Silent Cerebral Infarct Transfusion Multi-Center Clinical Trial

NCT00072761 | Completed Phase 3 Results DMC

• 2 other identifiers: R01NS428045U01NS042804-07
• Study Type: interventional
• Target: 196
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to determine the effectiveness of blood transfusion therapy for prevention of silent cerebral infarct (stroke) in children with sickle cell anemia.

Conditions

Sickle Cell Anemia; Stroke

Keywords

silent cerebral infarct; silent stroke; sickle cell anemia; stroke; transfusion therapy

Outcome Measures

Primary Outcomes (1)

• Recurrence of an Infarct, Defined as a Stroke or a New or Enlarged Silent Cerebral Infarct

  The primary end point was the recurrence of infarct or hemorrhage as determined by neuroimaging, clinical evidence of permanent neurologic injury, or both. A new infarct had to meet the criteria for a silent cerebral infarction; an enlarged silent cerebral infarct was defined as a previously identified silent cerebral infarct that increased by at least 3 mm along any linear dimension in any plane on MRI.

  From study entry to study exit

Study Arms (2)

Transfusion Group

ACTIVE COMPARATOR

Participants allocated to the transfusion arm will receive blood transfusion therapy every 4-6 weeks for 36 months.

Procedure: transfusion therapy

Observation Group

NO INTERVENTION

Participants allocated to the observation arm will be treated according to standard care and will receive a quarterly physical examination by a study hematologist for 36 months.

Interventions

transfusion therapy PROCEDURE

Those in the blood transfusion group will receive at least monthly blood transfusion therapy.

Transfusion Group

Eligibility Criteria

• Age: 5 Years - 14 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patient must have sickle cell anemia (hemoglobin SS) or sickle beta thalassemia (hemoglobin SB) as confirmed at the local institution.
• Participating institutions must submit documentation of the diagnostic hemoglobin analysis to the Statistical and Clinical Coordinating Centers to confirm the diagnosis of sickle cell anemia prior to randomization.
• Patient must be 5 through 14 years of age.
• Patient must have a cerebral infarct documented by MRI scan as read by the neuroradiology panel.
• Informed consent with assent in accordance with the institutional policies (institutional Institutional Review Board approval) and Federal guidelines (approved by the United States Department of Health and Human Services) must be signed by the patient's legally authorized guardian acknowledging written consent to join the study. When suitable, patients will be requested to give their assent to join the study.

You may not qualify if:

• Patient with a history of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke.
• Patients with a transcranial doppler (TCD) study with a time-averaged mean velocity greater than 200 cm/sec verified by the study radiologist.
• Patients with other neurological problems, such as neurofibromatosis, lead poisoning, or tuberous sclerosis.
• Patients with HIV infection.
• Pregnancy.
• Patients who received treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipate receiving anti-sickling drugs or hydroxyurea during the course of the study.
• Abnormal kidney function (creatinine \> 2x upper limit of normal).
• Patients on chronic blood transfusion therapy for other reasons.
• Patients judged not likely to be compliant by his/her hematologist and local nurse coordinator based on previous compliance in clinic appointments and following advice. Specifically, families that have missed at least two appointments without notification within 12 months prior to the trial or parents of potential patients that have been reported for medical or education neglect are not eligible for this trial.
• Patients unable to receive blood transfusion because of alloimmunization.
• Patients with permanent or semi-permanent metallic (braces on teeth) structures attached to their body. Such patients cannot obtain a MRI of the head to assess the presence of silent cerebral infarcts.
• Siblings randomized in the trial.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (19)

• Buchanan GR, DeBaun MR, Quinn CT, Steinberg MH. Sickle cell disease. Hematology Am Soc Hematol Educ Program. 2004:35-47. doi: 10.1182/asheducation-2004.1.35.

  PMID: 15561675 BACKGROUND

• Vendt BA, McKinstry RC, Ball WS, Kraut MA, Prior FW, Barton B, Casella JF, DeBaun MR. Silent Cerebral Infarct Transfusion (SIT) trial imaging core: application of novel imaging information technology for rapid and central review of MRI of the brain. J Digit Imaging. 2009 Jun;22(3):326-43. doi: 10.1007/s10278-008-9114-3. Epub 2008 Apr 9.

