Stroke With Transfusions Changing to Hydroxyurea

Terminated

Phase 3 Results

Trial Description

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.

Trial Stopped: The study has been stopped due to safety and futility concerns.

Conditions

Interventions

  • Transfusion Procedure/Surgery
    Intervention Desc: Blood exchange for stroke prophylaxis in sickle cell anemia
  • Hydroxyurea (Hydrea┬« and Droxia┬« Other names Return to top Hydroxycarbamide )Drug
    Intervention Desc: Hydroxyurea
    ARM 1: Kind: Experimental
    Label: 1
    Description: Hydroxyurea and phlebotomy
  • Phlebotomy Procedure
    Intervention Desc: Phlebotomy
    ARM 1: Kind: Experimental
    Label: 1
    Description: Hydroxyurea and phlebotomy
  • Chelation therapy Drug
    Intervention Desc: Chelation therapy is the administration of chelating agents to remove heavy metals from the body.
  • Red Cell Transfusions Procedure
    Intervention Desc: Red Blood Cell Transfusions
    ARM 1: Kind: Experimental
    Label: 2
    Description: Transfusion and chelation
  • Iron Chelation Procedure
    Intervention Desc: Iron Chelation Therapy
    ARM 1: Kind: Experimental
    Label: 2
    Description: Transfusion and chelation

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Prevention
  • Endpoint: Efficacy Study
  • Intervention: Parallel Assignment

Patient Involvement

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.

Outcomes

Type Measure Time Frame Safety Issue
Primary Secondary stroke
Secondary Comparisons of growth and development; frequency of non-stroke neurological and other sickle-related events; quality of life; neurocognitive decline; transfusion-, chelation-, hydroxyurea-, phlebotomy- and liver biopsy-related complications.
Secondary Comparisons of growth and development Measured at Month 30 No
Secondary Frequency of non-stroke neurological and other sickle-related events Measured at Month 30 No
Secondary Quality of life Measured at Month 30 No
Secondary Neurocognitive decline Measured at Month 30 No
Secondary Transfusion-, Chelation-, Hydroxyurea-, Phlebotomy- and Liver biopsy-related complications Measured at Month 30 No
Primary Occurrence of an Adjudicated Secondary Stroke During the 30-month Treatment Period Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months) Yes
Primary Liver Iron Content (LIC) Change-from-baseline Because the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 30 Months) No
Secondary 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) No
Secondary Pediatric Quality of Life (PedsQL) - Child Report (Change From Baseline) Baseline, midpoint (week 64), and study exit (up to 30 months of treatment) No
Secondary Barthel Index (Change From Baseline) Baseline and study exit after up to 30-month treatment period (due to study termination) No
Secondary 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) No
Secondary 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) No
Secondary Growth and Development - Height (Change From Baseline to Endpoint) Baseline to end of study participation (up to 136 weeks) No
Secondary Growth and Development - Weight (Change From Baseline to Endpoint) baseline to end of study participation (up to 136 weeks) No

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