Combination Therapy Compared With Single-Drug Therapy in Patients With Cardiac Diseases

DESIGN NARRATIVE:

Participants will be randomized to 1 year of treatment with L1/DFO combination therapy or DFO
monotherapy. At baseline, 6 months, and 1 year on therapy, cardiac function will be assessed
by MRI measurement of left ventricular ejection fraction (LVEF), T2*, Holter monitoring, and
electrocardiography. Additional monitoring for safety includes weekly blood testing, monthly
visits, and periodic eye and ear exams.

Inclusion Criteria:

- Transfusion-dependent beta-thalassemia (eight or more transfusion episodes in the
previous year)

- Left ventricular ejection fraction by MRI less than or equal to 56% by balanced
steady-state free precession (SSFP) or 63% by spoiled gradient recalled echo (SPGR)

- Currently on treatment with subcutaneous or intravenous DFO; participants must be
willing and able to chelate 7 days per week 12 - 24 hours per day

- Serum ferritin greater than 1000 µg/L or ferritin between 500 µg/L and 1000 µg/L and
cardiac T2* less than 20 ms

Exclusion Criteria:

- Pacemaker, severe claustrophobia, or other contraindications to MRI; severe congestive
heart failure (New York Heart Association Classification IV); congenital or acquired
valvular heart disease significant enough to require surgery or medications

- Currently receiving treatment for hepatitis; renal insufficiency defined by a
clinically significant abnormal serum creatinine with a calculated creatinine
clearance of less than 50 ml/min according to the Cockroft formula

- A neutrophil count less than 1.5 x 109/L on two or more occasions at least 4 weeks
apart within the past year and not associated with an acute viral illness or a
platelet count less than 80 x 109/L on two or more occasions at least 4 weeks apart
within the past year

- Treatment with L1 or Exjade during the previous 2 weeks or previous adverse experience
to L1 requiring suspension

- Infection with HIV

- Active participation in other investigational drug or device studies

- Unwilling to consider treatment with DFO at a dose of 50-60 mg/kg 12-24 hours per day
7 days per week

- Women who are pregnant or breast feeding

- Systemic infection or cardiovascular, hepatic, renal, pulmonary, or gastrointestinal
disease that would prevent patients from undergoing any of the study-required
treatments or procedures or requires treatment with any contraindicated medication(s)

- Presence of any other condition that, in the opinion of the investigator, would make
the patient unsuitable for enrollment or could interfere with the patient's compliance
with the protocol; may include but is not limited to alcohol or drug abuse

- For women of child-bearing potential, an inability or unwillingness to use a highly
effective method of contraception (e.g., implants, injectables, combined oral
contraceptives, or some intrauterine devices)