  PMID: 18398653 BACKGROUND

• Casella JF, King AA, Barton B, White DA, Noetzel MJ, Ichord RN, Terrill C, Hirtz D, McKinstry RC, Strouse JJ, Howard TH, Coates TD, Minniti CP, Campbell AD, Vendt BA, Lehmann H, Debaun MR. Design of the silent cerebral infarct transfusion (SIT) trial. Pediatr Hematol Oncol. 2010 Mar;27(2):69-89. doi: 10.3109/08880010903360367.

  PMID: 20201689 BACKGROUND

• Jordan LC, McKinstry RC 3rd, Kraut MA, Ball WS, Vendt BA, Casella JF, DeBaun MR, Strouse JJ; Silent Infarct Transfusion Trial Investigators. Incidental findings on brain magnetic resonance imaging of children with sickle cell disease. Pediatrics. 2010 Jul;126(1):53-61. doi: 10.1542/peds.2009-2800. Epub 2010 Jun 14.

  PMID: 20547639 BACKGROUND

• Bhatnagar P, Purvis S, Barron-Casella E, DeBaun MR, Casella JF, Arking DE, Keefer JR. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet. 2011 Apr;56(4):316-23. doi: 10.1038/jhg.2011.12. Epub 2011 Feb 17.

  PMID: 21326311 BACKGROUND

• Jordan LC, Casella JF, DeBaun MR. Prospects for primary stroke prevention in children with sickle cell anaemia. Br J Haematol. 2012 Apr;157(1):14-25. doi: 10.1111/j.1365-2141.2011.09005.x. Epub 2012 Jan 9.

  PMID: 22224940 BACKGROUND

• DeBaun MR, Sarnaik SA, Rodeghier MJ, Minniti CP, Howard TH, Iyer RV, Inusa B, Telfer PT, Kirby-Allen M, Quinn CT, Bernaudin F, Airewele G, Woods GM, Panepinto JA, Fuh B, Kwiatkowski JK, King AA, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Sabio H, Gonzalez CE, Saccente SL, Kalinyak KA, Strouse JJ, Fixler JM, Gordon MO, Miller JP, Noetzel MJ, Ichord RN, Casella JF. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure. Blood. 2012 Apr 19;119(16):3684-90. doi: 10.1182/blood-2011-05-349621. Epub 2011 Nov 17.

  PMID: 22096242 BACKGROUND

• Thangarajh M, Yang G, Fuchs D, Ponisio MR, McKinstry RC, Jaju A, Noetzel MJ, Casella JF, Barron-Casella E, Hooper WC, Boulet SL, Bean CJ, Pyle ME, Payne AB, Driggers J, Trau HA, Vendt BA, Rodeghier M, DeBaun MR. Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia. Br J Haematol. 2012 Nov;159(3):352-9. doi: 10.1111/bjh.12034. Epub 2012 Sep 7.

  PMID: 22958163 BACKGROUND

• Quinn CT, McKinstry RC, Dowling MM, Ball WS, Kraut MA, Casella JF, Dlamini N, Ichord RN, Jordan LC, Kirkham FJ, Noetzel MJ, Roach ES, Strouse JJ, Kwiatkowski JL, Hirtz D, DeBaun MR. Acute silent cerebral ischemic events in children with sickle cell anemia. JAMA Neurol. 2013 Jan;70(1):58-65. doi: 10.1001/jamaneurol.2013.576.

  PMID: 23108767 BACKGROUND

• Bean CJ, Boulet SL, Ellingsen D, Pyle ME, Barron-Casella EA, Casella JF, Payne AB, Driggers J, Trau HA, Yang G, Jones K, Ofori-Acquah SF, Hooper WC, DeBaun MR. Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease. Blood. 2012 Nov 1;120(18):3822-8. doi: 10.1182/blood-2011-06-361642. Epub 2012 Sep 10.

  PMID: 22966170 BACKGROUND

• Milton JN, Sebastiani P, Solovieff N, Hartley SW, Bhatnagar P, Arking DE, Dworkis DA, Casella JF, Barron-Casella E, Bean CJ, Hooper WC, DeBaun MR, Garrett ME, Soldano K, Telen MJ, Ashley-Koch A, Gladwin MT, Baldwin CT, Steinberg MH, Klings ES. A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia. PLoS One. 2012;7(4):e34741. doi: 10.1371/journal.pone.0034741. Epub 2012 Apr 27.

