This is a clinical research study in patients who have iron overload in the heart due to chronic blood transfusions. The study will have 2 treatment groups and will compare the safety and efficacy of chelation therapy with a medicine called deferasirox (ICL670) with another medicine called deferoxamine (DFO). The study is aimed at finding out which of the two medicines is the best for treating iron overload in the heart. Patients will be treated for 12 months (core study phase). Patients who complete the core study phase will be offered to continue their study treatment in a 12 months extension phase. During the core and extension, the effects of treatment on iron overload in the heart and the liver will be evaluated using specific magnetic resonance imaging (MRI) assessments.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
197
20 mg/kg/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day
50 mg/kg/day to 60 mg/kg/day infused subcutaneously in 8- to 12-hour intervals administered 5 to 7 days/week
40 mg/kg deferasirox once daily administered 30 minutes before taking food.
DFO at a target range of 50 mg/kg/day to 60 mg/kg/day via subcutaneous (sc) infusion lasting a period of 8 to 12 hrs administered for 5 to 7 days per week,
Novartis Investigative Site
Toronto, Ontario, Canada
Novartis Investigative Site
Nanning, Guangxi, China
Novartis Investigative Site
Limassol, Cyprus
Novartis Investigative Site
Al Mansurah, Egypt
Novartis Investigative Site
Cairo, Egypt
Novartis Investigative Site
Cagliari, CA, Italy
Novartis Investigative Site
Genova, GE, Italy
Novartis Investigative Site
Hazmiyeh, Lebanon
Novartis Investigative Site
Taipei, Taiwan, Taiwan
Novartis Investigative Site
Bangkok, Thailand
...and 11 more locations
Core Study: Change From Baseline in Myocardial T2* (Magnetic Resonance T2-star (T2*) Technique for the Measurement of Tissue Iron) After 12 Months Treatment
Non- inferiority in efficacy of deferasirox compared to deferoxamine (DFO) in treating cardiac iron overload as measured by T2\*. A non-inferiority margin of 0.9 (90%) was applied. Due to limitations in performing heart biopsies, T2\* (T2 star), a Magnetic Resonance (MR) relaxation parameter expressed in milliseconds, as is an important tool to noninvasively quantify cardiac iron concentration. Studies have shown that myocardial T2\* evaluations may predict cardiac events, e.g., impaired (\<56%) left ventricular ejection fraction (LVEF) is prevalent among patients with low T2\*: found in 62% of patients with T2\*\<8 ms; 20% with T2\* of 8-12 ms; and in 5% with T2\* \>12 ms (Tanner 2006)
Time frame: 12 Month
Core Study: Cardiac Function After 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF)
An absolute change from baseline in LVEF after 12 months treatment with deferasirox and compared to.DFO was tested using an analysis of covariance model including baseline left ventricular ejection fraction (LVEF) as a covariate.
Time frame: 12 Month
Core Study: Cardiac Function After 6 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF)
An absolute change from baseline in LVEF after 6 months treatment with deferasirox and DFO was summarized
Time frame: 6 Month
Core Study: Change From Baseline in Myocardial T2* After 6 Months Treatment
Summary statistics of T2\* ratio Month 6/baseline
Time frame: 6 Month
Core Study: Cardiac Function After 6 and 12 Months Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular End Systolic Volume Indices (LVESVI)
An absolute change from baseline in LVESVI after 6 and 12 months treatment with deferasirox and DFO was summarized. Changes in cardiovascular magnetic resonance (CMR) measured left ventricular end systolic after 6 and 12 months treatment. Left ventricular (LV) end-systolic volume indexed to body surface area (ESVI) is a simple yet powerful echocardiographic marker of LV remodeling that can be measured easily. Left ventricular (LV) end-systolic volume (ESV) has been shown to be an important determinant of survival after myocardial infarction (MI)
Time frame: 6 Month, 12 Month
Core Study: Core Study: Cardiac Function After 6 and 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular End Diastolic Volume Indices (LVEDVI)
An absolute change from baseline in LVEDVI after 6, and 12 months treatment with deferasirox and DFO was summarized
Time frame: 6 Month, 12 Month
Core Study: Cardiac Function After 6 and 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Mass Indices (LVMI)
An absolute change from baseline in LVMI after 6, and 12 months treatment with deferasirox and DFO was summarized
Time frame: 6 Month, 12 Month
Core Study: Cardiac Function and the Proportion of Patients Dropping Out Due to Cardiac Dysfunction After Treatment With Deferasirox vs. Deferoxamine
The number of patients withdrawn from the study due to LVEF \<50%, T2\* \<6 ms or significant decreases in T2\* ≥ 33% from baseline was provided per treatment group.
