Clinical Importance of Treating Iron Overload in Sickle Cell Disease

Patients with sickle cell anemia often require blood transfusion as part of the treatment
for their disease. Since each teaspoon of packed red blood cells contains about 5 mg of iron
and humans have no way to get rid of excess iron, the levels of iron in sickle cell patients
increase rapidly with each transfusion. Too much iron is extremely dangerous and causes
damage to blood vessels, red blood cells, liver, hormone producing glands and heart. It is
very difficult to know what damage due to iron overload in sickle cell patients because the
sickle cell disease itself causes organ damage to the same organs affected by iron.

The purpose of this project is to demonstrate that iron overload significantly increases the
morbidity of sickle cell disease and that treatment of the iron overload with Exjade®
prevents or attenuates iron-related morbidity. To accomplish this we will screen sickle cell
patients with a history of many blood transfusions to see if they have high iron levels.
Then we will treat the patients who have very high iron levels with a drug which will remove
the iron. Only patients with a very high iron level will be eligible for the treatment.
These patients will have been transfused many times before but cannot currently be on blood
transfusions. Before we start the treatment we will test the level of anemia, how fast the
red cells are being destroyed, how well their blood vessels work and how well their heart
works. When the treatment is over, we will repeat these tests and see if there is an
improvement.

To qualify for this study, you must carry the diagnosis of sickle cell anemia and you must
have received 10 or more blood transfusions in your life. You also cannot currently be on a
regular transfusion program where you are getting blood transfusions regularly planned more
than three times a year.

Inclusion Criteria:

- Male or female patients with sickle cell anemia (SS or SB thalassemia) with
transfusional iron overload.

- Currently not on chronic or frequent transfusion

- Age equal or greater then 14 years

- Patients with iron overload from repeated blood transfusion, as defined by one of the
following:

1. For patients greater then 16 years old receiving simple transfusions: estimated
lifetime history of receipt of at least 100 ml/kg or 15 adult units of packed
red blood cells, OR

2. For patients equal to or less then 16 years old receiving simple transfusions:
estimated lifetime history of receipt of at least 100 ml/kg of packed red blood
cells, OR

3. For any patient: liver iron content equal/greater then 3 mg Fe/g dw as measured
by biopsy or magnetic resonance imaging who have not been adequately chelated
since that measurement, OR

4. a serum ferritin equal/greater then 1000 ng/mL on at least two occasions, at
least two weeks apart, during the prior year. Samples must be obtained in the
absence of concomitant infection

- Life expectancy equal/greater then 12 months

- Sexually active women must use an effective method of contraception, or must have
undergone clinically documented total hysterectomy and/or oophorectomy, or tubal
ligation or be postmenopausal (defined as amenorrhea for at least 12 months)

Inclusion criteria for treatment pilot study

- Meets all inclusion criteria for screening

- LIC by MRI greater than or equal to 8 mg/g.

Exclusion Criteria:

- Blood transfusion within 12 weeks of the day 0 hemolysis labs

- Currently requires blood transfusion more than three times a year.

- Contraindication to MRI, including cardiac pacemaker, brain aneurysm clip, implanted
neurostimulator, insulin pump, cochlear implant, metal slivers in the eyes,
intrauterine device or any other MRI incompatible metal implants or intractable
claustrophobia.

- Serum creatinine above the upper limit of normal

- Concomitant treatment with erythropoietin or its analogs.

- AST or ALT greater then 250 U/L during screening (patients may be re-screened at a
later date if the cause of the elevation is known to be due to a transient process).

- Patients receiving currently on chelation will be asked to stop for one week before
starting or restarting Exjade. (a equal/greater then 1 week washout period prior to
first dose of study drug is required)

- History of HIV positive test result (ELISA or Western blot)

- History of drug or alcohol abuse within the 12 months prior to enrollment

- Patients with uncontrolled systemic hypertension

- Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable
cardiac or coronary artery disease not controlled by standard medical therapy

- Patients with a diagnosis of or history of clinically relevant ocular toxicity
related to iron chelation

- Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study
treatment

- Pregnancy (as documented in required screening laboratory test) or breast feeding

- Patients who received treatment with systemic investigational drug within the past 4
weeks or topical investigational drug within the past 7 days or are planning to
receive other investigational drugs while participating in the study

- Other surgical or medical condition which might significantly alter the absorption,
distribution, metabolism or excretion of study drug

- History of non-compliance to medical regimens or patients who are considered
potentially unreliable and/or not cooperative