Clinical trial NCT00122980: Stroke With Transfusions Changing to Hydroxyurea
Official title: Stroke With Transfusions Changing to Hydroxyurea
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hemochromatosis
Cerebrovascular Accident
Anemia, Sickle Cell
Hematologic Diseases
Keywords: Blood Diseases
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2005-07-22
Enrollment: 134
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period
timeFrame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)
measure: Liver Iron Content (LIC) Change-from-baseline
timeFrame: Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months)
Secondary outcomes:
measure: Pediatric Quality of Life (PedsQL) - Parent Report (Change From Baseline)
timeFrame: Baseline, mid-point (week 64), and study exit after up to 30-month treatment period (due to study termination)
measure: Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline)
timeFrame: Baseline, midpoint (week 64), and study exit (up to 30 months of treatment)
measure: Barthel Index (Change From Baseline)
timeFrame: Baseline and study exit after up to 30-month treatment period (due to study termination)
measure: Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)-Excluding Verbal
timeFrame: Baseline and study exit after up to 30-month treatment period (due to study termination)
measure: Woodcock-Johnson Test of Cognitive Abilities (WJ-C) and Achievement (WJ-III) (Change From Baseline)- Verbal Ability
timeFrame: Baseline and study exit after up to 30-month treatment period (due to study termination)
measure: Growth and Development - Height (Change From Baseline to Endpoint)
timeFrame: Baseline to end of study participation (up to 136 weeks)
measure: Growth and Development - Weight (Change From Baseline to Endpoint)
timeFrame: baseline to end of study participation (up to 136 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami, Jackson Memorial Hospital
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Egleston
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Grady
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Scottish Rite
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University, Children's Hospital of Michigan
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Children's Mercy Hospital
state: Missouri
city: Paterson
country: United States
facility: St. Joseph's Children's Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Brooklyn
country: United States
facility: State University of New York/Downstate Medical Center
state: New York
city: New Hyde Park
country: United States
facility: Schneider Children's Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center, Morgan Stanley Children's Hospital of New York-Presbyterian
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Baylor College of Medicine
name: Russell E. Ware, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rho Incorporated
name: Ronald W. Helms, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.