TCD With Transfusions Changing to Hydroxyurea
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The standard treatment used to help prevent stroke in children with sickle cell anemia and abnormal Transcranial Doppler (TCD) is monthly blood transfusions. A TCD exam measures how fast blood flows through blood vessels in the brain. Children with sickle cell disease and fast blood flow rates (or “increased velocities”) have a higher risk of stroke than children with normal velocities. An abnormal TCD is one that shows increased velocities.

Transfusions work well to lower the velocities and lower the risk of stroke, but have serious side effects including iron overload, and the risks of developing antibodies or getting an infection. Iron overload is a dangerous problem unless another treatment is given to remove the iron. This treatment is called “chelation.” Either Desferal® or Exjade® can be used to remove iron. Although effective, Desferal is given by a slow injection under the skin and is difficult to tolerate. Many patients cannot take it every day. Exjade is a newer chelation treatment that you take by mouth. Studies show that it removes iron as well as Desferal. Exjade may cause some changes in kidney and liver function that go away when it is stopped. Monthly blood tests are needed to look for these side‐effects.

Hydroxyurea is a medicine that has been shown to help children and adults with sickle cell anemia. Hydroxyurea can decrease the number of painful events, acute chest syndrome (pneumonia) episodes, blood transfusions and admissions to the hospital. Patients take it once a day either as a capsule or liquid. Hydroxyurea must be prescribed by a doctor. The U.S. Food & Drug Administration (FDA) has approved hydroxyurea for adults with severe sickle cell anemia. Results of the TWiTCH study will help the FDA decide if hydroxyurea should be approved for children, too.

Previous studies suggest hydroxyurea can lower TCD velocities but it is not known if hydroxyurea will be as good as blood transfusions to prevent stroke. If blood transfusions can be discontinued AND your child has iron overload, a monthly procedure to remove blood, called phlebotomy, can be used to remove excess iron, avoiding the need for chelation therapy. Phlebotomy is a safe and effective way of treating iron overload.

How does Hydroxyurea Work?

Red blood cells contain hemoglobin, which carries oxygen. In sickle cell patients, abnormal hemoglobin causes the red blood cells to become long, rigid and sticky. Sickling causes blockage of blood flow to vital organs, muscles and tissues. With hydroxyurea the cells have more fetal (baby) hemoglobin, become larger and less sticky, and travel easier through the blood vessels.

Is Changing Treatment Safe?

A special group of experts at the National Institutes of Health will monitor the safety of the TWiTCH Study. An important part of the study will check for the safety of hydroxyurea therapy in children with sickle cell anemia and abnormal TCD.

How will Hydroxyurea be Studied in Children with Abnormal TCD?

TWiTCH will enroll a total of about 148 children aged 4 to 15 years old with sickle cell anemia and abnormal TCD from about 26 major sickle cell programs in the United States and Canada. Children and families must agree to a random assignment (like flipping a coin) into one of two groups. One group will continue “standard” treatment with monthly blood transfusions and, if iron overloaded, daily chelation therapy; the other group will be given “alternative” treatment with hydroxyurea and, if needed, phlebotomy blood draw. At first, the hydroxyurea group will receive blood transfusions too, but eventually blood transfusions will be stopped. At that point, hydroxyurea will be given alone and will be the only treatment to lower TCD velocities and prevent stroke. After transfusions are stopped, monthly phlebotomy will be used if necessary to remove excess iron. Both groups will be treated for 24 months. They will have monthly testing of blood, have physical exams, and TCD exams every 3 months. If a TCD exam shows increased velocities, more frequent TCD exams will be done. An MRI of the liver will be used at baseline to determine how much iron is in the body. This test will be repeated at the end of the study. Some special tests will be done at the beginning, in the middle, and at the end of the study. The object is to compare the two groups to see if one treatment works just as well as the other to lower TCD velocities and help prevent stroke.

Are there Side Effects with Hydroxyurea?

The most common side‐effect of hydroxyurea is decreasing the number of blood cells, including the kind that fights infections. This problem goes away after hydroxyurea is stopped for a week or two. Monthly blood counts are required to look for this side effect. The long‐term effects of hydroxyurea are not known.

Coordinating Center for Clinical Trials
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