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Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (HUPrevent)

Primary Purpose

Sickle Cell Disease, Stroke

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Hydroxyurea
Placebo
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Sickle Cell Disease focused on measuring sickle cell disease, stroke, silent cerebral infarct, children

Eligibility Criteria

12 Months - 54 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria for Screening

  1. Participant must have sickle cell anemia (hemoglobin SS) or sickle Beta-zero (null) thalassemia (hemoglobin S-B0) as confirmed at the local institution by hemoglobin analysis after six months of age.
  2. Participant must be 9 to 48 months of age. All screening procedures except MRI can be completed between 9 and 12 months of age, with the exception of the MRI, for which the child must have reached the age of 12 months.
  3. Informed consent must be signed by the participant's legally authorized guardian acknowledging written consent to join the study.

Exclusion Criteria for Screening

  1. History of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke.
  2. Other neurological problems, such as neurofibromatosis, lead poisoning, non-febrile seizure disorder, or tuberous sclerosis.
  3. Known human immunodeficiency virus (HIV) infection.
  4. Treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipated treatment during the course of the study.
  5. Chronic blood transfusion therapy, ongoing or planned.
  6. Poor adherence likely per his/her hematologist and study coordinator based on previous compliance in clinic appointments and following advice.
  7. Presence or planned permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth), which their physicians believe will interfere with the MRI of the brain.
  8. History of two or more TCD studies with a velocity ≥ 200 cm/sec by the non-imaging technique, or ≥185 cm/sec for the imaging technique or a indeterminate TCD.
  9. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions.
  10. Other significant organ system dysfunction
  11. Known allergy or intolerance of hydroxyurea
  12. Significant prematurity (gestational age of < 32 weeks)

Inclusion Criteria for MRI of the Brain with Sedation

1. The parents or guardians must provide consent for sedation.

Exclusion Criteria for MRI of the Brain with Sedation

  1. Failure to pass MRI screening checklist
  2. Obstructive sleep apnea (OSA) and receiving therapy [e.g. continuous positive airway pressure], or being evaluated or followed by a specialist for management of severe OSA
  3. Less than 12 months of age.
  4. Allergic reactions such as urticaria or bronchospasm or previous adverse reactions to propofol, eggs, or soy products, if used at the participating center.
  5. Allergy or previous adverse reaction to pentobarbital, if used at the participating center
  6. Known major chromosomal abnormalities

  7. Known airway abnormalities that would increase the risk of sedation/anesthesia.

    Temporary Exclusions

  8. Room air oxygen saturation greater than or equal to 5% below the participant's baseline on the day of the MRI with sedation.
  9. Room air oxygen saturation <90% on the day of the MRI with sedation.
  10. Hemoglobin <6.5 g/dl (must be measured within 30 days of MRI).
  11. Temperature >38˚ C on the day of sedation

8. Upper or lower respiratory infection, active bronchospasm, acute chest syndrome, splenic sequestration or other acute complications of sickle cell disease other than pain in the last 4 weeks (from resolution of symptoms) 9. Pain crisis within two weeks requiring treatment with opiates

Inclusion Criteria for Randomization

  1. Participant must be 12 to 54 months of age
  2. Participant must have successfully completed screening procedures (TCD, MRI of the brain, neurology exam, and cognitive evaluation)

Exclusion Criteria for Randomization

  1. Participants whose MRI show a silent or overt cerebral infarct.
  2. Participants who have a non-imaging TCD study with a velocity ≥ 185 cm/sec or a TCD that is indeterminate.
  3. Participants with abnormal kidney function (creatinine > 0.8 mg/dl)
  4. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions.

Sites / Locations

  • University of Alabama
  • Johns Hopkins Hospital
  • Mercy Children's Hospital
  • St. Louis Children's Hospital
  • Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Hydroxyurea

Placebo

Arm Description

Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or Absolute Neutrophil Count (ANC) <4000

Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day

Outcomes

Primary Outcome Measures

Number of Randomized Participants With Central Nervous System Complications
A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.

Secondary Outcome Measures

Severe Adverse Events (SAE) Attributed to Study Procedures
Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Severe Adverse Events (SAE) Attributed to Sedated MRIs
Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Number of Participants Randomized
We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo.

