Evaluating Use of Deferasirox as Compared to Deferoxamine in Treating Cardiac Iron Overload

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Randomized, Open-label Phase II Trial Evaluating Deferasirox Compared With Deferoxamine in Patients With Cardiac Iron Overload Due to Chronic Blood Transfusions

Conditions
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Transfusional Iron Overload, Transfusional Hemosiderosis

Intervention / Treatment
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* Drug: Core Study: Deferasirox
* Drug: Core Study: Deferoxamine
* Drug: Extension: deferoxamine to deferasirox
* Drug: Extension: deferasirox to deferoxamine
* Drug: Deferasirox
* Drug: Deferoxamine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients, aged 10 years and above, with β-thalassemia major or DBA or sideroblastic anemia on chronic transfusion therapy, having given written consent to participate in the study. Patients with cardiac iron as measured by a myocardial T2* value that is ≥ 6ms but not ≥ 20 ms. Patients with a lifetime history of at least 50 units of red cell transfusions, and must be receiving at least ≥10 units/yr of red blood cells transfusions. Patients with a left ventricular ejection fraction (LVEF) ≥ 56 % as determined by cardiovascular magnetic resonance (CMR). Patients with liver iron content (LIC) value ≥ 3 mg Fe / g dw, as determined by liver MRI. Exclusion criteria: Patients with clinical symptoms of cardiac dysfunction. Patients unable to undergo study assessments including MRI Patients participating in another clinical trial or receiving an investigational drug. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox<br>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 | Drug: Core Study: Deferasirox<br>* 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<br>* Other names: ICL to ICL;Drug: Deferasirox<br> <br> |
| Active Comparator: Deferasirox Placebo<br>50 mg/kg/day to 60 mg/kg/day infused subcutaneously in 8- to 12-hour intervals administered 5 to 7 days/week | Drug: Core Study: Deferoxamine<br>* 50 mg/kg/day to 60 mg/kg/day infused subcutaneously in 8- to 12-hour intervals administered 5 to 7 days/week<br>* Other names: DFO to DFO;Drug: Deferoxamine<br> <br> |
| Experimental: Extension: deferoxamine to deferasirox<br>DFO to ICL (patients who switched from DFO to deferasirox in extension) | Drug: Extension: deferoxamine to deferasirox<br>* 40 mg/kg deferasirox once daily administered 30 minutes before taking food.<br>* Other names: DFO to ICL;|
| Experimental: Extension: deferasirox to deferoxamine<br>ICL to DFO (patients who switched from deferasirox to DFO in extension) | Drug: Extension: deferasirox to deferoxamine<br>* 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,<br>* Other names: ICL to DFO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 12 Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 6 Month | 
| Core Study: Change From Baseline in Myocardial T2* After 6 Months Treatment | Summary statistics of T2* ratio Month 6/baseline | 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) | 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 | 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 | 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. | 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 | 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) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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) | 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. | 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. | 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) | 12 Month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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iron overload, cardiac iron, haemosiderosis, myocardial T2*, left ventricular ejection fraction, LVEF, cardiac dysfunction, thalassaemia, Diamond Blackfan anemia, DBA, sideroblastic anemia, myelodysplastic syndromes, MDS (low and INT-1 risk as per the IPSS for MDS), liver MRI, deferasirox, deferoxamine, ICL670, DFO, cardiovascular magnetic resonance imaging