Please select the eligibility criteria that correspond to the clinical trial below.
Title: Sparing Conversion to Abnormal TCD Elevation (SCATE) - a Phase III Clinical Trial to Compare Standard Care (Observation) With Alternative Therapy (Hydroxyurea) for Reducing the Risk of Converting to an Abnormal TCD Velocity in Children With Sickle Cell Anemia and Conditional Pre-treatment TCD Velocities.
Brief Summary: The primary goal of the Phase III SCATE trial is to compare 30 months of alternative therapy (hydroxyurea) to standard care (observation) in children with sickle cell anemia and conditional (170 - 199cm/sec) Transcranial Doppler (TCD) velocities. For the alternative regimen (hydroxyurea) to be declared superior to the standard treatment regimen (observation), the hydroxyurea-treated group must have a three-fold reduction in the incidence of conversion to abnormal TCD velocities (≥ 200 cm/sec), compared to the standard treatment arm.


Options:
A: 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
B: Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSD, HbSOArab)
2. Age: ≥ 2 and \< 11 years of age, at the time of enrollment
3. Conditional TCD Velocity (170 - 199cm/sec) by Transcranial Doppler ultrasonography examination within 3 months of enrollment
4. Parent or guardian willing and able to provide informed consent
5. Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria:

1. Prior abnormal TCD Velocity
2. History of clinical stroke
3. Inability to take or tolerate daily oral hydroxyurea, including

   * Known allergy to hydroxyurea therapy
   * Known positive serology to HIV infection
   * Known malignancy
   * Current lactation
4. Abnormal laboratory values at initial evaluation (temporary exclusions):

   * Hemoglobin concentration \< 6.0 gm/dL
   * Absolute reticulocyte count \< 100 x 10\^9/L with a hemoglobin concentration \< 8.0 gm/dL
   * WBC count \< 3.0 x 10\^9/L
   * Absolute neutrophil count (ANC) \< 1.0 x 10\^9/L
   * Platelet count \< 100 x 10\^9/L
5. Current use of therapeutic agents for sickle cell disease (e.g., hydroxyurea, arginine, decitabine, magnesium, chronic transfusions). Subjects must be off therapeutic agents for sickle cell disease for at least 3 months prior to enrollment.
6. Current participation in other therapeutic clinical trials
7. Serum creatinine more than twice the upper limit for age OR ≥ 1.0 mg/dL
8. Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised
9. Pregnancy (for post-menarchal females only)
10. Erythrocyte transfusion within the past 2 months
11. Previous stem cell transplant or other myelosuppressive therapy
C: 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
D: Inclusion Criteria:

* Male and female subjects with a confirmed diagnosis of sickle cell disease (HbSS or HBS-β0 thalassemia) between the ages of 18 and 65 years, inclusive
* Subjects who are being treated with hydroxyurea must be on a stable dose for at least 8 weeks, with the intent of remaining on the same dose of hydroxyurea throughout the clinical trial including the protocol-specified follow-up period. Subjects who are not treated with hydroxyurea should not plan to begin treatment during the study period.
* Body Mass Index (BMI) of 17.5 to 35 kg/m2; and a total body weight \>40 kg (88 lbs

Exclusion Criteria:

* History of a recent major surgery, within 3 months of baseline visit.
* Serious infection (requiring hospitalization or parenteral antibiotics) within 1 month of baseline visit.
* History of cerebrovascular accident or seizure disorder.
* Subjects with a history of clinically significant orthostatic blood pressure (BP) changes or clinically significant orthostatic symptoms.
* Known previous diagnosis of acute hepatitis of any aetiology Hepatitis B or C or Human immunodeficiency virus (HIV) infection.
* History of any malignancy except for subjects who had a basal or squamous cell cancer which has been treated and fully resolved for a minimum of 5 years.
* History or evidence of cardiac disease including: myocardial infarction, cardiac arrhythmia
* Systemic therapy with any of the following medications that are strong or moderate CYP3A4 inhibitors within 7 days or 5 half-lives (whichever is longer) or CYP3A inducers within 28 days prior to the first dose of the trial medication, or during the trial.
* Use of PDE5 inhibitors within 7 days prior to the first dose of the trial medication, or at any time during the trial.
* Creatinine clearance \<30ml/min.
* Hemoglobin level \<6 gm/dL.
* Alanine transaminase (ALT/SGPT) and Aspartate aminotransferase (AST/SGOT) \>2x upper limit of normal, (based on clinic laboratory normal range).
* Any condition possibly affecting drug absorption (eg, gastrectomy).
* A positive urine drug screen for illicit drug.
* History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
* Treatment with an investigational drug within 2 months (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication.
* 12-lead ECG demonstrating QTc \>450 or a QRS interval \>120 msec msec at Screening.
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
* A family history of long QT syndrome and/or ECG abnormalities at screening or randomization, including those listed below:

  * Subjects with pre-randomization evidence of QTcF prolongation (defined as \>450 ms) at screening or baseline are not eligible for randomization.
  * Predominant heart rhythm other than normal sinus rhythm eg, atrial fibrillation, atrial flutter, supraventricular tachycardia.
  * Atrioventricular (AV) block greater than first degree.
* Use of concomitant medications that prolong the QT/QTc interval
* Pregnant females and, breast feeding females and females of childbearing potential; male and female subjects of childbearing potential who are unwilling or unable to use highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 30 days after the last dose of investigational product.
* Subjects who lack the capacity to consent for themselves.

Answer: B