Silent Cerebral Infarct Transfusion Multi-Center Clinical Trial

Silent cerebral infarct (stroke) is the most common cause of severe cognitive impairments
and related neurological functions in children with sickle cell anemia. Currently there
exists no systemic strategy to identify or treat children with silent strokes.

The primary aim of this trial is to determine the effectiveness of blood transfusion therapy
for the prevention of silent strokes in children with sickle cell anemia. This trial will
also determine if blood transfusion therapy will prevent further cerebral injury and if the
measured benefits of the therapy outweigh the risks associated with it.

Participants in this multi-center trial will be randomly assigned to one of 2 groups-the
blood transfusion group or the observation group. Those in the blood transfusion group will
receive at least monthly blood transfusion therapy. All participants will have history and
physical examinations every 3 months, and magnetic resonance imaging (MRI) at the beginning
of their entry into the study and at study exit.

Advances in the understanding and treatment of silent strokes will likely lead to a decrease
in the burden associated with cerebral injury in children with sickle cell anemia and change
the standard care for these children.

Statistical Analyses: The original statistical analysis plan suggested a simple difference
in proportions between the proportion of individuals with an endpoint in the transfusion
group and the proportion of individuals with an endpoint in the usual care group using a
traditional chi squared test. The data should be analyzed according to an intent to treat
principal. Because of various logistical concerns in SIT, some individuals were not imaged
within the 36-month window (30-42 months). We propose using all available information by
changing the primary analysis from a dichotomous (yes/no) endpoint to a traditional
epidemiological endpoint of an incidence rate in the group randomized to transfusion to the
incidence rate in the group randomized to usual care. We will compute the incidence ratio:

(a/ta)/(b/tb)

Where "a" is the number of endpoints in the transfusion group, "ta" is the sum of the
individual times at risk of the individuals randomized to the transfusion group, "b" is the
number of endpoints in the observation group and "tb" is the sum of the individual times at
risk of the individuals randomized to the observation group.

Since the standard statistical test for it being different than 1.0 involves the assumption
of a Poisson distribution, we will compute an "exact" 95% confidence interval using a
bootstrap with a large number of replications.

INCLUSION:

- Patient must have sickle cell anemia (hemoglobin SS) or sickle beta thalassemia
(hemoglobin SB) as confirmed at the local institution.

- Participating institutions must submit documentation of the diagnostic hemoglobin
analysis to the Statistical and Clinical Coordinating Centers to confirm the
diagnosis of sickle cell anemia prior to randomization.

- Patient must be 5 through 14 years of age.

- Patient must have a cerebral infarct documented by MRI scan as read by the
neuroradiology panel.

- Informed consent with assent in accordance with the institutional policies
(institutional Institutional Review Board approval) and Federal guidelines (approved
by the United States Department of Health and Human Services) must be signed by the
patient's legally authorized guardian acknowledging written consent to join the
study. When suitable, patients will be requested to give their assent to join the
study.

EXCLUSION:

- Patient with a history of a focal neurologic event lasting more than 24 hours with
medical documentation or a history of prior overt stroke.

- Patients with a transcranial doppler (TCD) study with a time-averaged mean velocity
greater than 200 cm/sec verified by the study radiologist.

- Patients with other neurological problems, such as neurofibromatosis, lead poisoning,
or tuberous sclerosis.

- Patients with HIV infection.

- Pregnancy.

- Patients who received treatment with anti-sickling drugs or hydroxyurea within 3
months or anticipate receiving anti-sickling drugs or hydroxyurea during the course
of the study.

- Abnormal kidney function (creatinine > 2x upper limit of normal).

- Patients on chronic blood transfusion therapy for other reasons.

- Patients judged not likely to be compliant by his/her hematologist and local nurse
coordinator based on previous compliance in clinic appointments and following advice.
Specifically, families that have missed at least two appointments without
notification within 12 months prior to the trial or parents of potential patients
that have been reported for medical or education neglect are not eligible for this
trial.

- Patients unable to receive blood transfusion because of alloimmunization.

- Patients with permanent or semi-permanent metallic (braces on teeth) structures
attached to their body. Such patients cannot obtain a MRI of the head to assess the
presence of silent cerebral infarcts.

- Siblings randomized in the trial.