Please select the eligibility criteria that correspond to the clinical trial below.
Title: TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A Phase III Randomized Trial to Compare Standard Therapy (Erythrocyte Transfusions) With Alternative Therapy (Hydroxyurea) for the Maintenance of Lowered TCD Velocities in Pediatric Subjects With Sickle Cell Anemia and Abnormal Pre-treatment TCD Velocities
Brief Summary: The primary goal of the Phase III TWiTCH trial is to compare 24 months of alternative therapy (hydroxyurea) to standard therapy (transfusions) for pediatric subjects with sickle cell anemia and abnormally high (≥200 cm/sec) Transcranial Doppler (TCD) velocities, who currently receive chronic transfusions to reduce the risk of primary stroke. For the alternative treatment regimen (hydroxyurea) to be declared non-inferior to the standard treatment regimen (transfusions), after adjusting for baseline differences, the hydroxyurea-treated group must have a mean TCD velocity similar to that observed with transfusion prophylaxis.


Options:
A: INCLUSION:

* Patient must have sickle cell anemia (hemoglobin SS) or sickle beta thalassemia (hemoglobin SB) as confirmed at the local institution.
* Participating institutions must submit documentation of the diagnostic hemoglobin analysis to the Statistical and Clinical Coordinating Centers to confirm the diagnosis of sickle cell anemia prior to randomization.
* Patient must be 5 through 14 years of age.
* Patient must have a cerebral infarct documented by MRI scan as read by the neuroradiology panel.
* Informed consent with assent in accordance with the institutional policies (institutional Institutional Review Board approval) and Federal guidelines (approved by the United States Department of Health and Human Services) must be signed by the patient's legally authorized guardian acknowledging written consent to join the study. When suitable, patients will be requested to give their assent to join the study.

EXCLUSION:

* Patient with a history of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke.
* Patients with a transcranial doppler (TCD) study with a time-averaged mean velocity greater than 200 cm/sec verified by the study radiologist.
* Patients with other neurological problems, such as neurofibromatosis, lead poisoning, or tuberous sclerosis.
* Patients with HIV infection.
* Pregnancy.
* Patients who received treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipate receiving anti-sickling drugs or hydroxyurea during the course of the study.
* Abnormal kidney function (creatinine \> 2x upper limit of normal).
* Patients on chronic blood transfusion therapy for other reasons.
* Patients judged not likely to be compliant by his/her hematologist and local nurse coordinator based on previous compliance in clinic appointments and following advice. Specifically, families that have missed at least two appointments without notification within 12 months prior to the trial or parents of potential patients that have been reported for medical or education neglect are not eligible for this trial.
* Patients unable to receive blood transfusion because of alloimmunization.
* Patients with permanent or semi-permanent metallic (braces on teeth) structures attached to their body. Such patients cannot obtain a MRI of the head to assess the presence of silent cerebral infarcts.
* Siblings randomized in the trial.
B: Inclusion Criteria:

* Majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis (screening may begin at 7 months of age)

Exclusion Criteria:

* Chronic transfusion therapy
* Cancer
* Less than 5th percentile (10th percentile for the pilot study) height, weight, or head circumference for age
* Severe developmental delay (e.g., cerebral palsy or other mental retardation, Grade III/IV intraventricular hemorrhage)
* Stroke with neurological deficit
* Surgical splenectomy
* Participating in other clinical intervention trials
* Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin
* Known hemoglobin S-beta plus thalassemia (hemoglobin A present)
* Any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe
* Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/sec results in ineligibility)
* Previous or current treatment with hydroxyurea (HU) or another anti-sickling drug
* The following exclusion criteria are transient; patients can be re-evaluated for eligibility:

  1. Hemoglobin less than 6.0 gm/dL
  2. Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL
  3. Neutrophil count less than 2,000/cu mm
  4. Platelet count less than 130,000/cu mm
  5. Blood transfusion in the 2 months prior to study entry unless HbA is less than 10%
  6. ALT greater than twice the upper limit of normal
  7. Ferritin less than 10 ng/ml
  8. Serum creatinine greater than twice the upper limit of normal for age
  9. Bayley standardized mental score below 70
C: Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia,HbSOArab)
2. Age range of 4.0-15.99 years, inclusive, at the time of enrollment
3. Documented index (pre-treatment) abnormally high TCD Velocity by Transcranial Doppler ultrasonography. An abnormally high index TCD is defined as TCD V greater than or equal to 200 cm/sec, or abnormally high TCDi V greater than or equal to185cm/sec, or TCD maximum V greater than or equal to 250 cm/sec.
4. At least 12 months of chronic monthly erythrocyte transfusions since the index abnormal TCD examination
5. Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) for the past 6 months before enrollment
6. Parent or guardian willing and able to provide informed consent with verbal or written assent from the child
7. Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria:

