Beta-thalassemia, Iron Overload
Conditions
Keywords
Iron Chelation, Deferasirox, Chelator, Desferal, beta-thalassemia, Iron overload
Brief summary
The purpose of this trial is to evaluate changes in cardiac iron as measured by MRI T2\* in beta-thalassemia patients with deferasirox treatment.
Interventions
DRUGDeferasirox
Oral deferasirox 30mg/kg/day once per day for 77 weeks.
Sponsors
Novartis
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female β-thalassemia outpatients on chronic transfusion therapy (defined as \> 8 transfusions per year) * Lifetime minimum of 100 previous packed red blood cell transfusions * Patients currently on chelation therapy will require a one day wash out prior to the first dose of study drug * Age ≥ 10 years * Sexually active females of childbearing potential must have a negative serum or urine pregnancy test and use an effective method of contraception, or must have undergone clinically documented total hysterectomy.
Exclusion criteria
* Ejection Fraction \< 56 % measured using steady-state free precession imaging by MRI * 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 * Abnormal laboratory values as defined by the protocol * Clinical or laboratory evidence of active Hepatitis B or Hepatitis C * History of HIV positive test result (ELISA or Western blot) * Uncontrolled systemic hypertension * Second or third degree A-V block * Life-threatening arrhythmias, including sustained ventricular tachycardia and aborted sudden death, within the last year * History of cardiac conditions or unstable cardiac disease not controlled by standard medical therapy * History of clinically relevant ocular toxicity related to iron chelation * Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study treatment * Pregnancy or breast feeding (documented negative pregnancy test required for study entry) * Patients enrolled in an ongoing clinical trial of deferasirox (ICL670) cannot be withdrawn in order to participate in this study * Treatment with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days * Other surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug * History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative * Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | From Baseline to 25, 49, 77 Week | Cardiac T2\* was measured in the short axis plane at the widest point of a 4-chamber localizer using custom breath-hold R2\* gradient echo sequences modeled after techniques used by Anderson et al (2001) and Westwood et al (2003). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | From Baseline to 25, 49, 77 Week | MRI evaluation of liver iron concentration has been validated by liver biopsy (St Pierre et al 2005). Studies comparing T2\* values of liver iron concentration (LIC) with LIC as assessed by biopsy have confirmed that T2\* values reflect liver iron content (Wood et al 2003b). Direct tissue-validation of cardiac T2\* measurements in humans has not been performed because endomyocardial biopsy is a dangerous and unreliable indicator of cardiac iron overload (Olson et al 1989, Fitchett et al 1980). However, it has been shown that cardiac T2\* accurately reflects cardiac iron in a gerbil iron cardiomyopathy model (Wood et al 2004b). T2\* measurements have shown excellent inter-scanner and inter-exam reproducibility, making them suitable for longitudinal monitoring (Westwood et al 2003a, Westwood et al 2003b). |
| Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | From Baseline to 25, 49, 77 Week | Magnetic resonance imaging (MRI)-measured cardiac T2\* and cardiac function reflected by left and right ventricle ejection fraction. A standardized MRI protocol for T2\* acquisition technique will be used in the centers. Images will be reviewed centrally by an expert MRI reader. |
| Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | From Baseline to 25, 49, 77 Week | Serum ferritin will be assessed at each study visit. Analysis was performed in Completer population consists of those participants who had a Week 77 MRI. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 4 centers in the United States
Pre-assignment details
A total number of participants planned for this study was 30. The total number of 28 participants enrolled in the study, of these 22 completed the study and 6 discontinued the study.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox Participants received Deferasirox 30 mg/kg/day orally OD, 30 minutes before breakfast, preferably around the same time every morning if possible. Deferasirox tablets were dropped into water or orange juice, or apple juice and stirred until completely dispersed. For doses less than 1 g, tablets were dissolved in at least 100 mL of liquid; for doses of 1 to 3 g, tablets were dissolved in at least 200 mL. After tablets were fully disintegrated, the liquid was promptly consumed. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal laboratory value | 1 |
| Overall Study | Abnormal test procedure result | 1 |
| Overall Study | Adverse Event | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Deferasirox |
|---|---|
| Age, Continuous | 22.6 years STANDARD_DEVIATION 8.67 |
| Race/Ethnicity, Customized Black | 0 participants |
| Race/Ethnicity, Customized Caucasian | 9 participants |
| Race/Ethnicity, Customized Oriental | 7 participants |
| Race/Ethnicity, Customized Other | 12 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 8 / 27 |
Outcome results
Primary
Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2*
Cardiac T2\* was measured in the short axis plane at the widest point of a 4-chamber localizer using custom breath-hold R2\* gradient echo sequences modeled after techniques used by Anderson et al (2001) and Westwood et al (2003).
