title: The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial: an adaptive trial design case study.
abstract: BACKGROUND
  The '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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  As 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.
  
  
  CONCLUSIONS
  Two 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01369069 June 2011.
authors.affiliation: Berry Consultants, LLC, 4301 Westbank Dr Bldg B Suite 140, Austin, TX, 78746, USA. jason@berryconsultants.com.|University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA. jason@berryconsultants.com.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Connor
authors.affiliation: Berry Consultants, LLC, 4301 Westbank Dr Bldg B Suite 140, Austin, TX, 78746, USA. kristine@berryconsultants.com.
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Broglio
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, 135 Cannon Street Suit 303, Charleston, SC, 29425, USA. durkalsv@musc.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Durkalski
authors.affiliation: Department of Emergency Medicine, University of Michigan Health System, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA. wmeurer@med.umich.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Meurer
authors.affiliation: Department of Neurology, University of Virginia Health System, PO Box 800394, Charlottesville, VA, 22908, USA. KJ4V@hscmail.mcc.virginia.edu.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnston
mesh_terms: D001499:Bayes Theorem; D002545:Brain Ischemia / Q000188:drug therapy*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007328:Insulin / Q000008:administration & dosage*; D012107:Research Design; D018401:Sample Size; D020521:Stroke / Q000188:drug therapy*
chemical_list: D007328:Insulin