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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT01389024
Other study ID # NA_00041623
Secondary ID 3UL1RR025005
Status Recruiting
Phase Phase 2
First received
Last updated
Start date October 2011
Est. completion date August 2019

Study information

Verified date July 2018
Source Johns Hopkins University
Contact Diane Weiss, BA
Phone 410-955-6132
Email dweiss14@jhmi.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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, 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.


Recruitment information / eligibility

Status Recruiting
Enrollment 40
Est. completion date August 2019
Est. primary completion date August 2019
Accepts healthy volunteers No
Gender All
Age group 12 Months to 54 Months
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Hydroxyurea
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.
Placebo
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.

Locations

Country Name City State
United States Johns Hopkins Hospital Baltimore Maryland
United States Sinai Hospital Baltimore Maryland
United States University of Alabama Birmingham Alabama
United States Mercy Children's Hospital Kansas City Missouri
United States Columbia University New York New York
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States St. Louis Children's Hospital Saint Louis Missouri

Sponsors (11)

Lead Sponsor Collaborator
Johns Hopkins University Children's Hospital of Philadelphia, Columbia University, Medical University of South Carolina, Mercy Children's Hospital, National Center for Research Resources (NCRR), RTI International, Sinai Hospital of Baltimore, University of Alabama at Birmingham, Vanderbilt University School of Medicine, Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View 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. — View 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. Epub 2006 Mar 14. — View 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. Epub 2007 Apr 11. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Proportion of participants with severe adverse events attributed to study procedures We will evaluate the safety of study procedures including the sedation required to obtain magnetic resonance imaging (MRI) of the brain in young children and administration of hydroxyurea. 3 years
Secondary Proportion of participants undergoing randomization We will evaluate the proportion of screened participants that undergo randomization to hydroxyurea or placebo 6 months
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