Stroke With Transfusions Changing to Hydroxyurea

NCT ID: NCT00122980

Last Updated: 2013-01-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 134 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-10-31
• Study Completion Date: 2010-12-31

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).

Detailed Description

BACKGROUND:

Stroke occurs in 10% of children with SCA and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload can cause chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death in young patients with SCA and stroke. An alternative to transfusions for secondary stroke prevention that also addresses the issue of transfusion acquired iron overload is clearly needed. Hydroxyurea can prevent acute vaso-occlusive events in SCA, but its utility for cerebrovascular disease and for the prevention of secondary stroke in SCA is not proven. Pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA; after transfusions are discontinued, serial phlebotomy reduces iron burden.

DESIGN NARRATIVE:

This is a Phase III randomized clinical trial for children with SCA. The hypothesis is that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence rate and significantly reduce the hepatic iron burden. The primary aim 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. Additional aims include comparisons of growth and development, frequency of non-stroke neurological and other sickle-related events, and quality of life. The use of hydroxyurea for secondary stroke prevention, coupled with removal of excess iron by phlebotomy, would represent a significant improvement in the management of individuals with SCA and stroke. If hydroxyurea is effective for the prevention of secondary stroke, it may also be beneficial for other children with SCA and cerebrovascular disease, including those at risk for primary stroke.

The trial includes approximately 130 children (5.0-18.9 years of age with 65 subjects per treatment arm) with SCA who have had symptomatic cerebral infarctions and have been treated with red cell transfusions for at least 18 months. After completing baseline screening studies, half the participants will be switched to a therapeutic program of hydroxyurea and phlebotomy. Half of the participants will remain on transfusion and chelation. The composite primary endpoint in this study is to compare two modalities of treatment for the prevention of secondary stroke and management of iron overload. The impetus for this trial is the fact that long-term transfusion and chelation therapy in children is difficult, is frequently unsuccessful, and is often complicated by severe symptomatic iron overload, particularly of the heart, lungs, and liver.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

1

Hydroxyurea and phlebotomy

Group Type: ACTIVE_COMPARATOR

Hydroxyurea

Intervention Type: DRUG

Hydroxyurea

Phlebotomy

Intervention Type: PROCEDURE

Phlebotomy

2

Transfusion and chelation

Group Type: ACTIVE_COMPARATOR

Red Cell Transfusions

Intervention Type: PROCEDURE

Red Blood Cell Transfusions

Iron Chelation

Intervention Type: PROCEDURE

Iron Chelation Therapy

Interventions

Red Cell Transfusions

Red Blood Cell Transfusions

Intervention Type: PROCEDURE

Iron Chelation

Iron Chelation Therapy

Intervention Type: PROCEDURE

Hydroxyurea

Hydroxyurea

Intervention Type: DRUG

Phlebotomy

Phlebotomy

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following:

1. Multiple RBC alloantibodies making cross-matching difficult or impossible

2. RBC autoantibodies making cross-matching difficult or impossible

3. Religious objection to transfusions that preclude their chronic use

4. Non-compliance with transfusions in the 6 months prior to study entry (temporary exclusion)

• Inability to take or tolerate daily oral hydroxyurea, due to any of the following:

1. Known allergy to hydroxyurea therapy

2. HIV infection

3. Cancer

4. Pregnant or breastfeeding

5. Previous stem cell transplant or other myelosuppressive therapy

• Clinical and laboratory evidence of hypersplenism, due to any of the following:

1. Palpable splenomegaly greater than 5 cm below the left costal margin and

2. Transfusion requirement greater than 250 mL/kg in the 12 months prior to study entry

• Abnormal laboratory values at initial evaluation (temporary exclusion):

1. Pre-transfusion hemoglobin concentration less than 7.0 gm/dL

2. White blood cell (WBC) count less than 3.0 x 109/L

3. Absolute neutrophil count (ANC) less than 1.5 x 109/L

4. Platelet count less than 100 x 109/L

5. Serum creatinine more than twice the upper limit for age OR greater than or equal to 1.0 mg/dL

• Current participation in other therapeutic clinical trials
• Current use of other therapeutic agents for SCA (e.g., arginine, decitabine, magnesium)
• Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the study physician makes study participation ill-advised
• Inability or unwillingness to complete required screening studies, including blood tests, brain MRI/magnetic resonance angiography (MRA), and liver biopsy
• A sibling enrolled in SWiTCH

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

St. Jude Children's Research Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Russell E. Ware, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Ronald W. Helms, PhD

Role: PRINCIPAL_INVESTIGATOR

Rho Incorporated

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Children's National Medical Center

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

Nemours Children's Clinic

Jacksonville, Florida, United States

University of Miami, Jackson Memorial Hospital

Miami, Florida, United States

Nemours Children's Clinic

Orlando, Florida, United States

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, United States

Children's Healthcare of Atlanta at Grady

Atlanta, Georgia, United States

Children's Healthcare of Atlanta at Scottish Rite

Atlanta, Georgia, United States

Children's Memorial Hospital

Chicago, Illinois, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Wayne State University, Children's Hospital of Michigan

Detroit, Michigan, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

The Children's Mercy Hospital

Kansas City, Missouri, United States

St. Joseph's Children's Hospital

Paterson, New Jersey, United States

State University of New York/Downstate Medical Center

Brooklyn, New York, United States

Schneider Children's Hospital

New Hyde Park, New York, United States

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

New York, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

East Carolina University

Greenville, North Carolina, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

Eastern Virginia Medical School

Norfolk, Virginia, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 24914136 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23861242 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22318199 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 21826782 (View on PubMed)

Other Identifiers

1U01HL078787-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

SWiTCH

Identifier Type: -

Identifier Source: org_study_id