1. Completed overt clinical stroke or TIA
2. Inability to obtain TCD velocities due to anatomical abnormalities such as a) Inadequate bone windows b) Previous revascularization procedures (e.g., EDAS)
3. Known severe vasculopathy or moya-moya disease on brain MRA
4. Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following: a) Multiple RBC alloantibodies making cross-matching difficult or impossible b) RBC autoantibodies making cross-matching difficult or impossible c) Religious objection to transfusions that preclude their chronic use d) Non-compliance with transfusions over the past 6 months before enrollment (temporary exclusion)
5. Inability to take or tolerate daily oral hydroxyurea, including a) Known allergy to hydroxyurea therapy b) Positive serology to HIV infection c) Malignancy d) Current lactation e) Previous stem cell transplant or other myelosuppressive therapy
6. Clinical and laboratory evidence of hypersplenism (temporary exclusions): a) Palpable splenomegaly greater than 5cm below the left costal margin AND b) Transfusion requirement greater than 250 mL/kg over the previous 12 months
7. Abnormal laboratory values at initial evaluation (temporary exclusions): a) Pre-transfusion hemoglobin concentration less than 8.0 gm/dL b) WBC count less than 3.0 x 10\^9/L c) Absolute neutrophil count (ANC) less than 1.5 x 10\^9/L d) Platelet count less than 100 x 10\^9/L e) Serum creatinine more than twice the upper limit for age OR greater than or equal to 1.0 mg/dL
8. Current participation in other therapeutic clinical trials
9. Current use of other therapeutic agents for sickle cell disease (e.g., arginine, decitabine, magnesium). Subjects must have been off hydroxyurea for at least 3- months prior to enrollment.
10. Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the CI makes participation ill-advised.
11. Inability or unwillingness to complete required screening and exit studies, including TCD ultrasonography, brain MRI/MRA, liver MRI and blood tests.
12. A sibling enrolled in TWiTCH
13. Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female).
D: Inclusion Criteria for the Observational and Trial Cohorts:

* Hemoglobin diagnosis of SS (two copies of the hemoglobin S gene), SC (one copy of the hemoglobin S gene and one copy of the hemoglobin C gene), or S-β thalassemia (β+ or β0)
* No clinically apparent ACS
* No prior participation in either part of the study

Inclusion Criteria for the Trial Cohort, in addition to the above criteria:

* sPLA2 level greater than 100 ng/mL within the same 24-hour window that coincides with fever and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window
* Fever greater than 38.0º C within the same 24-hour window that coincides with elevated sPLA2 level (greater than 100 ng/mL) and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window
* Chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window of an abnormal sPLA2 level and fever
* Hemoglobin levels equal or less than 10 g/dL at time of study entry
* Informed consent of parent(s) or legal guardian; informed consent or assent of participant as applicable

Exclusion Criteria for Observational and Trial Cohorts:

* Existing diagnosis of a new pulmonary infiltrate diagnosed by chest radiography (pleural effusion not obscuring lung parenchyma will not exclude the person from the study)
* Any coexisting medical condition for which the physician feels that a transfusion may be needed within 24 hours (e.g., severe anemia, stroke)
* Red Blood Cell (RBC) transfusion in the 60 days before study entry
* Unwillingness to sign consent form, or if a minor, unwillingness of parent/guardian to sign consent form
* Treatment with any investigational drug or device in the 30 days before study entry (hydroxyurea is allowable)
* History of alloimmunization that would prevent the participant from receiving blood within 8 hours of eligibility for study entry or history of a life-threatening transfusion reaction
* Objection to transfusion for religious or other reasons from either the participant or guardian
* History of treatment with systemic steroids within 1 week of study entry (inhaled steroids are acceptable)
* Pregnant

Answer: C