Full Information

First Posted
June 30, 2011
Last Updated
December 5, 2022
Sponsor
Johns Hopkins University
Collaborators
National Center for Research Resources (NCRR), Washington University School of Medicine, Vanderbilt University School of Medicine, University of Alabama at Birmingham, Children's Hospital of Philadelphia, Medical University of South Carolina, RTI International, Columbia University, Children's Mercy Hospital Kansas City, Sinai Hospital of Baltimore
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1. Study Identification

Unique Protocol Identification Number
NCT01389024
Brief Title
Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease
Acronym
HUPrevent
Official Title
Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
August 16, 2012 (Actual)
Primary Completion Date
May 24, 2022 (Actual)
Study Completion Date
May 24, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
National Center for Research Resources (NCRR), Washington University School of Medicine, Vanderbilt University School of Medicine, University of Alabama at Birmingham, Children's Hospital of Philadelphia, Medical University of South Carolina, RTI International, Columbia University, Children's Mercy Hospital Kansas City, Sinai Hospital of Baltimore

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a pilot study of hydroxyurea versus placebo to reduce central nervous system complications (abnormally fast blood flow to the brain, silent cerebral infarct or stroke) in young children with sickle cell disease. The investigators plan to identify children 12 to 48 months old without central nervous system complications and randomly assign 20 to treatment with hydroxyurea and 20 to treatment with placebo for 36 months. Neither the study doctors nor the participants will know which treatment they are receiving.
Detailed Description
Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly morbid complications of sickle cell disease (SCD) in children. Current approaches to the prevention and treatment of neurological complications in SCD include screening by transcranial Doppler ultrasound (TCD) to identify children with elevated cerebral blood flow velocity who are at increased risk for strokes; these children are then typically treated with chronic transfusions indefinitely. Hydroxyurea (HU) may have beneficial effects on central nervous system (CNS) complications in SCD and reduces the frequency of painful crisis, acute chest syndrome and transfusion. The safety of HU in infants and children has been suggested in a National Institutes of Health (NIH) sponsored phase III trial; however, the exact indications for the use of HU in children remain unclear, as well as its efficacy in preventing central nervous system (CNS) complications of SCD. Our preliminary data suggest that, if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%, the majority of pediatric hematologists would prescribe HU to all young children with SCD. The long term goal of this project is to perform a primary prevention trial to demonstrate the neuroprotective effect of HU and broaden the indications for HU in children. The goals of this proposal are to: 1) conduct an internal pilot randomized placebo-controlled trial of HU to reduce the CNS complications of SCD (the term internal pilot is used, as the results from the participants in the pilot will be analyzed as part of a definitive phase III trial to follow); 2) demonstrate the safety of hydroxyurea and study procedures in young children with SCD; and 3) create the leadership, network of clinical centers and other procedures necessary to conduct a definitive phase III trial demonstrating the efficacy of HU for primary prevention of the neurological complications of SCD. The primary endpoint for the internal pilot and definitive phase III trials will be the development of abnormal TCD, SCI, transient ischemic attack (TIA) or stroke. To begin the internal pilot trial, the investigators obtained Clinical and Translational Science Award (CTSA) support at Johns Hopkins and Washington University; these sites will screen 40 participants 9-48 months of age and randomly assign and follow 20 participants for three years. Four additional centers (Children's Hospital of Philadelphia, Vanderbilt University, Children's Hospital Medical Center, Cincinnati and the University of Alabama, Birmingham) began enrollment (up to 20 patients screened and 10 participants randomly assigned per site), to provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70 participant years of follow-up. Additional sites have been added. Participants must have TCD measurements that are well below transfusion thresholds and magnetic resonance imaging (MRI) of the brain without evidence of SCI. Participants in the internal pilot will continue into a phase III trial, to complete 3 years on HU or placebo. The information from the internal pilot trial will be used to improve the design of the definitive phase III trial. The results of these studies could lead to true primary prevention of CNS complications of SCD, including abnormal TCD, SCI, neurocognitive impairment and stroke. In doing so, this study could also reduce the burden of chronic transfusions and change clinical practice by broadening the indications for HU.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease, Stroke
Keywords
sickle cell disease, stroke, silent cerebral infarct, children

