Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease

NCT01389024 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: NA_000416233UL1RR025005
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 5

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.

Conditions

Sickle Cell Disease; Stroke

Keywords

sickle cell disease; stroke; silent cerebral infarct; children

Outcome Measures

Primary Outcomes (1)

• 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.

  3 years

Secondary Outcomes (3)

• Severe Adverse Events (SAE) Attributed to Study Procedures

  3 years

• Severe Adverse Events (SAE) Attributed to Sedated MRIs

  3 years

• Number of Participants Randomized

  6 months

Study Arms (2)

Hydroxyurea

EXPERIMENTAL

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

Drug: Hydroxyurea

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Hydroxyurea DRUG

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.

Also known as: Droxia, Hydrea

Hydroxyurea

Placebo DRUG

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.

Also known as: Sugar

Placebo

Eligibility Criteria

• Age: 12 Months - 54 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Other significant organ system dysfunction
• Known allergy or intolerance of hydroxyurea
• Significant prematurity (gestational age of \< 32 weeks)
• \. The parents or guardians must provide consent for 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.

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Center for Research Resources (NCRR): collaborator
• Washington University School of Medicine: collaborator
• Vanderbilt University School of Medicine: collaborator
• University of Alabama at Birmingham: collaborator
• Children's Hospital of Philadelphia: collaborator
• Medical University of South Carolina: collaborator
• RTI International: collaborator
• Columbia University: collaborator
• Children's Mercy Hospital Kansas City: collaborator
• Sinai Hospital of Baltimore: collaborator

Study Sites (5)

University of Alabama

Birmingham, Alabama, 35233, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Mercy Children's Hospital

Kansas City, Missouri, 64108, United States

Location

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• 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.

  PMID: 19500105 BACKGROUND

• 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.

  PMID: 17429008 BACKGROUND

• 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.

  PMID: 16537809 BACKGROUND

• 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.

  PMID: 20201689 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Stroke

Interventions

Hydroxyurea; Sugars

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals; Carbohydrates

Limitations and Caveats

Interpretation is limited by small sample size.

Results Point of Contact

• Title: Dr. James Casella
• Organization: The Johns Hopkins University School of Medicine

jcasella@jhmi.edu

410-955-6132

Study Officials

• James F. Casella, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2011
• First Posted: July 7, 2011
• Study Start: August 16, 2012
• Primary Completion: May 24, 2022
• Study Completion: May 24, 2022
• Last Updated: July 10, 2024
• Results First Posted: December 28, 2022

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)