Clinical Importance of Treating Iron Overload in Sickle Cell Disease

Inclusion Criteria:

• Male or female patients with sickle cell anemia (SS or SB thalassemia) withtransfusional 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 thefollowing:

1. For patients greater then 16 years old receiving simple transfusions: estimatedlifetime history of receipt of at least 100 ml/kg or 15 adult units of packed redblood 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 bloodcells, OR

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

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

• Life expectancy equal/greater then 12 months

• Sexually active women must use an effective method of contraception, or must haveundergone clinically documented total hysterectomy and/or oophorectomy, or tuballigation 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, implantedneurostimulator, insulin pump, cochlear implant, metal slivers in the eyes,intrauterine device or any other MRI incompatible metal implants or intractableclaustrophobia.

• 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 alater 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 beforestarting or restarting Exjade. (a equal/greater then 1 week washout period prior tofirst 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 unstablecardiac or coronary artery disease not controlled by standard medical therapy

• Patients with a diagnosis of or history of clinically relevant ocular toxicity relatedto iron chelation

• Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent studytreatment

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

• Patients who received treatment with systemic investigational drug within the past 4weeks or topical investigational drug within the past 7 days or are planning toreceive 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 consideredpotentially unreliable and/or not cooperative