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hydroxyurea
Arm Type
Experimental
Arm Description
Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or Absolute Neutrophil Count (ANC) <4000
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Other Intervention Name(s)
Droxia, Hydrea
Intervention Description
Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an Absolute Neutrophil Count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar
Intervention Description
Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Primary Outcome Measure Information:
Title
Number of Randomized Participants With Central Nervous System Complications
Description
A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Severe Adverse Events (SAE) Attributed to Study Procedures
Description
Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Time Frame
3 years
Title
Severe Adverse Events (SAE) Attributed to Sedated MRIs
Description
Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Time Frame
3 years
Title
Number of Participants Randomized
Description
We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
54 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for Screening Participant must have sickle cell anemia (hemoglobin SS) or sickle Beta-zero (null) thalassemia (hemoglobin S-B0) as confirmed at the local institution by hemoglobin analysis after six months of age. Participant must be 9 to 48 months of age. All screening procedures except MRI can be completed between 9 and 12 months of age, with the exception of the MRI, for which the child must have reached the age of 12 months. Informed consent must be signed by the participant's legally authorized guardian acknowledging written consent to join the study. Exclusion Criteria for Screening History of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke. Other neurological problems, such as neurofibromatosis, lead poisoning, non-febrile seizure disorder, or tuberous sclerosis. Known human immunodeficiency virus (HIV) infection. Treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipated treatment during the course of the study. Chronic blood transfusion therapy, ongoing or planned. Poor adherence likely per his/her hematologist and study coordinator based on previous compliance in clinic appointments and following advice. Presence or planned permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth), which their physicians believe will interfere with the MRI of the brain. History of two or more TCD studies with a velocity ≥ 200 cm/sec by the non-imaging technique, or ≥185 cm/sec for the imaging technique or a indeterminate TCD. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions. Other significant organ system dysfunction Known allergy or intolerance of hydroxyurea Significant prematurity (gestational age of < 32 weeks) Inclusion Criteria for MRI of the Brain with Sedation 1. The parents or guardians must provide consent for sedation. Exclusion Criteria for MRI of the Brain with Sedation Failure to pass MRI screening checklist Obstructive sleep apnea (OSA) and receiving therapy [e.g. continuous positive airway pressure], or being evaluated or followed by a specialist for management of severe OSA Less than 12 months of age. Allergic reactions such as urticaria or bronchospasm or previous adverse reactions to propofol, eggs, or soy products, if used at the participating center. Allergy or previous adverse reaction to pentobarbital, if used at the participating center Known major chromosomal abnormalities Known airway abnormalities that would increase the risk of sedation/anesthesia. Temporary Exclusions Room air oxygen saturation greater than or equal to 5% below the participant's baseline on the day of the MRI with sedation. Room air oxygen saturation <90% on the day of the MRI with sedation. Hemoglobin <6.5 g/dl (must be measured within 30 days of MRI). Temperature >38˚ C on the day of sedation 8. Upper or lower respiratory infection, active bronchospasm, acute chest syndrome, splenic sequestration or other acute complications of sickle cell disease other than pain in the last 4 weeks (from resolution of symptoms) 9. Pain crisis within two weeks requiring treatment with opiates Inclusion Criteria for Randomization Participant must be 12 to 54 months of age Participant must have successfully completed screening procedures (TCD, MRI of the brain, neurology exam, and cognitive evaluation) Exclusion Criteria for Randomization Participants whose MRI show a silent or overt cerebral infarct. Participants who have a non-imaging TCD study with a velocity ≥ 185 cm/sec or a TCD that is indeterminate. Participants with abnormal kidney function (creatinine > 0.8 mg/dl) Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James F. Casella, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Mercy Children's Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
St. Louis Children's Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19500105
Citation
Kwiatkowski JL, Zimmerman RA, Pollock AN, Seto W, Smith-Whitley K, Shults J, Blackwood-Chirchir A, Ohene-Frempong K. Silent infarcts in young children with sickle cell disease. Br J Haematol. 2009 Aug;146(3):300-5. doi: 10.1111/j.1365-2141.2009.07753.x. Epub 2009 Jun 4.
Results Reference
background
PubMed Identifier
17429008
Citation
Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE. Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood. 2007 Aug 1;110(3):1043-7. doi: 10.1182/blood-2006-11-057893. Epub 2007 Apr 11.
Results Reference
background
PubMed Identifier
16537809
Citation
Strouse JJ, Cox CS, Melhem ER, Lu H, Kraut MA, Razumovsky A, Yohay K, van Zijl PC, Casella JF. Inverse correlation between cerebral blood flow measured by continuous arterial spin-labeling (CASL) MRI and neurocognitive function in children with sickle cell anemia (SCA). Blood. 2006 Jul 1;108(1):379-81. doi: 10.1182/blood-2005-10-4029. Epub 2006 Mar 14.
Results Reference
background
PubMed Identifier
20201689
Citation
Casella JF, King AA, Barton B, White DA, Noetzel MJ, Ichord RN, Terrill C, Hirtz D, McKinstry RC, Strouse JJ, Howard TH, Coates TD, Minniti CP, Campbell AD, Vendt BA, Lehmann H, Debaun MR. Design of the silent cerebral infarct transfusion (SIT) trial. Pediatr Hematol Oncol. 2010 Mar;27(2):69-89. doi: 10.3109/08880010903360367.
Results Reference
background

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Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease

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