome (mRS)

  5. Study Innovation Response Adaptive Randomization (RAR) GlucoStabilizer – electronic decision support tool Responder Analysis (sliding dichotomy) successful outcome based on enrollment stroke severity allows consideration of expected outcome to be considered in determination of favorable outcome

  6. Identifying Patients Usually emergency room Could be arrival to ward upon direct transfer from OSH or in-house stroke Screen all acute ischemic stroke pts with onset within 12 hours and blood glucose > 110 Define plan for alerting screening team/ enrolling team

  7. Consent – General Concepts • Use standard consent procedures per local regulatory requirements • Written informed consent with process documented • No emergency exemption • Randomization recommended but not required to occur w/in 3 hours of arrival to enrolling ED (hospital)

  8. Inclusion Criteria • Age 18 years or older • Diagnosis of ischemic stroke defined as acute neurological deficit occurring in one or more cerebral vascular territories. Neuroimaging must exclude ICH. • Treatment must begin w/in 12 hrs of stroke symptom onset and is recommended w/in 3 hrs of hospital arrival • Known history of type 2 diabetes &glucose >110 mg/dL OR blood glucose ≥150 mg/dL in pts w/o known diabetes • Baseline NIHSS 3-22 • Pre-stroke mRS of 0 if NIHSS of 3-7 OR pre-stroke mRS of 0 or 1 if NIHSS of 8-22 • Able to provide a valid informed consent

  9. Exclusion Criteria • Known history of type 1 diabetes • Substantial neurological or psychiatric illness that would confound neurological or outcome assessment • Received experimental therapy for enrollment stroke. IV tPA (up to 4.5 hrs), IA tPA &IA therapies including FDA cleared devices allowed. Non FDA cleared devices excluded. • Pregnant or breast-feeding • Other serious conditions that make pt unlikely to survive 90 days • Inability to follow protocol or return for 90 day f/u • Renal dialysis

  10. Randomization– General Concepts • WebDCU-based randomization • Randomization time is start of treatment time • Must be randomized within 12 hours of symptom onset (recommended but not required within 3 hours of arrival to enrolling hospital) • RAR – Response Adaptive Randomization • Start out 1:1 (flip of coin) • RAR – higher chance of being enrolled in treatment group that has better outcomes

  11. Treatment Groups - General Concepts Control Group • BG target 80-179 mg/dL • SQ insulin (regular human) per sliding scale • IV saline drip (to mimic IV insulin drip to maintain blind) • Q1 hr glucose checks for first four hours • Q3 hr glucose checks after 1st 4 hrs– but insulin given only at 06:00, 12:00, 18:00 and 24:00 if indicated • Basal insulin only for Level 3 indicated

  12. Treatment Groups - General Concepts Intervention Group • BG target 80-130 mg/dL • Glucose checks and IV insulin (regular human) drip adjustments per GlucoStabilizer (computer decision support tool) • For pts who are PO or on bolus tube feeds, SQ meal insulin (rapid acting analog) per meal carbohydrate diet • For pts who are NPO or on continuous tube feeds, SQ saline administered (to mimic SQ insulin to maintain blind)

  13. Control Group

  14. Control GroupInitiation of Treatment • Enter orders/notify pharmacy • Start SHINE laptop and select Control Group • Re-check glucose when IV saline is ready • Start IV saline infusion per protocol (displayed on control treatment screen) & adjust as needed w/ EACH glucose check • Check glucose once to start and then q1hr x4 hrs, then q3hr (03:00, 06:00, 09:00, 12:00, 15:00, 18:00, 21:00 and 24:00) • Give insulin per sliding scale ONLY at 06:00, 12:00, 18:00 and 24:00

  15. Getting Started

  16. Control Group Computer Screen

  17. Control Group Documenting

  18. Control GroupContinuation of Treatment • Check glucose per study sliding scale schedule • Give SQ insulin only at the designated times if indicated by the sliding scale (≥180 mg/dL) • All patients start at Level 1 for first 24 hrs (opportunity to advance to more aggressive glucose control at 24 & 48 hrs if indicated) • Adjust IV saline rate if indicated after each glucose check • Same procedure whether eating or not

  19. Shifting from Q1 to Q3 hour glucose checks in control group • First glucose check for SHINE study treatment protocol as soon as saline bag ready to drip • Q 1hr check for first 4 glucose checks (one check to start and then four more) • After the 4th Q 1 hr check, start glucose checks on Q 3hr schedule, but skip 1st scheduled check if <1 hr from previous check unless it is a SQ insulin dosing time