Time frame: 12 Month
Core Study: Safety and Tolerability of Deferasirox vs Deferoxamine Over the 12 Months Treatment Period.
Number of patients with adverse events, serious adverse events and death
Time frame: 12 Month
Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Area Under the Plasma Concentration-time Curve for a Dosing Interval (AUCtau)
The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, area under the plasma concentration-time curve for a dosing interval (AUCtau)
Time frame: 12 Month
Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Cmax)
The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, maximum plasma concentration (Cmax)
Time frame: 12 Month
Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Time Points of Concentration Data
The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. For trough concentration assessments, a 2-mL blood sample was to be taken on arrival at the study site, i.e. prior to the patient receiving the daily deferasirox dose (pre-dose blood sample). A second 2-mL blood sample was to be taken 2 hours later (post-dose sample). At all other visits (Visits 3 - 14), a pre-dose sample was to be taken. For PK profile assessments, 3 blood samples were taken after 1, 2, and 4 hours post-dose in addition to the 2-mL pre-dose
Time frame: Month 1 and month 2 (pre-dose, 1,2 and 4 hours post-dose)
Extension Study: Change From Baseline in Myocardial T2* After 24 Months Treatment
The measured T2\* values, the ratio (post-baseline / baseline T2\*) at Month 6, 12, 18 and 24 was summarized for FAS population along with two-sided 95% CIs. The geometric means of the ratio was presented for all treatment groups
Time frame: Months 6, 12, 18 and 24
Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Ejection Fraction (LVEF)
Cardiac function endpoints (LVEF) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline
Time frame: Months 6, 12, 18 and 24
Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Systolic Volume Indices (LVESVI)
Cardiac function endpoints (LVESVI) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline
Time frame: Months 6, 12, 18 and 24
Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Diastolic Volume Indices (LVEDVI)
Cardiac function endpoint (LVEDVI ) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline
Time frame: Months 6, 12, 18 and 24
Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Mass Indices (LVMI)
Cardiac function endpoints (LVMI) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes
Time frame: Months 6, 12, 18 and 24
Extension Study: The Cardiac Iron Concentration From T2* Values
Cardiac iron concentration (derived from T2\* values) at baseline, Months 6, 12, 18 and 24 were summarized by descriptive statistics. The absolute change from baseline at Months 6, 12, 18 and 24 were also summarized by treatment group. Lliver iron concentration is expressed in units (mg of iron / g of liver tissue dry weight (dw)
Time frame: Months 6, 12, 18 and 24
Extension Study: Change in Liver Iron Concentration (LIC) From Baseline at Month 24
Results of liver iron content (LIC) measurements by MRI was summarized by descriptive statistics. The absolute value and the absolute change from baseline in LIC at Months 6, 12, 18 and 24 were provided by treatment group.
Time frame: Months 6, 12, 18 and 24
Extension Study: Change in Serum Ferritin From Baseline by Month
Serum ferritin values was summarized by descriptive statistics. Absolute value and the absolute change from baseline in serum ferritin by month was provided by treatment group.
Time frame: Months 6, 12, 18 and 24
Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Tmax)
The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, time to reach maximum plasma concentration (Tmax)
Time frame: 12 Month
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