Sickle Cell Disease, Stroke
Conditions
Keywords
sickle cell disease, stroke, silent cerebral infarct, children
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.
Interventions
DRUGHydroxyurea
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.
DRUGPlacebo
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.
Sponsors
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
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Months to 54 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Randomized Participants With Central Nervous System Complications | 3 years | A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severe Adverse Events (SAE) Attributed to Study Procedures | 3 years | Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed. |
| Severe Adverse Events (SAE) Attributed to Sedated MRIs | 3 years | Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed. |
| Number of Participants Randomized | 6 months | We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo. |
Countries
United States
Participant flow
Pre-assignment details
28 participants were consented for the study. 18 were fully screened including an MRI of the brain. 12 participants were randomized to the two arms of the study.
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyurea 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 ANC \<4000
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. | 6 |
| Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/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. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Hydroxyurea | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 25.5 Months STANDARD_DEVIATION 11.6 | 19.7 Months STANDARD_DEVIATION 10.2 | 22.6 Months STANDARD_DEVIATION 10.8 |
| Bilirubin | 2.6 mg/dL STANDARD_DEVIATION 1.2 | 2.0 mg/dL STANDARD_DEVIATION 0.9 | 2.3 mg/dL STANDARD_DEVIATION 1.1 |
| Creatinine | 0.25 mg/dL STANDARD_DEVIATION 0.08 | 0.22 mg/dL STANDARD_DEVIATION 0.04 | 0.24 mg/dL STANDARD_DEVIATION 0.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin | 7.8 g/dL STANDARD_DEVIATION 0.9 | 8.3 g/dL STANDARD_DEVIATION 1.1 | 8.1 g/dL STANDARD_DEVIATION 1 |
| Hemoglobin Phenotype Hb-SS | 6 Participants | 5 Participants | 11 Participants |
| Hemoglobin Phenotype Hgb S-β0 thalassemia | 0 Participants | 1 Participants | 1 Participants |
| Mean corpuscular hemoglobin concentration | 34.3 g/dL STANDARD_DEVIATION 1.6 | 33.6 g/dL STANDARD_DEVIATION 1.3 | 34.0 g/dL STANDARD_DEVIATION 1.5 |
| Mean corpuscular volume | 82.9 fL STANDARD_DEVIATION 5.1 | 79.2 fL STANDARD_DEVIATION 9.9 | 81.1 fL STANDARD_DEVIATION 7.7 |
| Platelet count | 417,333 platelets per mm^3 | 319,833 platelets per mm^3 | 368,583 platelets per mm^3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Reticulocyte count | 17.7 % STANDARD_DEVIATION 8.8 | 16.0 % STANDARD_DEVIATION 7.2 | 16.9 % STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
| Transcranial Doppler (TCD) TAMMV | 127.5 cm/sec STANDARD_DEVIATION 23.9 | 109.8 cm/sec STANDARD_DEVIATION 18.3 | 118.7 cm/sec STANDARD_DEVIATION 22.3 |
| Weight at screening | 12.8 kg STANDARD_DEVIATION 2.2 | 12.4 kg STANDARD_DEVIATION 4.8 | 12.6 kg STANDARD_DEVIATION 3.6 |
| White blood cell count | 15,228 cells/mm^3 | 14,442 cells/mm^3 | 14,835 cells/mm^3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 16 |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 3 / 16 |
| serious Total, serious adverse events | 5 / 6 | 6 / 6 | 4 / 16 |
Outcome results
Primary
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.
Time frame: 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxyurea | Number of Randomized Participants With Central Nervous System Complications | 1 Participants |
| Placebo | Number of Randomized Participants With Central Nervous System Complications | 4 Participants |
p-value: 0.291490% CI: [0.009, 1.66]Poisson Regression
Secondary
Number of Participants Randomized
We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxyurea | Number of Participants Randomized | 12 Participants |
Secondary
Severe Adverse Events (SAE) Attributed to Sedated MRIs
Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Time frame: 3 years
Population: 18 participants underwent MRIs as part of screening. A total of 41 MRIs were performed including screening, annual or for cause MRIs. 29 of the 41 MRIs were performed with sedation. For this analysis, the overall number of participants analyzed was the total number of sedated (29) MRIs performed. The primary intent was only to look at the effects of sedated MRI. This outcome was not pre-specified to be collected by arm nor to evaluate treatment effect.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Hydroxyurea | Severe Adverse Events (SAE) Attributed to Sedated MRIs | 3 MRIs |
Secondary
Severe Adverse Events (SAE) Attributed to Study Procedures
Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.
Time frame: 3 years
Population: 18 participants underwent MRIs as part of screening. A total of 41 MRIs were performed including screening, annual or for cause MRIs. For this analysis, the overall number of participants analyzed is the total number of MRIs (41) performed. This outcome was not pre-specified to be collected by arm nor to evaluate treatment effect.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Hydroxyurea | Severe Adverse Events (SAE) Attributed to Study Procedures | 3 MRIs |