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HemochromatosisPhase 3NCT00122980

Stroke With Transfusions Changing to Hydroxyurea

A Phase 3 study testing Red Cell Transfusions, Iron Chelation and Hydroxyurea in people with Hemochromatosis and Cerebrovascular Accident, run by St. Jude Children's Research Hospital at 28 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 5 to 18 years
What is being tested?
Red Cell Transfusions, Iron Chelation and Hydroxyurea
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
134 participants
Where
28 sitesUnited States
Study dates
Oct 2006to Dec 2010
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 5 to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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

Who cannot join

  • 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
  • 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:
Show all 25Show fewer
  • 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
  • Abnormal laboratory values at initial evaluation (temporary exclusion):
  • Pre-transfusion hemoglobin concentration less than 7.0 gm/dL
  • White blood cell (WBC) count less than 3.0 x 109/L
  • Absolute neutrophil count (ANC) less than 1.5 x 109/L
  • Platelet count less than 100 x 109/L
  • 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

Trial locations and contacts

28 sites in 1 country.

28 sites in 1 country

United States28 sites

  • Children's Healthcare of Atlanta at Egleston

    Atlanta, Georgia, 30322

  • Children's Healthcare of Atlanta at Grady

    Atlanta, Georgia, 30322

  • Children's Healthcare of Atlanta at Scottish Rite

    Atlanta, Georgia, 30342

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35233

  • Boston Children's Hospital

    Boston, Massachusetts, 02115

  • State University of New York/Downstate Medical Center

    Brooklyn, New York, 11203

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • Children's Memorial Hospital

    Chicago, Illinois, 60614

  • Cincinnati Children's Hospital

    Cincinnati, Ohio, 45229

  • University of Texas Southwestern Medical Center at Dallas

    Dallas, Texas, 75390-9063

  • Wayne State University, Children's Hospital of Michigan

    Detroit, Michigan, 48201

  • East Carolina University

    Greenville, North Carolina, 27834

  • Baylor College of Medicine

    Houston, Texas, 77030-2399

  • University of Mississippi Medical Center

    Jackson, Mississippi, 39216

  • Nemours Children's Clinic

    Jacksonville, Florida, 32207

  • The Children's Mercy Hospital

    Kansas City, Missouri, 64108

  • St. Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • University of Miami, Jackson Memorial Hospital

    Miami, Florida, 33136

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Schneider Children's Hospital

    New Hyde Park, New York, 11040

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

    New York, New York, 10032

  • Eastern Virginia Medical School

    Norfolk, Virginia, 23510

  • Nemours Children's Clinic

    Orlando, Florida, 32806

  • St. Joseph's Children's Hospital

    Paterson, New Jersey, 07503

  • The Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15213

  • Montefiore Medical Center

    The Bronx, New York, 10467

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

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).

Read the 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.

Being tested
Red Cell Transfusions, Iron Chelation, Hydroxyurea, Phlebotomy
Keywords
Blood Diseases
Medical subject headings
Hemochromatosis, Stroke, Anemia, Sickle Cell, Hematologic Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Red Cell TransfusionsProcedure or surgery

    Red Blood Cell Transfusions

  • Iron ChelationProcedure or surgery

    Iron Chelation Therapy

  • HydroxyureaDrug

    Hydroxyurea

  • PhlebotomyProcedure or surgery

    Phlebotomy

Study groups in NCT00122980
Study groupRoleWhat they receive
1Active comparatorHydroxyurea and phlebotomy
Receives: Drug: Hydroxyurea; Procedure: Phlebotomy
2Active comparatorTransfusion and chelation
Receives: Procedure: Red Cell Transfusions; Procedure: Iron Chelation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

  2. 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.

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

Secondary outcomes (7)

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

    The PedsQL(TM) Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics.

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

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

    The PedsQLTM Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It has a Likert 5-points scale (never to almost always) which were transformed to a 0 to 100 scale based on the PedsQL scoring algorithms, higher scores indicating better quality of life characteristics.

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

  3. Barthel Index (Change From Baseline)

    The Barthel Index is a measure of activities of daily living (ADL) and assesses the degree of disability in a particular participant. The index records indicators of independence in terms of the disability caused by impairments, such as those that may be sequelae of stroke. The index was used as a record of what the participant did, not as a record of what the participant could do. Barthel scores range from 0 to 100, with higher scores indicating greater independence in daily living activities (caring for oneself).

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

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

    This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Scaled scores range from 0-100. Higher scores mean better abilities/achievements.

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

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

    This test is designed to assess both broad and narrow cognitive abilities in children age 4 years and above as well as to measure major aspects of academic achievement in persons aged 2-90 years. Higher scores mean better abilities/achievements. Scaled scores range from 0-100.

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

  6. Growth and Development - Height (Change From Baseline to Endpoint)

    Measured: Baseline to end of study participation (up to 136 weeks)

  7. Growth and Development - Weight (Change From Baseline to Endpoint)

    Measured: baseline to end of study participation (up to 136 weeks)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2005 (estimated)
  2. Study startOct 2006
  3. Primary completionJun 2010
  4. Study completionDec 2010

Why it stopped: The study has been stopped due to safety and futility concerns.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
134 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00122980
Sponsor's protocol ID
SWiTCH
Other IDs
1U01HL078787-01A1
Status last verified
Aug 2012
First submitted
20 Jul 2005
Last updated
18 Jan 2013
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 24914136

  • 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.

    PubMed 23861242

  • 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.

    PubMed 22318199

  • 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.

    PubMed 21826782

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Red Cell Transfusions, Iron Chelation and Hydroxyurea in people with Hemochromatosis and Cerebrovascular Accident, run by St. Jude Children's Research Hospital at 28 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 18 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Aug 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period (time frame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00122980, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2013.

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