Stroke With Transfusions Changing to Hydroxyurea

This study has been terminated.
(The study has been stopped due to safety and futility concerns.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00122980
First received: July 20, 2005
Last updated: January 14, 2013
Last verified: August 2012
  Purpose

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).


Condition Intervention Phase
Hemochromatosis
Cerebrovascular Accident
Anemia, Sickle Cell
Hematologic Diseases
Procedure: Red Cell Transfusions
Procedure: Iron Chelation
Drug: Hydroxyurea
Procedure: Phlebotomy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Stroke With Transfusions Changing to Hydroxyurea

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
    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.

  • Liver Iron Content (LIC) Change-from-baseline [ Time Frame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline) [ Time Frame: Baseline, mid-point (week 64), and study exit after up to 30-month treatment period (due to study termination) ] [ Designated as safety issue: No ]
    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.

  • Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) [ Time Frame: Baseline, midpoint (week 64), and study exit (up to 30 months of treatment) ] [ Designated as safety issue: No ]
    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.

  • Barthel Index (Change From Baseline) [ Time Frame: Baseline and study exit after up to 30-month treatment period (due to study termination) ] [ Designated as safety issue: No ]
    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).

  • Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal [ Time Frame: Baseline and study exit after up to 30-month treatment period (due to study termination) ] [ Designated as safety issue: No ]
    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.

  • Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability [ Time Frame: Baseline and study exit after up to 30-month treatment period (due to study termination) ] [ Designated as safety issue: No ]
    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.

  • Growth and Development - Height (Change From Baseline to Endpoint) [ Time Frame: Baseline to end of study participation (up to 136 weeks) ] [ Designated as safety issue: No ]
  • Growth and Development - Weight (Change From Baseline to Endpoint) [ Time Frame: baseline to end of study participation (up to 136 weeks) ] [ Designated as safety issue: No ]

Enrollment: 134
Study Start Date: October 2006
Study Completion Date: December 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Hydroxyurea and phlebotomy
Drug: Hydroxyurea
Hydroxyurea
Procedure: Phlebotomy
Phlebotomy
Active Comparator: 2
Transfusion and chelation
Procedure: Red Cell Transfusions
Red Blood Cell Transfusions
Procedure: Iron Chelation
Iron Chelation Therapy

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.

  Eligibility

Ages Eligible for Study:   5 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00122980

  Show 28 Study Locations
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Russell E. Ware, MD, PhD Baylor College of Medicine
Principal Investigator: Ronald W. Helms, PhD Rho Incorporated
  More Information

No publications provided by St. Jude Children's Research Hospital

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00122980     History of Changes
Other Study ID Numbers: SWiTCH, 1U01HL078787-01A1
Study First Received: July 20, 2005
Results First Received: December 28, 2011
Last Updated: January 14, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:
Blood Diseases

Additional relevant MeSH terms:
Anemia
Anemia, Sickle Cell
Hematologic Diseases
Hemochromatosis
Cerebral Infarction
Stroke
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Iron Overload
Iron Metabolism Disorders
Metabolic Diseases
Brain Infarction
Brain Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Hydroxyurea
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 21, 2014