  20. Sliding Scale Insulin Level Changes • All patients on Level 1 for first 24 hours (start time is time of randomization) • Advance level only if indicated at 24 & 48 hrs • At end of 1st 24 hrs, advance to Level 2 onlyif the latest 2 glucose levels ≥180 mg/dL; otherwise stay on Level 1 • At end of 48 hrs, advance to next level (2 or 3) onlyif the latest 2 glucose levels ≥ 180 mg/dL; otherwise stay on current level • Level 3 includes one-time SQ basal insulin (Lantus) given at end of 48 hrs (sliding scale insulin doses for Level 3 are the same as Level 2) • Do not backwards/go down a level unless safety monitor recommends

  21. Sliding Scale Insulin Level Changes

  22. Level 3 Control TreatmentBasal Insulin • Level 3 is only level on sliding scale that includes basal insulin • To calculate basal insulin dose - add all the insulin units given in the previous 24 hrs; 40% of that total is the dose of basal insulin to be given once as close as possible to 48 hrs from randomization (round up if >.5, round down if <.5) • Use only glargine (Lantus) insulin for basal insulin • After one-time dose of SQ basal insulin – continue schedule for SQ sliding scale insulin Level 3 (same as Level 2 sliding scale)

  23. Control Group - Meals • 60 gram carbohydrate diet per meal should be ordered • NO estimate of meal consumption required and NO meal insulin given in control group (only SQ sliding scale insulin at 06:00, 12:00, 18:00 and 24:00 if indicated) • Pts should eat only after their glucose check and the SQ insulin has been given as needed at 6:00, 12:00, and 18:00. (If meal arrives before these times, hold until time for glucose check and insulin dose if indicated) • Only protocol-approved snacks during the 72 hour SHINE treatment protocol

  24. Intervention Group

  25. Intervention GroupInitiation of Treatment • Enter orders/notify pharmacy • Start SHINE laptop and select Intervention Group • Re-check glucose when IV insulin infusion is ready • Start IV insulin infusion per GlucoStabilizer recommendation

  26. Getting Started

  27. Intervention Group Computer Screen

  28. Intervention GroupContinuation of Treatment • Recheck and enter glucose in GlucoStabilizer • Adjust IV insulin drip per GlucoStabilizer recommendation • For pts that are PO or receiving bolus tube feeds, give meal insulin per protocol • For pts that are NPO or receiving continuous tube feeds, give SQ saline 0.05 cc after check closest to 09:00 and 21:00 to simulate SQ insulin injections in control group

  29. Intervention Group Meals • Order 60 gram carbohydrate diet for breakfast, lunch & dinner for pts who are eating or on bolus tube feeds • PO - Allow 20 minutes from start of eating – then estimate the proportion of meal consumed • Bolus tube feeds – estimate proportion of bolus given • SQ meal insulin (rapid acting analog) given based on proportion of meal consumed & dose recommended per GlucoStabilizer • Only protocol-approved snacks during 72 hour SHINE study treatment period

  30. Intervention Group SQ Meal Insulin for PO pts • Meal consumed – all or nearly all • Enter 60carb meal into GlucoStabilizer • Give dose of meal insulin recommended • Meal consumed– none or nearly none • DO NOT make an entry into GlucoStabilizer • DO NOT give meal insulin • Meal consumed– partial or in between • Enter 30carb meal into GlucoStabilizer • Give dose of meal insulin recommended

  31. Intervention Group Meal Insulin Computer Screens

  32. Data Entry • Standard chart documentation is required per site procedure • Additionally, glucose and study treatment data will be entered in control treatment screen of study laptop

  33. Special situations Hypoglycemia Pauses in study protocol Discontinuing study protocol < 72 hours Transition from study protocol

  34. Hypoglycemia ProtocolsGeneral Concepts • The hypoglycemia prevention and management protocol begins when glucose falls <80 mg/dL • But, actual hypoglycemia is defined as <70 mg/dL • Severe hypoglycemia (primary safety outcome) is defined as <40 mg/dL • Any glucose level that falls <70 mg/dL requires additional info: • Laboratory serum glucose level – send but give D50 before result available • Symptomatic or asymptomatic assessment

  35. Hypoglycemia ProtocolsGlucose <80 mg/dL • STOP all SQ and IV study treatments • Give D50 slow IV push • Control Group: 1/2 ampoule (25 ml) • Intervention Group: per GlucoStabilizer • Recheck glucose • Control Group: q 15 min and give another ½ ampoule (25 ml) D50 as long as glucose <80 mg/dL • Intervention Group: q 15 min per GlucoStabilizer

