Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea

Therapuetic Areas:Hematology
Age Range:4 - 15
Start Date:August 2011
End Date:December 2016
Contact:Russell E. Ware, MD, PhD

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TCD With Transfusions Changing to Hydroxyurea (TWiTCH): 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

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.

Despite the clear results of the STOP and the follow-up STOP II trials, the use of chronic
erythrocyte transfusions for primary stroke prevention in children with Sickle Cell Anemia
(SCA) remains controversial for many practicing hematologists, as well as for patients and
families. Transfusions have proven clinical efficacy in preventing first stroke in children
with SCA and abnormal TCD velocities, but their indefinite use may still be difficult to

The risk of transfusion acquired iron overload is now recognized as a serious consequence of
chronic erythrocyte transfusions in children with SCA. After one to two years of monthly
transfusions, virtually every patient will have excess hepatic iron deposition that warrants
intervention with chelation therapy. The effectiveness of iron chelation has not yet been
realized, despite the availability of the oral chelator deferasirox (Exjade®), due to its
lack of palatability and increasing recognition of serious drug-related toxicities including
renal and hepatic dysfunction. Simply put, indefinite erythrocyte transfusions cannot be
viewed as adequate and acceptable long-term therapy for primary stroke prevention in SCA.
There is an urgent need to develop an equivalent effective alternative therapy for the
prevention of primary stroke in children with SCA, specifically one that better manages iron
overload and improves quality of life.

Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0

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

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).
We found this trial at
1200 Moursund Street
Houston, Texas 77030
(713) 798-4951
Baylor College of Medicine Baylor College of Medicine in Houston, the only private medical school...
Houston, TX
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