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 participants with severe forms of sickle cell anemia (HbSS or HbSβ° thalassemia)
* Age: between 3.0 and 15.0 years at the time of enrollment
* Parent or guardian willing and able to provide informed consent
* Ability to comply with study related treatments, evaluations, and follow-up

There are no exclusion criteria applicable to the TCD screening portion of SACRED.

For participants with conditional TCD velocities, the following criteria will disqualify them from the treatment phase of SACRED:

Exclusion Criteria:

* Known medical condition making participation ill-advised (e.g., acute or chronic infectious disease including HIV, known allergy to hydroxyurea therapy, or malignancy)
* Abnormal historical laboratory values (most recent pre-enrollment values):

  1. Anemia: Hemoglobin concentration \< 6.0 gm/dL
  2. Reticulocytopenia: Absolute reticulocyte count \< 100 x 10˄9/L with a hemoglobin concentration \< 8.0 gm/dL
  3. Neutropenia: Absolute neutrophil count (ANC) \< 1.0 x 10˄9/L
  4. Thrombocytopenia: Platelet count \< 80 x10˄9 /L
  5. Known abnormal renal function (serum creatinine \>2X upper limit for age AND ≥ 1.0 mg/dL)
* Pregnancy (for post-menarchal females only)
B: Inclusion Criteria:

* Sickle cell anemia patients (SS/Sb0)
* \< 15 years old
* History of abnormal transcranial doppler (TCD) (≥ 200 cm/sec)
* Siblings from the same parental couple
* Parents amenable to Human Leucocyte Antigen (HLA) typing, SCT if an HLA-identical sibling is available or to long-term transfusion program

Exclusion Criteria:

* Sickle cell patients older than 15 years
* no history of abnormal transcranial doppler (TCD) (≥ 200 cm/sec)
* no sibling from the same parental couple
* parents averse to HLA typing, SCT if an HLA-identical sibling is available or to long-term transfusion program
C: Inclusion Criteria:

1. Pediatric participants with a severe form of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSD, HbSOArab)
2. Age: ≥ 2 and ≤ 17 years of age, at the time of enrollment
3. Time-averaged maximum velocity (TAMV) TCD Velocity in the conditional (170 - 199 cm/sec) or abnormal (≥200 cm/sec) range by Transcranial Doppler ultrasonography examination within 6 months of enrollment, abnormal or conditional TCD velocity and currently on commercial hydroxyurea for primary stroke prevention, or previously enrolled in SCATE, a previous stroke with abnormal or conditional TCD prior to stroke event.
4. Parent or guardian willing and able to provide informed consent and child gives assent
5. Ability to comply with study related treatments, evaluations, and follow- up visits

Exclusion Criteria:

1. Inability to take or tolerate daily oral hydroxyurea, including

   * Known allergy to hydroxyurea therapy
   * Known positive serology to HIV infection
   * Known malignancy
   * Current lactation
2. Abnormal historical laboratory values (most recent pre-enrollment values unless previously enrolled in SCATE):

   * Hemoglobin concentration \< 6.0 gm/dL
   * Absolute reticulocyte count \< 100 x 109/L with a hemoglobin concentration \< 8.0 gm/dL
   * White Blood Cell (WBC) count \< 3.0 x 109/L
   * Absolute neutrophil count (ANC) \< 1.0 x 109/L
   * Platelet count \< 100 x 109/L
3. Use of therapeutic agents for sickle cell disease (e.g., hydroxyurea, arginine, decitabine, magnesium, chronic transfusions) within 3 months of enrollment unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or were previously enrolled in the SCATE study or for secondary stroke prevention in a child with a previous stroke.
4. Current participation in other therapeutic clinical trials, except SCATE
5. Known serum creatinine more than twice the upper limit for age AND

   * 1.0 mg/dL
6. Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised
7. Pregnancy (for post-menarchal females only)
8. Erythrocyte transfusion within the past 2 months
9. Previous stem cell transplant or other myelosuppressive therapy (unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or for secondary stroke prevention in a child with a previous stroke or were previously enrolled in SCATE)
D: 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).

Answer: D