  36. Hypoglycemia ProtocolsAdditional steps for glucose <70mg/dL • Send serum sample for glucose to lab. Do not delay D50. • DO NOT draw serum sample from IV line where D50 given • Hypoglycemia symptomatic questionnaire q15 min. Once BG>70mg/dL or symptoms have resolved, one final assessment is required. • Neuro check each time glucose <70 mg/dL • NIHSS for worsening as soon as possible; if ≥4 point increase on the NIHSS from previous and persistent, recheck in 24 hrs • Once glucose ≥80 mg/dL, resume treatment protocols

  37. Pauses in SHINE Control Treatment Protocol When restarting protocol, if glucose checks or SQ insulin were: • NOT missed, maintain schedule. Resume saline infusion at the next scheduled glucose • MISSED, immediately check the POC glucose upon return and resume IV saline. If SQ insulin dosing time was missed, give SQ insulin if indicated immediately. Return to schedule for glucose checks and subcutaneous insulin injections. • Do not check glucose levels <1 hour apart unless it is a scheduled dosing time. • Do not give SQ insulin injections <3 hours apart.

  38. Pauses in SHINE Intervention Treatment Protocol • When able to restart protocol, recheck glucose • Use result of glucose check to resume IV insulin drip • If IV drip off for <3 hrs, use “Resume” option in GlucoStabilizer • If IV drip off for ≥3 hrs, use “Start New Drip” option in GlucoStabilizer • If a meal is eaten late, give SQ meal insulin with meal per protocol • If SQ saline dose was missed (NPO or continuous tube feed pts) • Give 0.05 cc SQ saline • If next saline dosing time in <3 hrs, then skip it

  39. Study treatment by group and nutritional status

  40. Discontinuation of SHINE Treatment • Any study pt clinically ready for hospital discharge prior to 72 hrs of treatment may be discontinued from SHINE protocol (not a protocol deviation) • 6 hrs prior to discharge • D/C SHINE study infusion (insulin or saline) • D/C SHINE sliding scale SQ insulin protocol • GlucoStabilizer Drip Weaning Report (24 hr insulin total) available for review for intervention group only • Any subsequent SQ insulin Rx at discretion of treating physician should be >3 hrs after last SHINE SQ insulin • Oral diabetes Rx per treating team

  41. Transition to Standard Care • Per ADA guidelines scheduled subcutaneous insulin that delivers basal, nutritional and correction components is preferred. • Consider that oral agents are not recommended in hospitalized patients, but may be initiated or resumed in anticipation of discharge per ADA guidelines. • Consider individualized discharge planning per ADA guidelines

  42. Summary – Clinical Study Outcomes • Primary Study Outcome – 3 month mRS • Primary Safety Outcome – frequency of severe hypoglycemia (<40 mg/dL) in intervention group versus control group • Additional Outcomes • 6 week phone call – mRS by phone, SAEs • 3 month - BI, NIHSS, QOL

  43. Outcome Visits • Assessor for outcomes visits mustbe blinded to treatment • Visits • 6 week visit – by phone • mRS and SAEs • 3 month visit – in person • mRS, NIHSS, BI, SSQOL • SAEs • Unblinding survey (patient and investigator)

  44. Bedding for SHINE patients

  45. Bedding for SHINE Patients • Hospitals have different regulations for unit/level of care required for insulin drip • For the 72 hours of study treatment, all patients must be bedded in a location that would support and allow delivery of insulin drip therapy. • Must not differentially bed intervention and control patients as this will bias the study due to differential level of care

  46. Bedding for SHINE Patients • If your hospital supports insulin drip therapy in ICU, step down, stroke unit & floor level settings: • May bed any pt in any one of these insulin drip supporting environments according to clinical need • If your hospital supports insulin drip therapy in ICU, step down, stroke unit BUT NOT in floor level settings: • May only bed any pt in ICU, SDU, ASU and may not bed any pt on the floor during the 72 hr study treatment period regardless of treatment group (intervention or control)

  47. Bedding for SHINE Patients If your hospital ONLY supports insulin drip therapy in ICU then: • All SHINE patients must be cared for in ICU for 72 hours unless discharged OR • There must be a special plan in place with your institution to manage this

  48. Pharmacy

  49. Treatment Assignment • Randomization generated by study team in WebDCU • Study team provides copy of treatment assignment to pharmacy (may be faxed, scanned or delivered in person)

  50. Study Treatment by Group

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