TWiTCH - TCD With Transfusions Changing to Hydroxyurea: A Phase III randomized clinical 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 (Version 1.0)
TWiTCH is a Phase iii randomized clinical trial comparing alternative therapy (alternative arm x hydroxyurea and phlebotomy) to standard therapy (Standard arm x erythrocyte transustions and iron chelation) to reduce the risk of primary stroke in pediatric subjects with sickle cell anemia, who currently receive chronic transfusions for abnormal TCD velocities.
Standard treatment arm:
1) erythrocyte transfusions to reduce the risk of primary stroke: Half of the subjects are
randomized to monthly (4 (+-) 1 weeks) transfusions, given to raise the
hemoglobin concentration and suppress the subject's production of sickled cells.
The target %HbS will be 30% as per usual practice, but should not exceed the upper limit (45%) currently used by the
academic community for primary stroke prevention.
2) Chelation therapy to reduce hepatic iron overload: exjade[RegisteredTM] (deferasirox) is an FDa approved
oral iron chelator for use in children and adults with sickle cell anemia and
transfusional iron overload. For TWiTCH subjects who have documented iron overload
at study entry, deferasirox is prescribed at 10-40 mg/kg/day and administered orally once a day. For
subjects who do not tolerate deferasirox or do not wish to take this therapeutic agent,
Desferal[RegisteredTM] (deferoxamine mesylate) can be utilized for iron chelation. Subjects
receiving chelation therapy will have standard toxicity monitoring including periodic
blood testing and visual/auditory examinations.
alternative treatment arm:
1) Hydroxyurea therapy to reduce the risk of primary stroke: Half of the subjects will
be randomized to hydroxyurea, available as capsules, or liquid formulation (100 mg/mL). Hydroxyurea will be administered once daily by mouth. Subjects will be monitored monthly (every 4 (+-) 1 weeks) to obtain weight
measurements, history and physical examination, and local complete blood counts,
including the white blood cell (WBC) differential and reticulocytes. Hydroxyurea will be titrated according to myelosuppression, and will be increased to the maximum tolerated dose (MTD) as defined by hematological toxicity and laboratory response, even if the subject has clinical well-being at a lower hydroxyurea dose. The
target absolute neutrophil count (anC) on hydroxyurea therapy will be 2.0-4.0 x 109/L. Hydroxyurea dosing will commence at 20 mg/kg/day. Dose escalation will occur in 5 mg/kg/day increments, adjusting every 8 weeks unless hematological toxicity occurs or the target neutropenia (anC 2.0-4.0 x 109/L) is achieved. Based on pilot data and experience in the Phase iii Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, most pediatric subjects require hydroxyurea doses of 20-30 mg/kg/day to reach this target anC. Hydroxyurea will be reduced or even temporarily discontinued for hematological toxicities, e.g., anC [Less Than] 1.0x 109/L or platelets [Less Than] 80 x 109/L.
2) overlap of hydroxyurea therapy with transfusions: During the hydroxyurea dose
escalation to MTD, transfusions will continue to reduce the risk of primary stroke. Transfusions will overlap with hydroxyurea therapy for approximately 6-9 months, and will be discontinued only when MTD is reached and endogenous fetal hemoglobin (HbF) production is sufficient to help reduce the risk of primary stroke.
3) Phlebotomy to reduce hepatic iron overload: For TWiTCH subjects who have documented iron overload at study entry or develop iron overload during the study treatment phase, a monthly phlebotomy regimen will commence
after the transfusion overlap is completed, to remove peripheral venous blood and reduce the total body iron burden. Venous blood (5-10 mL/kg, maximum 500 mL) will be removed every 4 (+-) 1 weeks as tolerated, with immediate replacement of the removed blood volume with at least an equal volume of normal saline.
Subjects who meet all of the following criteria are eligible for enrollment into the study:
1) Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbS[BETA]0 thalassemia,
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 TCD is defined as TCD V>=200 cm/sec, or abnormally
high TCDi V >= 185cm/sec, or TCD maximum V >= 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 <= 45% (the upper limit
of the established academic community standard) for the past 6 months before
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