Stroke With Transfusions Changing to Hydroxyurea

NCT00122980 | Terminated Phase 3 Results DMC

• 2 other identifiers: SWiTCH1U01HL078787-01A1
• Study Type: interventional
• Target: 134
• Locations: 1 country
• Sites: 28

Brief Summary

The purpose of this study is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload in children with sickle cell anemia (SCA).

Conditions

Hemochromatosis; Cerebrovascular Accident; Anemia, Sickle Cell; Hematologic Diseases

Keywords

Blood Diseases

Outcome Measures

Primary Outcomes (2)

• Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period

  Secondary stroke is the first component of the composite primary endpoint and considers the number of participants with recurrent secondary stroke events during 30 months of treatment. Stroke was defined as any clinical event with brain injury due to vascular disease. All neurological events underwent formal stroke adjudication.

  Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)

• Liver Iron Content (LIC) Change-from-baseline

  LIC change-from-baseline is the second component of the composite primary endpoint. LIC was measured by quantitative liver biopsy at baseline and at 30 months or exit from the study.LIC values were transformed into Log10 values prior to computing the change from baseline.

  Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)

Secondary Outcomes (7)

• Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline)

  Baseline, mid-point (week 64), and study exit after up to 30-month treatment period (due to study termination)

• Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline)

  Baseline, midpoint (week 64), and study exit (up to 30 months of treatment)

• Barthel Index (Change From Baseline)

  Baseline and study exit after up to 30-month treatment period (due to study termination)

• Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal

  Baseline and study exit after up to 30-month treatment period (due to study termination)

• Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability

  Baseline and study exit after up to 30-month treatment period (due to study termination)

Study Arms (2)

1

ACTIVE COMPARATOR

Hydroxyurea and phlebotomy

Drug: Hydroxyurea; Procedure: Phlebotomy

2

ACTIVE COMPARATOR

Transfusion and chelation

Procedure: Red Cell Transfusions; Procedure: Iron Chelation

Interventions

Red Cell Transfusions PROCEDURE

Red Blood Cell Transfusions

2

Iron Chelation PROCEDURE

Iron Chelation Therapy

2

Hydroxyurea DRUG

Hydroxyurea

1

Phlebotomy PROCEDURE

Phlebotomy

1

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSOArab)
• Age range of 5.0-18.9 years, inclusive, at the time of study entry
• Initial (primary) completed overt clinical stroke after the age of one year (12 months) with documented infarction on brain computed tomography (CT) or magnetic resonance imaging (MRI)
• At least 18 months of chronic monthly erythrocyte transfusions since primary stroke
• Transfusional iron overload, defined as a previously documented liver iron concentration (LIC) greater than or equal to 5.0 mg Fe per gram of dry weight liver or serum ferritin greater than or equal to 500 ng/mL on two independent measurements
• Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) in the 6 months prior to study entry
• Parent or guardian willing and able to provide informed consent with verbal or written assent from the child (less than 18 years of age) or subject willing and able to provide informed consent (older than 18 years of age)
• Ability to comply with study-related treatments, evaluations, and follow-up

You may not qualify if:

• Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following:
• Multiple RBC alloantibodies making cross-matching difficult or impossible
• RBC autoantibodies making cross-matching difficult or impossible
• Religious objection to transfusions that preclude their chronic use
• Inability to take or tolerate daily oral hydroxyurea, due to any of the following:
• Known allergy to hydroxyurea therapy
• HIV infection
• Cancer
• Pregnant or breastfeeding
• Previous stem cell transplant or other myelosuppressive therapy
• Clinical and laboratory evidence of hypersplenism, due to any of the following:
• Palpable splenomegaly greater than 5 cm below the left costal margin and
• Transfusion requirement greater than 250 mL/kg in the 12 months prior to study entry
• Pre-transfusion hemoglobin concentration less than 7.0 gm/dL
• White blood cell (WBC) count less than 3.0 x 109/L

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (28)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Nemours Children's Clinic

