DESIGN OF THE SILENT CEREBRAL INFARCT TRANSFUSION (SIT) TRIAL

Abstract

Background: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. Procedure: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12–18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. Conclusion: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.

Keywords :

• blood transfusion therapy
• clinical trials
• hemoglobinopathies
• sickle cell anemia
• silent cerebral infarcts

ACKNOWLEDGMENTS

This study is supported by cooperative agreements U01-NS042804 and U01-NS042940 from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health. The authors would like to acknowledge the extraordinary efforts of the study coordinators for the SIT Trial and the families and children with SCA who were participants in the trial.

Coordinators

Coordinators for the SIT Trial at the time of this submission include Liz Dackiw from Johns Hopkins University School of Medicine, Anjum Zaki (Subsite coordinator) from the Georgetown University Hospital, Joan Marasciulo (Subsite coordinator) from the Sinai Hospital, Chrissy Rhoads, (Subsite coordinator) from University of Maryland, Barbara Speller-Brown from Children's National Medical Center, Ruth Baldwin and Fran Wright from the University of North Carolina, Mary DeBarr from the Rainbow Babies and Children's Hospital, Kami Perdue from The Research Center at Nationwide Children's Hospital, Marlene Eaton from the Cincinnati Comprehensive Sickle Cell Center, Cincinnati Children's Hospital Medical Center, Cindy Davis from Indiana University Purdue University Indianapolis, Cynthia Burnett from Wayne State University, Janice R. Beatty from Northwestern University, Danielle Jirovec from Medical College of Wisconsin, Susan Sarcone from the Children's Mercy Hospital and Clinics, Cindy Terrill and Terianne Lindsey from Washington University School of Medicine, Angela Mull from the Arkansas Children's Hospital Research Institute, Mary D. Jones from University of Alabama at Birmingham, Kim Gross from University of Mississippi Medical Center, Bogdan Dinu from Baylor College of Medicine, Michael Henson and Brad Cook from University of Texas Southwestern Medical Center, Jacqueline Davis from Wake Forest University Health Sciences, Jeffrey E. Olson from Children's Hospital of Philadelphia, Giselle Padmore-Pennington from Guy's and Saint Thomas’ Hospital NHS Foundation Trust, Heather Newell from The Royal London NHS Trust, Annette Gilmore from Central Middlesex Hospital North West London Hospitals NHS Trust, Annie Kamdem from Hôpital Intercommual de Créteil, and Nagina Parmar from University of Toronto.

Active Clinical Centers

James F. Casella, (Principal Investigator), Harold Lehman and John J. Strouse (Coinvestigators) from Johns Hopkins University School of Medicine, Corina Gonzalez (Subsite Investigator) from Georgetown University Hospital, Jason Fixler and Joseph M. Wiley (Subsite Investigators) from Sinai Hospital, Neil Grossman (Subsite Investigator) from the University of Maryland, Helge Hartung (Principal Investigator) (previously Caterina P. Minniti and Ana Burgos) from Children's National Medical Center, Rupa Redding-Lallinger, MD (Principal Investigator) from University of North Carolina, Beng Fuh (Principal Investigator) (previously Charles Daeschner and Mario Grossi) from East Carolina University, Brian Berman (Principal Investigator) (previously Anthony Villella) from the Rainbow Babies and Children's Hospital, Melissa M. Rhodes (Principal Investigator) (previously Mark A. Ranalli) from Ohio State University, Karen Kalinyak (Principal Investigator) from the Cincinnati Children's Hospital Medical Center, Mark Heiny (Principal Investigator) (previously Kathleen Neville) from Indiana University Purdue University Indianapolis, Sharada A. Sarnaik (Principal Investigator) from Wayne State University, Alexis A. Thompson (Principal Investigator) from Northwestern University, Julie A. Panepinto (Principal Investigator) from Medical College of Wisconsin, Gerald M. Woods (Principal Investigator) from Children's Mercy Hospital and Clinics, Allison King (Principal Investigator) from Washington University School of Medicine, Thomas H. Howard (Principal Investigator) from University of Alabama at Birmingham, Rathi V. Iyer (Principal Investigator) from University of Mississippi Medical Center, Gladstone Airewele (Principal Investigator) from Baylor College of Medicine, Charles T. Quinn (Principal Investigator) from University of Texas Southwestern Medical Center, Hernan Sabio (Principal Investigator) from Wake Forest University Health Sciences, Janet L. Kwiatkowski (Principal Investigator) from The Children's Hospital of Philadelphia, Melanie Kirby-Allen (Principal Investigator) from University of Toronto, Fenella Kirkham (Principal Investigator) from University College London Institute of Child Health, Baba Inusa (Principal Investigator) from Guy's and Saint Thomas’ Hospital NHS Foundation Trust, Paul Telfer (Principal Investigator) from The Royal London NHS Trust, and Françoise Bernaudin (Principal Investigator) from Hôpital Intercommual de Créteil.

Inactive Clinical Centers

Scott T. Miller (Principal Investigator) from the State University of New York – Downstate, Suzanne L. Saccente (Principal Investigator) from Arkansas Children's Hospital Research Institute, Charles Scher (Principal Investigator) from Tulane University Health Sciences Center, Thomas Coates (Principal Investigator) from Children's Hospital of Los Angeles, Michelle Afif (Principal Investigator) (previously Joanna Howard) from Central Middlesex Hospital North West London Hospitals NHS Trust, and David Rees from King's College Hospital NHS Foundation Trust.

Resource Centers

Project Office: Deborah Hirtz (Project Scientist) and Claudia S. Moy (Program Director) from the National Institutes of Health – National Institute of Neurological Disorders and Stroke.

