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

Study Overview
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Brief Summary
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The purpose of this study is to determine whether left ventricular function improves more rapidly with deferoxamine (DFO) and deferiprone (L1) combination therapy than with DFO monotherapy in patients with thalassemia and decreased ejection fractions. Secondary aims include evaluating changes in myocardial iron burden using T2* and estimating the relative incidence and severity of chelator-induced toxicity.

Detailed Description
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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.

Official Title
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Thalassemia Clinical Research Network - Cardiac L1/DFO Trial

Conditions
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Cardiovascular Diseases, Heart Diseases, Beta-Thalassemia

Intervention / Treatment
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* Drug: Deferoxamine
* Drug: Deferiprone (L1)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L1/DFO<br>Deferoxamine (DFO) and deferiprone (L1) combination therapy | Drug: Deferoxamine<br>* Deferoxamine will be given daily for 12-24h/day 7 days a week either subcutaneous or intravenous at up to 50-60 mg/kg/day.<br>* Other names: DFO;Drug: Deferiprone (L1)<br>* The dose of L1, 75mg/kg in three divided oral doses, is the maximum dose at which toxicity has been tested in prospective trials<br>* Other names: L1;|
| Active Comparator: DFO<br>Deferoxamine (DFO) monotherapy | Drug: Deferoxamine<br>* Deferoxamine will be given daily for 12-24h/day 7 days a week either subcutaneous or intravenous at up to 50-60 mg/kg/day.<br>* Other names: DFO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricular Ejection Fraction (LVEF). | The primary outcome variable is change in left ventricular ejection fraction (blood ejected from the heart into the body) as measured by MRI from baseline to one year. The unit of primary outcome (left ventricular ejection fraction) is the percent of the blood in left ventricle. | Baseline to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*. |  | one year | 
| Change in Left Ventricular (LV) Volume From Screening to One Year. |  | one year | 
| Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year. |  | one year | 
| Change in Holter Monitor Scores From Baseline to One Year. |  | one year | 
| Initiation of or Increase in Cardiac Medications |  | continuous | 
| Adverse Events |  | continous |