Silent Cerebral Infarct Transfusion Multi-Center Clinical Trial

Stroke Clinical Trial

— SIT  

Official title:

Silent Cerebral Infarct Transfusion Multi-Center Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00072761
• Other study ID #: R01NS42804
• Secondary ID: 5U01NS042804-07
• Status: Completed
• Phase: Phase 3
• First received: November 10, 2003
• Last updated: January 7, 2016
• Start date: December 2004
• Est. completion date: December 2013

Study information

• Verified date: January 2016
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

Description:

Silent cerebral infarct (stroke) is the most common cause of severe cognitive impairments and related neurological functions in children with sickle cell anemia. Currently there exists no systemic strategy to identify or treat children with silent strokes.

The primary aim of this trial is to determine the effectiveness of blood transfusion therapy for the prevention of silent strokes in children with sickle cell anemia. This trial will also determine if blood transfusion therapy will prevent further cerebral injury and if the measured benefits of the therapy outweigh the risks associated with it.

Participants in this multi-center trial will be randomly assigned to one of 2 groups-the blood transfusion group or the observation group. Those in the blood transfusion group will receive at least monthly blood transfusion therapy. All participants will have history and physical examinations every 3 months, and magnetic resonance imaging (MRI) at the beginning of their entry into the study and at study exit.

Advances in the understanding and treatment of silent strokes will likely lead to a decrease in the burden associated with cerebral injury in children with sickle cell anemia and change the standard care for these children.

Statistical Analyses: The original statistical analysis plan suggested a simple difference in proportions between the proportion of individuals with an endpoint in the transfusion group and the proportion of individuals with an endpoint in the usual care group using a traditional chi squared test. The data should be analyzed according to an intent to treat principal. Because of various logistical concerns in SIT, some individuals were not imaged within the 36-month window (30-42 months). We propose using all available information by changing the primary analysis from a dichotomous (yes/no) endpoint to a traditional epidemiological endpoint of an incidence rate in the group randomized to transfusion to the incidence rate in the group randomized to usual care. We will compute the incidence ratio:

(a/ta)/(b/tb)

Where "a" is the number of endpoints in the transfusion group, "ta" is the sum of the individual times at risk of the individuals randomized to the transfusion group, "b" is the number of endpoints in the observation group and "tb" is the sum of the individual times at risk of the individuals randomized to the observation group.

Since the standard statistical test for it being different than 1.0 involves the assumption of a Poisson distribution, we will compute an "exact" 95% confidence interval using a bootstrap with a large number of replications.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 196
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 14 Years

Eligibility

INCLUSION:

• 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.

EXCLUSION:

• 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Cerebral Infarction
• Sickle Cell Anemia
• Stroke

Intervention

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

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

Buchanan GR, DeBaun MR, Quinn CT, Steinberg MH. Sickle cell disease. Hematology Am Soc Hematol Educ Program. 2004:35-47. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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, Rhode — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes

External Links

•   official study website