Time frame: From Baseline to 25, 49, 77 Week
Population: The analysis was performed in Completer population (CP) consists of those participants who had a Week 77 MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Baseline | 9.92 milliseconds (msec) | Standard Deviation 3.922 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 25 | 11.73 milliseconds (msec) | Standard Deviation 6.091 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 25 Absolute Change from Baseline | 1.77 milliseconds (msec) | Standard Deviation 3.203 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 49 | 11.93 milliseconds (msec) | Standard Deviation 6.489 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 49 Absolute Change from Baseline | 2.01 milliseconds (msec) | Standard Deviation 3.792 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 77 | 12.10 milliseconds (msec) | Standard Deviation 6.461 |
| Deferasirox | Magnetic Resonance Imaging (MRI) T2* and Absolute Change From Baseline in MRI T2* | Week 77 Absolute Change from Baseline | 2.18 milliseconds (msec) | Standard Deviation 3.927 |
Secondary
Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks
MRI evaluation of liver iron concentration has been validated by liver biopsy (St Pierre et al 2005). Studies comparing T2\* values of liver iron concentration (LIC) with LIC as assessed by biopsy have confirmed that T2\* values reflect liver iron content (Wood et al 2003b). Direct tissue-validation of cardiac T2\* measurements in humans has not been performed because endomyocardial biopsy is a dangerous and unreliable indicator of cardiac iron overload (Olson et al 1989, Fitchett et al 1980). However, it has been shown that cardiac T2\* accurately reflects cardiac iron in a gerbil iron cardiomyopathy model (Wood et al 2004b). T2\* measurements have shown excellent inter-scanner and inter-exam reproducibility, making them suitable for longitudinal monitoring (Westwood et al 2003a, Westwood et al 2003b).
Time frame: From Baseline to 25, 49, 77 Week
Population: The analysis was performed in Completer population consists of those participants who had a Week 77 MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Baseline | 19.85 mg Fe/g dw liver | Standard Deviation 3.309 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 25 | 17.23 mg Fe/g dw liver | Standard Deviation 15.393 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 25 Absolute Change from Baseline | -2.89 mg Fe/g dw liver | Standard Deviation 4.169 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 49 | 17.0 mg Fe/g dw liver | Standard Deviation 17.548 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 49 Absolute Change from Baseline | -2.85 mg Fe/g dw liver | Standard Deviation 4.883 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 77 | 16.62 mg Fe/g dw liver | Standard Deviation 20.114 |
| Deferasirox | Change From Baseline in Liver Iron Concentration (LIC) Was Measured by MRI R2 From Absolute Change From Baseline to 101 Weeks | Week 77 Absolute Change from Baseline | -3.23 mg Fe/g dw liver | Standard Deviation 7.708 |
Secondary
Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks
Magnetic resonance imaging (MRI)-measured cardiac T2\* and cardiac function reflected by left and right ventricle ejection fraction. A standardized MRI protocol for T2\* acquisition technique will be used in the centers. Images will be reviewed centrally by an expert MRI reader.
Time frame: From Baseline to 25, 49, 77 Week
Population: The analysis was performed in Completer population consisting of those participants who had a Week 77 MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Baseline | 64.01 percentage of participants | Standard Deviation 6.751 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 77 | 63.84 percentage of participants | Standard Deviation 6.112 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 77 Absolute change from baseline | 0.11 percentage of participants | Standard Deviation 7.299 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 25 | 62.17 percentage of participants | Standard Deviation 6.352 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 25 Absolute change from baseline | -1.84 percentage of participants | Standard Deviation 7.306 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 49 | 61.61 percentage of participants | Standard Deviation 13.726 |
| Deferasirox | Left Ventricular Ejection Fraction (LVEF) and Change in Left Ventricular Ejection Fraction From Baseline to 101 Weeks | Week 49 Absolute change from baseline | -2.68 percentage of participants | Standard Deviation 14.546 |
Secondary
Serum Ferritin and Changes From Baseline in Serum Ferritin During Study
Serum ferritin will be assessed at each study visit. Analysis was performed in Completer population consists of those participants who had a Week 77 MRI.
Time frame: From Baseline to 25, 49, 77 Week
Population: The analysis was performed in Completer population consists of those participants who had a Week 77 MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Baseline | 4343.75 μg/L | Standard Deviation 3486.525 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 25 | 4280.77 μg/L | Standard Deviation 5261.563 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 25 Absolute change from baseline | -62.98 μg/L | Standard Deviation 2294.635 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 49 | 3759.29 μg/L | Standard Deviation 3966.107 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 49 Absolute change from baseline | -593.36 μg/L | Standard Deviation 1534.04 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 77 | 3179.81 μg/L | Standard Deviation 3439.357 |
| Deferasirox | Serum Ferritin and Changes From Baseline in Serum Ferritin During Study | Week 77 Absolute change from baseline | -882.74 μg/L | Standard Deviation 1368.202 |