  PMID: 22558097 BACKGROUND

• DeBaun MR, Armstrong FD, McKinstry RC, Ware RE, Vichinsky E, Kirkham FJ. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood. 2012 May 17;119(20):4587-96. doi: 10.1182/blood-2011-02-272682. Epub 2012 Feb 21.

  PMID: 22354000 BACKGROUND

• Glassberg JA, Wang J, Cohen R, Richardson LD, DeBaun MR. Risk factors for increased ED utilization in a multinational cohort of children with sickle cell disease. Acad Emerg Med. 2012 Jun;19(6):664-72. doi: 10.1111/j.1553-2712.2012.01364.x.

  PMID: 22687181 BACKGROUND

• An P, Barron-Casella EA, Strunk RC, Hamilton RG, Casella JF, DeBaun MR. Elevation of IgE in children with sickle cell disease is associated with doctor diagnosis of asthma and increased morbidity. J Allergy Clin Immunol. 2011 Jun;127(6):1440-6. doi: 10.1016/j.jaci.2010.12.1114. Epub 2011 Mar 9.

  PMID: 21388662 BACKGROUND

• DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH, Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B, Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H, Kraut MA, Ball WS Jr, Hirtz D, Casella JF. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21;371(8):699-710. doi: 10.1056/NEJMoa1401731.

  PMID: 25140956 RESULT

• Hsu P, Gay JC, Lin CJ, Rodeghier M, DeBaun MR, Cronin RM. Economic evaluation of regular transfusions for cerebral infarct recurrence in the Silent Cerebral Infarct Transfusion Trial. Blood Adv. 2021 Dec 14;5(23):5032-5040. doi: 10.1182/bloodadvances.2021004864.

  PMID: 34607344 DERIVED

• Dowling MM, Noetzel MJ, Rodeghier MJ, Quinn CT, Hirtz DG, Ichord RN, Kwiatkowski JL, Roach ES, Kirkham FJ, Casella JF, DeBaun MR. Headache and migraine in children with sickle cell disease are associated with lower hemoglobin and higher pain event rates but not silent cerebral infarction. J Pediatr. 2014 May;164(5):1175-1180.e1. doi: 10.1016/j.jpeds.2014.01.001. Epub 2014 Feb 13.

  PMID: 24529619 DERIVED

• Savage WJ, Barron-Casella E, Fu Z, Dulloor P, Williams L, Crain BJ, White DA, Jennings JM, Van Eyk JE, Debaun MR, Everett A, Casella JF. Plasma glial fibrillary acidic protein levels in children with sickle cell disease. Am J Hematol. 2011 May;86(5):427-9. doi: 10.1002/ajh.21995.

  PMID: 21523806 DERIVED

• Williams LM, Fu Z, Dulloor P, Yen T, Barron-Casella E, Savage W, Van Eyk JE, Casella JF, Everett A. Hemoglobin depletion from plasma: considerations for proteomic discovery in sickle cell disease and other hemolytic processes. Proteomics Clin Appl. 2010 Dec;4(12):926-30. doi: 10.1002/prca.201000054.

  PMID: 21179892 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; Stroke

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Limitations and Caveats

The SIT Trial results are not directly applicable to all children with SCA. Those who were on hydroxyurea therapy for severe disease, had abnormally elevated TCDs, were receiving blood transfusion for stroke prevention or had epilepsy were excluded.

Results Point of Contact

• Title: Michael R. DeBaun, MD, MPH
• Organization: Vanderbilt University School of Medicine

m.debaun@vanderbilt.edu

615-875-3040

Study Officials

• Michael R. DeBaun, MD, MPH

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor or Pediatrics and Medicine, JC Peterson Endowed Chair, Vice Chair of Clinical Research

Study Record Dates

• First Submitted: November 10, 2003
• First Posted: November 13, 2003
• Study Start: December 1, 2004
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: February 8, 2016
• Results First Posted: February 8, 2016

Record last verified: 2016-01

Locations

US (1)