Beta-Thalassemia, Cardiovascular Diseases, Heart Diseases
Conditions
Brief summary
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
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.
Interventions
DRUGDeferoxamine
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.
DRUGDeferiprone (L1)
The dose of L1, 75mg/kg in three divided oral doses, is the maximum dose at which toxicity has been tested in prospective trials
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Carelon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left Ventricular Ejection Fraction (LVEF). | Baseline to one year | 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. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*. | one year |
| Initiation of or Increase in Cardiac Medications | continuous |
| Adverse Events | continous |
| Change in Holter Monitor Scores From Baseline to One Year. | one year |
Countries
United States
Participant flow
Recruitment details
First patient enrolled in August, 2005 and study closed due to low enrollment in June, 2008. 8 participating sites.
Pre-assignment details
Patients were evaluated for eligibility based on the following criterial. If not eligible, they were not randomized to a treatment arm.
Participants by arm
| Arm | Count |
|---|---|
| Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy DFO + L1 DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous.
L1 Administered daily at 75 mg/kg in 3 divided doses taken orally and timed so that 2 of 3 doses will be simultaneous with DFO infusion. | 11 |
| Deferoxamine (DFO) + Monotherapy DFO + Placebo DFO Administered daily at 50-60 mg/kg for 12-24 hr/day 7 days a week either subcutaneous or intravenous.
Placebo Administered orally three times daily. | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study closed due to low enrollment. | 11 | 9 |
Baseline characteristics
| Characteristic | Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy | Deferoxamine (DFO) + Monotherapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 8 Participants | 19 Participants |
| Age, Continuous | 26.5 years STANDARD_DEVIATION 5.1 | 25.8 years STANDARD_DEVIATION 7.6 | 26.15 years STANDARD_DEVIATION 6.18 |
| Region of Enrollment Canada | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Lebanon | 2 participants | 2 participants | 4 participants |
| Region of Enrollment United States | 6 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 11 | 6 / 9 |
| serious Total, serious adverse events | 6 / 11 | 3 / 9 |
Outcome results
Primary
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.
Time frame: Baseline to one year
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Deferoxamine (DFO) and Deferiprone (L1) Combination Therapy | Change in Left Ventricular Ejection Fraction (LVEF). | 7.2 Percent of the blood in left ventricle | Standard Error 1.9 |
| Deferoxamine (DFO) + Monotherapy | Change in Left Ventricular Ejection Fraction (LVEF). | 6.3 Percent of the blood in left ventricle | Standard Error 3.3 |
Comparison: The intended sample size of 86 patients (N=43 per arm) had 80% power to detect a 5% difference in LVEF between the two arms after 1 year of treatment, assuming a standard deviation of change in LVEF of 7.46%, and 20% loss to follow-up. The study was stopped early by NHLBI when analysis of the interim data confirmed a required sample size of 86 that was not achievable within the required time frame within the participating or planned centres.p-value: 0.89Mixed Models Analysis
Secondary
Adverse Events
Time frame: continous
Secondary
Change in ECHO LV Volume, Ejection Fraction, Shortening Fraction, and VCFc/Wall Stress Z-score From Baseline to One Year.
Time frame: one year
Secondary
Change in Holter Monitor Scores From Baseline to One Year.
Time frame: one year
Secondary
Change in Left Ventricular (LV) Volume From Screening to One Year.
Time frame: one year
Secondary
Evaluate Whether L1/DFO Combination Therapy is Superior to DFO Monotherapy in Lowering Myocardial Iron Burden Estimated by Myocardial T2*.
Time frame: one year
Secondary
Initiation of or Increase in Cardiac Medications
Time frame: continuous