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 Criteria:

* Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSOArab)
* Age range of 5.0-18.9 years, inclusive, at the time of study entry
* Initial (primary) completed overt clinical stroke after the age of one year (12 months) with documented infarction on brain computed tomography (CT) or magnetic resonance imaging (MRI)
* At least 18 months of chronic monthly erythrocyte transfusions since primary stroke
* Transfusional iron overload, defined as a previously documented liver iron concentration (LIC) greater than or equal to 5.0 mg Fe per gram of dry weight liver or serum ferritin greater than or equal to 500 ng/mL on two independent measurements
* Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) in the 6 months prior to study entry
* Parent or guardian willing and able to provide informed consent with verbal or written assent from the child (less than 18 years of age) or subject willing and able to provide informed consent (older than 18 years of age)
* Ability to comply with study-related treatments, evaluations, and follow-up

Exclusion Criteria:

* Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following:

  1. Multiple RBC alloantibodies making cross-matching difficult or impossible
  2. RBC autoantibodies making cross-matching difficult or impossible
  3. Religious objection to transfusions that preclude their chronic use
  4. Non-compliance with transfusions in the 6 months prior to study entry (temporary exclusion)
* Inability to take or tolerate daily oral hydroxyurea, due to any of the following:

  1. Known allergy to hydroxyurea therapy
  2. HIV infection
  3. Cancer
  4. Pregnant or breastfeeding
  5. Previous stem cell transplant or other myelosuppressive therapy
* Clinical and laboratory evidence of hypersplenism, due to any of the following:

  1. Palpable splenomegaly greater than 5 cm below the left costal margin and
  2. Transfusion requirement greater than 250 mL/kg in the 12 months prior to study entry
* Abnormal laboratory values at initial evaluation (temporary exclusion):

  1. Pre-transfusion hemoglobin concentration less than 7.0 gm/dL
  2. White blood cell (WBC) count less than 3.0 x 109/L
  3. Absolute neutrophil count (ANC) less than 1.5 x 109/L
  4. Platelet count less than 100 x 109/L
  5. Serum creatinine more than twice the upper limit for age OR greater than or equal to 1.0 mg/dL
* Current participation in other therapeutic clinical trials
* Current use of other therapeutic agents for SCA (e.g., arginine, decitabine, magnesium)
* Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the study physician makes study participation ill-advised
* Inability or unwillingness to complete required screening studies, including blood tests, brain MRI/magnetic resonance angiography (MRA), and liver biopsy
* A sibling enrolled in SWiTCH
B: Inclusion Criteria:

* Pediatric subjects with documented sickle cell anemia (HbSS supported by hemoglobin electrophoresis or by peripheral blood smear showing sickled red blood cells)
* Age range of 1.00-3.99 years, inclusive, at the time of enrollment
* Weight at least 5.0 kg at the time of enrollment
* Willingness to comply with all study-related treatments, evaluations, and follow up

Exclusion Criteria:

* Known chronic medical condition (e.g., HIV, malignancy, active clinical tuberculosis)
* Severe malnutrition determined by impaired growth parameters as defined by WHO (weight for length/height or weight-for-length/height \> 3 z-scores below the median WHO growth standards)
* Pre-existing severe hematological toxicity:

  1. Hb \<4.0 g/dL
  2. Hb \<6.0 g/dL AND ARC \<100 x 10E9/L
  3. Hb \<7.0 g/dL AND ARC \<80 x 10E9/L
  4. Platelets \<80 x 10E9/L
  5. ANC \<1.0 x 10E9/L
* Alanine transaminase (ALT) or creatinine \>2 times the upper limit of normal for age
* Blood transfusion within 30 days prior to enrollment
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:

* Diagnosis of HbSC disease
* Hemoglobin level between 8 and 12.5 g/dL
* At least one vaso-occlusive event (e.g., pain, acute chest syndrome) in the 12 months prior to study entry. An episode of pain is defined as the occurrence of pain in the extremities, back, abdomen, chest, or head that lasts at least 2 hours; requires a visit to a hospital, emergency room, clinic, or provider's office; and is not explained except by SCD. Acute chest syndrome is defined as a new pulmonary infiltrate on a chest x-ray associated with a fever (greater than 38.5° C), tachypnea, wheezing, cough, or chest pain.
* Regular compliance with comprehensive care
* In a steady disease state and not experiencing an acute complication of SCD (i.e., no hospitalization, pain event, or episode of acute chest syndrome within the 1 month prior to study entry)

Exclusion Criteria:

* Previous transfusion with remaining hemoglobin A greater than 10%
* Previous treatment with hydroxyurea within the last 3 months
* Previous treatment with magnesium within the 3 months prior to study entry (including vitamins containing magnesium)
* Poor compliance with previous treatment regimens
* Liver dysfunction (SGPT greater than twice the upper limit of normal) within the 1 month prior to study entry
* Kidney dysfunction (creatinine greater than or equal to 1.0 mg/dL for participants less than 18 years of age; greater than or equal to 1.2 mg/dL for participants 18 years of age or older) within the 1 month prior to study entry
* Pregnant
* Ten or more hospital admissions for pain in the 12 months prior to study entry
* Daily use of narcotics
* Treatment with any investigational drug in the 3 months prior to study entry
* Less than 3% red blood cells with density greater than 41 g/dL (as measured by the ADVIA 120 system)
* Positive HIV test
* Other long-term illness or disorder other than SCD that could adversely affect performance in the study (e.g., tuberculosis)

Answer: C