Clinical Coordinating Center: Michael R. DeBaun (Principal Investigator for the Clinical Coordinating Center and SIT Trial), Teresa Roediger (Project Manager), (previously Colleen Kilbourne-Glynn) and Cindy Terrill (Project Manager) from Washington University School of Medicine.

Statistical and Data Coordinating Center: Bruce Barton (Principal Investigator) and Adrienne Brandon (Project Manager) from Maryland Medical Research Institute.

Electronic Radiology Laboratory (ERL): Fred Prior (Director), Stephen M. Moore (Systems Administrator), and Bruce A. Vendt (Project Manager) from the Mallinckrodt Institute of Radiology.

Biologic Repository: James F. Casella, (Director), Kimberly Jones, John J. Strouse, and Emily Barron-Casella from Johns Hopkins University School of Medicine. Margaret Penno and Tanya Ray from the Genetic Resources Core Facility Cell Center (GRCF).

Committees

Data and Safety Monitoring Board: David Schoenfeld (Chair), Massachusetts General Hospital,; Thomas Adamkiewicz, Morehouse School of Medicine; Stephen Ashwal, Loma Linda University; H. Stacy Nicholson, Oregon Health & Science University; Guillaume Sebire, Universite De Sherbrooke; Janice Cordell, National Institutes of Health.

Advisory Committee: William Powers (Chair), University of North Carolina, Robert J. Adams, Medical University of South Carolina; Jeffrey Schatz, University of South Carolina; Yuko Palesch, Medical University of South Carolina.

Executive Committee: Michael R, DeBaun (Chair and Principal Investigator for the SIT Trial), Robert C. McKinstry, III, and Michael J. Noetzel, Washington University School of Medicine; James F. Casella (Vice Chair and Co-principal Investigator for the SIT Trial), Johns Hopkins University School of Medicine; Bruce Barton, Maryland Medical Research Institute; Rebecca N. Ichord, Children's Hospital of Philadelphia; Fred Prior, Mallinckrodt Institute of Radiology, Washington University School of Medicine; Deborah Hirtz, National Institutes of Health – National Institute of Neurological Disorders and Stroke; and Desiree White, Washington University Department of Psychology. 2004–2005 Site Investigators: Caterina Minniti, Children's National Medical Center; Thomas Coates, Children's Hospital of Los Angeles; Thomas H. Howard, University of Alabama at Birmingham. 2005–2006 Site Investigators: Gladstone Airewele, Baylor College of Medicine; Karen Kalinyak, Cincinnati Comprehensive Sickle Cell Center; Anthony Villella, Rainbow Babies and Children's Hospital. 2006–2007 Site Investigators: Charles T. Quinn, University of Texas Southwestern; Julie A. Panepinto, Medical College of Wisconsin; Rupa Redding-Lallinger, University of North Carolina-Chapel Hill,. 2007–2008 Site Investigators: Thomas H. Howard, University of Alabama at Birmingham; Sharada Sarnaik, Wayne State University. 2008–2009 Site Investigators: Charles T. Quinn, University of Texas Southwestern; Sharada Sarnaik, Wayne State University; Beng Fuh, East Carolina University.

Neurology Committee: Michael J. Noetzel (Chair), Washington University School of Medicine; Michael Dowling, University of Texas Southwestern Medical Center; Deborah Hirtz, National Institutes of Health – National Institute of Neurological Disorders and Stroke; Rebecca N. Ichord, Children's Hospital of Philadelphia; E. Steve Roach, Nationwide Children's Hospital.

Psychology Committee: Desiree White (Chair), Washington University Department of Psychology,; T. David Elkin, University of Mississippi Medical Center; Mary M. George, Baylor College of Medicine; H. Gerry Taylor, Rainbow Babies and Children's Hospital.

Neuroradiology Committee: Robert C. McKinstry, III (Chair), Washington University School of Medicine; William S. Ball, Jr., University of Cincinnati; Michael A. Kraut, Johns Hopkins Hospital; Marilyn Siegel, Washington University School of Medicine.

Publications and Presentation Committee: Comprised of members of the SIT Trial executive committee. Additional members of the Publications Committee may be appointed by the chair of the executive committee on an ad hoc basis.

Protocol Review Committee: Comprised of members of the SIT Trial executive committee. Additional members of the Protocol Review Committee may be appointed by the chair of the executive committee on an ad hoc basis.

Definitions

Silent cerebral infarct-like lesions: An MRI signal abnormality visible on two views on the T-2 weighted images (axial and coronal). The signal abnormality must measure at least 3 mm in one dimension, based on consensus of two of three neuroradiologists.

Silent cerebral infarct: A silent cerebral infarct is a silent cerebral infarct-like lesion as reported by the neuroradiology committee that has been adjudicated as silent by the neurology committee. A lesion is adjudicated as silent only if the neurological examination is normal or there is an abnormality on the neurological exam that cannot be explained by the location of the MRI lesion.

Transient Ischemic Attack (TIA): A neurological deficit lasting less than 24 h with a negative MRI of the brain

Screening: Patient visits, testing to determine eligibility and patient/parent willingness to participate in the trial.

Stroke: A neurological deficit lasting more than or less than 24 h with a positive MRI (new vascular lesion which could explain deficit) or a neurological deficit lasting more than 24 h with a negative MRI or vascular lesion that does not explain deficit.

NOTE

Additional Materials

Additional figures and tables as well as a copy of the full protocol for the SIT Trial are included as supplemental online material (http://sitstudy.wustl.edu).