Jacksonville, Florida, 32207, United States

Location

University of Miami, Jackson Memorial Hospital

Miami, Florida, 33136, United States

Location

Nemours Children's Clinic

Orlando, Florida, 32806, United States

Location

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, 30322, United States

Location

Children's Healthcare of Atlanta at Grady

Atlanta, Georgia, 30322, United States

Location

Children's Healthcare of Atlanta at Scottish Rite

Atlanta, Georgia, 30342, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Wayne State University, Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

The Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

St. Joseph's Children's Hospital

Paterson, New Jersey, 07503, United States

Location

State University of New York/Downstate Medical Center

Brooklyn, New York, 11203, United States

Location

Schneider Children's Hospital

New Hyde Park, New York, 11040, United States

Location

Columbia University Medical Center, Morgan Stanley Children's Hospital of New York-Presbyterian

New York, New York, 10032, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

East Carolina University

Greenville, North Carolina, 27834, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75390-9063, United States

Location

Baylor College of Medicine

Houston, Texas, 77030-2399, United States

Location

Eastern Virginia Medical School

Norfolk, Virginia, 23510, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (4)

• Helton KJ, Adams RJ, Kesler KL, Lockhart A, Aygun B, Driscoll C, Heeney MM, Jackson SM, Krishnamurti L, Miller ST, Sarnaik SA, Schultz WH, Ware RE; SWiTCH Investigators. Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial. Blood. 2014 Aug 7;124(6):891-8. doi: 10.1182/blood-2013-12-545186. Epub 2014 Jun 9.

  PMID: 24914136 DERIVED

• Alvarez O, Yovetich NA, Scott JP, Owen W, Miller ST, Schultz W, Lockhart A, Aygun B, Flanagan J, Bonner M, Mueller BU, Ware RE; Investigators of the Stroke With Transfusions Changing to Hydroxyurea Clinical Trial (SWiTCH). Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial. Am J Hematol. 2013 Nov;88(11):932-8. doi: 10.1002/ajh.23547. Epub 2013 Aug 30.

  PMID: 23861242 DERIVED

• Ware RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012 Apr 26;119(17):3925-32. doi: 10.1182/blood-2011-11-392340. Epub 2012 Feb 7.

  PMID: 22318199 DERIVED

• Ware RE, Schultz WH, Yovetich N, Mortier NA, Alvarez O, Hilliard L, Iyer RV, Miller ST, Rogers ZR, Scott JP, Waclawiw M, Helms RW. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatr Blood Cancer. 2011 Dec 1;57(6):1011-7. doi: 10.1002/pbc.23145. Epub 2011 Aug 8.

  PMID: 21826782 DERIVED

MeSH Terms

Conditions

Hemochromatosis; Stroke; Anemia, Sickle Cell; Hematologic Diseases

Interventions

Erythrocyte Transfusion; Iron Chelating Agents; Hydroxyurea; Phlebotomy

Condition Hierarchy (Ancestors)

Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Iron Overload; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemic and Lymphatic Diseases; Hemoglobinopathies

Intervention Hierarchy (Ancestors)

Blood Component Transfusion; Blood Transfusion; Biological Therapy; Therapeutics; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals; Urea; Amides; Organic Chemicals; Blood Specimen Collection; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Limitations and Caveats

The trial was stopped early due to a projected futility of the liver iron component of the primary endpoint in conjunction with the significantly higher number of strokes in the Hydroxyurea/Phlebotomy arm as compared to the Transfusion/Chelation arm.

Results Point of Contact

• Title: Russell E. Ware, MD, PhD, Director, Texas Children's Hematology Center
• Organization: Baylor College of Medicine

reware@bcm.edu

(832) 824-1368

Study Officials

• Russell E. Ware, MD, PhD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

• Ronald W. Helms, PhD

  Rho Incorporated

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2005
• First Posted: July 22, 2005
• Study Start: October 1, 2006
• Primary Completion: June 1, 2010
• Study Completion: December 1, 2010
• Last Updated: January 18, 2013
• Results First Posted: August 17, 2012

Record last verified: 2012-08

Locations

US (28)